Abstract
Background
To describe 52-week longitudinal clinical outcomes after escalation of subcutaneous tocilizumab (TCZ-SC) from every 2 weeks (Q2W) to once weekly (Q1W) in rheumatoid arthritis (RA) patients with inadequate clinical control during Q2W dosing, and contextualize findings using a TCZ-SC Q2W continuation cohort.
Methods
This single-center retrospective observational study included 58 patients with RA who escalated from TCZ-SC Q2W to Q1W. The primary outcome was the overall longitudinal change in the Clinical Disease Activity Index (CDAI) through week 52, assessed using a complete-case Friedman test. Linear mixed-effects models using all available observations were fitted as sensitivity analyses. Secondary analyses included the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR), matrix metalloproteinase-3 (MMP-3), laboratory safety and renal outcomes, re-adjudicated difficult-to-treat (D2T) RA status, follow-up disposition, individual-level concomitant treatment intensification, and a Q2W continuation contextual comparison.
Results
The median CDAI decreased from 16.00 at Q1W escalation to 8.20 at week 52 (complete-case Friedman test, n = 42, P < 0.001). In mixed-effects sensitivity analyses, model-estimated week-52 changes were − 5.89 points for CDAI (95% CI, − 8.15 to − 3.63), − 1.29 points for DAS28-ESR (95% CI, − 1.63 to − 0.95), − 45.8% for MMP-3 (95% CI, − 54.9% to − 34.7%), and − 4.79 mL/min/1.73 m2 for estimated glomerular filtration rate (eGFR) (95% CI, − 7.65 to − 1.92). Five patients (8.6%) fulfilled the stricter D2T RA definition. Fifteen patients lacked week-52 CDAI data because of Q1W discontinuation or interruption (n = 13) or transfer of care (n = 2); the incomplete follow-up group had higher baseline disease activity. Seven patients had documented regular systemic treatment intensification during weeks 0–12; after excluding them, the median 12-week ΔCDAI remained − 3.00 (P < 0.001). In the exploratory 12-week comparison, the median ΔCDAI was − 2.85 in the Q1W escalation cohort and − 3.40 in the Q2W residual-activity subgroup, with no significant between-group difference (P = 0.754). No serious infections or treatment discontinuations due to adverse events were documented.
Conclusions
Disease activity decreased after Q1W escalation, with directionally consistent sensitivity analyses. However, the 12-week CDAI changes did not differ significantly between the Q1W escalation cohort and the Q2W residual-activity subgroup. These descriptive findings do not establish an incremental or causal benefit of Q1W escalation.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1186/s41927-026-00696-y.
Keywords: Rheumatoid arthritis, Tocilizumab, Subcutaneous administration, Disease activity, Biological disease-modifying antirheumatic drugs, Real-world evidence, Renal function
Key Points
• In selected patients with RA, CDAI decreased over 52 weeks after escalation from TCZ-SC Q2W to Q1W, with directionally consistent results in mixed-effects sensitivity analyses.
• Individual-level re-adjudication of D2T RA status emphasized the importance of distinguishing dose escalation within the same drug from failure of distinct b/tsDMARD mechanisms.
• An exploratory 12-week comparison showed no significant difference in ΔCDAI between the Q1W escalation cohort and the Q2W residual-activity subgroup; an incremental or causal benefit of Q1W escalation was not established.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1186/s41927-026-00696-y.
Introduction
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by persistent synovitis, progressive joint damage, and functional impairment. Despite substantial therapeutic advances, some patients fail to achieve sustained disease control with conventional synthetic, biological, or targeted synthetic disease-modifying antirheumatic drugs (csDMARDs, bDMARDs, and tsDMARDs) [1–3].
The European Alliance of Associations for Rheumatology introduced the concept of difficult-to-treat (D2T) RA, which includes persistent or problematic signs or symptoms despite treatment failure of at least two b/tsDMARDs with different mechanisms of action, after csDMARD therapy has failed or is contraindicated [4]. In retrospective real-world cohorts, the application of this definition requires careful individual-level review of treatment histories, mechanisms of action, and reasons for treatment failure, because dose escalation within the same drug and therapies introduced after the index date should not be counted as distinct mechanism failures.
Interleukin-6 (IL-6) receptor inhibition is an established treatment option for patients with RA who have an inadequate response to methotrexate (MTX) or other DMARDs [2, 3]. Tocilizumab (TCZ), a humanized monoclonal antibody targeting the IL-6 receptor, has demonstrated efficacy in clinical trials [5–8]. Suppression of inflammation is an important component of preventing long-term structural damage and functional decline [9], and observational studies have described the clinical use and safety of TCZ as monotherapy or combination therapy in routine practice [10, 11].
Subcutaneous TCZ (TCZ-SC) can be administered every 2 weeks (Q2W) or once weekly (Q1W). In clinical practice, escalation from Q2W to Q1W may be considered when disease control remains inadequate during Q2W dosing. The SHINOBI study reported improved clinical responses after escalation from Q2W to Q1W in selected patients with insufficient disease control [12]. However, real-world data describing longitudinal clinical outcomes, laboratory safety parameters, and background treatment stability after TCZ-SC Q1W escalation remain limited. Assessment of residual disease activity during IL-6 receptor blockade requires caution. TCZ suppresses acute-phase reactants such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), which may lead to underestimation of clinical disease activity when composite indices incorporating inflammatory markers, such as Disease Activity Score in 28 joints using ESR (DAS28-ESR), are used [13]. Therefore, the Clinical Disease Activity Index (CDAI), which does not include acute-phase reactants, may provide complementary information when evaluating residual disease activity during TCZ treatment.
Because escalation decisions in routine practice are made by treating rheumatologists rather than by protocol-defined thresholds, observational studies should carefully describe patient selection, data availability, concomitant therapies, and contextual comparison data. Patients who continue TCZ-SC Q2W during the same period may provide useful contextual information regarding natural fluctuations and regression to the mean, although such comparisons cannot establish the causal superiority of Q1W escalation.
Renal and laboratory safety are also important considerations in real-world RA management [14], especially in patients receiving concomitant medications that may affect kidney function, such as tacrolimus (TAC) [15], iguratimod (IGU) [16–18], and non-steroidal anti-inflammatory drugs (NSAIDs) [19]. The interpretation of renal changes may also be influenced by comorbidities such as hypertension and diabetes mellitus, underscoring the importance of describing renal outcomes and relevant background factors in routine clinical practice.
Therefore, this study aimed to describe longitudinal clinical outcomes, inflammatory biomarkers, concomitant therapies, and safety parameters over 52 weeks after escalation from TCZ-SC Q2W to Q1W in patients with RA who had inadequate clinical control during Q2W dosing. We also re-adjudicated D2T RA status using individual-level treatment histories and performed an exploratory contextual analysis using patients who continued TCZ-SC Q2W during the same period.
Methods
Study design and patients
This retrospective observational study was conducted at a single tertiary rheumatology center in Japan between January 2017 and March 2024. Patients were eligible if they met the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA [20] and were escalated from TCZ-SC Q2W to TCZ-SC Q1W because of inadequate clinical control during Q2W dosing. All patients received TCZ-SC 162 mg Q2W before escalation and 162 mg Q1W after escalation.
Inadequate clinical control was determined by the treating rheumatologist in routine practice and generally reflected persistent clinical disease activity, failure to achieve the intended treatment target, or residual inflammatory symptoms despite TCZ-SC Q2W administration. No protocol-defined DAS28-ESR or CDAI threshold was used to mandate escalation, and the decision to escalate was based on the overall clinical judgment of the treating rheumatologist. The index date for the Q1W escalation cohort was defined as the date of escalation from TCZ-SC Q2W to Q1W dosing. Clinical outcomes were analyzed among patients with available follow-up data after escalation, and safety outcomes were assessed in all patients who received at least one dose of TCZ-SC Q1W. Because escalation was based on the rheumatologist’s discretion, selection bias could not be excluded.
Re-adjudication of D2T RA
D2T RA status was re-adjudicated retrospectively at the individual-patient level using treatment histories available before TCZ-SC Q1W escalation. The csDMARD component was considered fulfilled when the patient had a history of inadequate disease control under csDMARD-based therapy leading to bDMARD or tsDMARD therapy, intolerance, or a contraindication. The current tolerance of low-dose MTX at the time of Q1W escalation was not considered to negate the prior csDMARD inadequate response.
Prior b/tsDMARDs were classified according to mechanism of action, including tumor necrosis factor inhibitors (TNFi), IL-6 receptor inhibitors, abatacept, and Janus kinase inhibitors (JAKi). TCZ-SC Q1W itself and all therapies introduced after Q1W escalation were not counted for the D2T classification. In the main re-adjudication, inadequate clinical control during ongoing TCZ-SC Q2W was considered to indicate current IL-6 receptor inhibitor failure. To avoid overestimating D2T RA status due to dose escalation within the same drug, a stricter classification was applied, in which the ongoing TCZ-SC Q2W regimen was excluded as a qualifying bDMARD failure. This stricter classification required csDMARD inadequate response, intolerance, or contraindication; failure of at least two b/tsDMARDs with different mechanisms of action before Q1W escalation; persistent active disease; and problematic management.
Q2W continuation contextual comparator
To contextualize the outcomes observed after Q1W escalation, we identified patients who continued TCZ-SC Q2W during the study period. This Q2W continuation cohort did not overlap with the Q1W escalation cohort according to patient identifiers. Because Q1W escalation in routine practice was generally considered after an initial period of Q2W treatment rather than after 52 weeks, week 12 after TCZ-SC Q2W initiation was used as a pseudo-index for the Q2W continuation cohort.
Among the 242 patients in the overall Q2W continuation cohort, 215 with available CDAI data at week 12 constituted the Q2W continuation analytical cohort. Among these 215 patients, those with residual disease activity at week 12, defined as CDAI > 10, were analyzed as a clinically relevant landmark subgroup. Changes from weeks 12 to 24 were evaluated in exploratory analyses. For the direct exploratory comparison, the 12-week ΔCDAI was calculated from Q1W escalation to week 12 in the Q1W escalation cohort and from the week-12 pseudo-index to week 24 in the Q2W residual-activity subgroup. This analysis was exploratory and was performed with the intention of contextualizing natural fluctuation and regression to the mean; it was not designed to establish the causal superiority of Q1W escalation over continued Q2W dosing.
Data collection and clinical assessments
Demographic and clinical data, including age, sex, disease duration, comorbidities, treatment history before TCZ-SC Q1W escalation, and concomitant medications, were extracted from electronic medical records. Concomitant medications included MTX, prednisolone (PSL), TAC, iguratimod (IGU), salazosulfapyridine (SASP), bucillamine (BUC), mizoribine (MZR), and NSAIDs when available.
In the Q1W escalation cohort, disease activity was assessed using DAS28-ESR and CDAI at baseline, defined as the date of escalation from TCZ-SC Q2W to Q1W, and at weeks 12, 24, 36, and 52. The disease activity components, including tender and swollen joint counts and global assessments, were also collected when available. Laboratory assessments included CRP, ESR, matrix metalloproteinase-3 (MMP-3), white blood cell count, hemoglobin, platelet count, liver and biliary enzymes, total bilirubin, total cholesterol, serum creatinine, and estimated glomerular filtration rate (eGFR) at the same time points.
Follow-up disposition and concomitant treatment assessment
Follow-up disposition through week 52 was determined using electronic medical records. In the Q1W escalation cohort, complete CDAI follow-up was defined as the availability of CDAI data at baseline and weeks 12, 24, 36, and 52; all other patients were classified as having incomplete follow-up data. Reasons for missing week-52 CDAI data and treatment discontinuation or interruption were categorized according to documented clinical records. Baseline characteristics were compared between the complete- and incomplete-case groups to assess potential attrition bias.
Individual-level initiation or dose escalation of regular concomitant treatments was evaluated at prespecified visits. Regular systemic treatment intensification included initiation or dose escalation of PSL, MTX, SASP, BUC, IGU, TAC, or MZR. NSAID initiation was assessed separately. Early treatment intensification was defined as a higher recorded dose at week 12 relative to the baseline. Over the 52-week period, treatment intensification was defined as a higher recorded dose at weeks 12, 24, 36, or 52 than at the immediately preceding available, prespecified visit. A sensitivity analysis of the 12-week CDAI change excluded patients with documented early regular systemic treatment intensification. Episodic intra-articular corticosteroid injections, short-term systemic corticosteroid interventions between prespecified visits, and within-class NSAID switching were not systematically captured and were therefore not included in the quantitative treatment intensification analysis.
Outcomes
The primary outcome was the overall longitudinal change in CDAI from baseline through weeks 12, 24, 36, and 52 after escalation to TCZ-SC Q1W. CDAI was prioritized because it does not include acute-phase reactants and may therefore complement DAS28-ESR during IL-6 receptor blockade.
The secondary outcomes included longitudinal changes in the DAS28-ESR, MMP-3, CRP, ESR, tender and swollen joint counts, CDAI disease activity categories, background treatments, and laboratory safety parameters. Additional exploratory analyses evaluated follow-up disposition and baseline characteristics according to the completeness of CDAI follow-up, individual-level regular concomitant treatment intensification, and the 12-week change in CDAI in the Q1W escalation cohort versus the Q2W residual-activity subgroup. Renal outcomes, including changes in serum creatinine and estimated glomerular filtration rate (eGFR), and the proportion of patients with a ≥ 10% decline in eGFR from baseline to week 52, were evaluated as exploratory outcomes. For the Q1W escalation cohort, baseline was defined as the date of escalation from TCZ-SC Q2W to Q1W. For the Q2W continuation comparator, week 12 after TCZ-SC Q2W initiation served as the pseudo-index, and the subsequent 12-week ΔCDAI was calculated from the pseudo-index to week 24.
Safety assessment
Safety was assessed throughout the 52-week observation period using the medical records and laboratory data. Adverse events, infections, treatment discontinuation, and laboratory abnormalities were recorded when they were documented. The laboratory safety parameters included white blood cell count, hemoglobin, platelet count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (γGTP), total bilirubin, total cholesterol, serum creatinine, and eGFR.
Renal outcomes were evaluated using serum creatinine levels and eGFR. For the exploratory renal analysis, a decline in renal function was defined as a ≥10% decrease in eGFR at week 52 compared with baseline among patients with paired baseline and week-52 eGFR data. Exploratory subgroup analyses of ΔeGFR from baseline to week 52 were performed according to TAC use during follow-up, hypertension, and diabetes mellitus.
Statistical analysis
Continuous variables are presented as medians with interquartile ranges (IQRs), and categorical variables are presented as numbers and percentages of the total. Descriptive summaries at each time point were calculated using all available data, without imputation.
As outcomes were measured repeatedly within the same individuals at predefined follow-up visits, overall longitudinal changes in CDAI, DAS28-ESR, MMP-3, and selected laboratory parameters were assessed using complete-case Friedman tests. The CDAI Friedman test was the primary longitudinal analysis, whereas the Friedman tests for the other outcomes were exploratory. The complete-case sample size for each analysis is reported in the corresponding figure or supplementary table. Pairwise Wilcoxon signed-rank tests were not used as the primary longitudinal analysis because repeated pairwise testing may increase the risk of type I errors. For exploratory paired comparisons involving two time points, Wilcoxon signed-rank tests were performed.
For sensitivity analyses, linear mixed-effects models were fitted for CDAI, DAS28-ESR, MMP-3, and eGFR using all available observations without imputation. Each model included visit as a categorical fixed effect and a patient-specific random intercept, with baseline as the reference visit, and was fitted using maximum likelihood. Model-estimated changes from baseline were reported with 95% confidence intervals; two-sided P values and confidence intervals were based on Wald tests. MMP-3 was natural-log transformed because of its right-skewed distribution, and the estimates were back-transformed and expressed as percentage changes from the baseline.
To assess potential attrition bias, baseline characteristics were compared between the complete- and incomplete-case groups using Mann–Whitney U tests for continuous variables and Fisher’s exact tests for categorical variables. The absolute standardized differences were also calculated descriptively.
Exploratory between-group comparisons were performed using the Mann–Whitney U test for continuous variables and Fisher’s exact test for categorical variables. For the direct contextual comparison, the 12-week ΔCDAI was compared between patients in the Q1W escalation cohort with paired baseline and week-12 data and patients in the Q2W residual-activity subgroup with paired week-12 and week-24 data. ΔCDAI was defined as the later value minus the index value; negative values indicated an improvement. This nonrandomized, unmatched comparison was descriptive and not intended to establish causal superiority or equivalence.
A sensitivity analysis excluding patients with documented regular systemic treatment intensification during weeks 0–12 was performed using the Wilcoxon signed-rank test among patients with paired baseline and week-12 CDAI data. P values from the mixed-effects sensitivity analyses, attrition comparisons, contextual comparator analyses, and other exploratory analyses were not adjusted for multiple comparisons.
Because this was a retrospective observational study that included all eligible patients during the study period, no a priori sample size calculation was performed. A post-hoc power analysis was not performed. Given the limited sample size and number of outcome events, multivariate analyses were not performed to avoid model overfitting.
Statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Japan), a graphical user interface for R [21], and Python (ver. 3.13.5). Data processing, linear mixed-effects modeling, supplementary analyses, and figure generation were performed in Python using the pandas, NumPy, SciPy, statsmodels, and Matplotlib libraries. Two-sided P values < 0.05 were considered statistically significant for the primary complete-case Friedman analysis; all other P values were considered exploratory. During the preparation of this manuscript, the authors used ChatGPT (OpenAI) to assist with language editing, manuscript drafting and revision, and the development and verification of Python code for statistical analyses and data visualization. All outputs were critically reviewed and verified by the authors, who take full responsibility for the final content.
Results
Patient characteristics
A total of 58 patients were included in the Q1W escalation cohort of this study. The baseline characteristics at the time of escalation from TCZ-SC Q2W to Q1W are presented in Table 1. The median age at Q1W escalation was 58.2 years (IQR 49.5–70.1), 44 patients (75.9%) were female, and the median disease duration was 8.7 years (IQR 3.5–13.7). The median duration of TCZ-SC Q2W treatment before escalation was 2.0 months (IQR 1.0–12.8 months). Data availability, longitudinal outcomes, laboratory safety parameters, and concomitant medications are summarized in Supplementary Table S1; baseline and pseudo-index characteristics of the Q1W escalation and Q2W continuation comparator cohorts are summarized in Supplementary Table S2; and individual-level details of D2T RA cases identified in the stricter classification are summarized in Supplementary Table S3.
Table 1.
Baseline characteristics at the time of escalation from TCZ-SC Q2W to Q1W
| Characteristic | Available, n | Value |
|---|---|---|
| Demographics and comorbidities | ||
| Age at Q1W escalation, years | 58 | 58.2 (49.5–70.1) |
| Female, n (%) | 58 | 44 (75.9) |
| Disease duration at Q1W escalation, years | 58 | 8.7 (3.5–13.7) |
| Hypertension, n (%) | 58 | 18 (31.0) |
| Diabetes mellitus, n (%) | 58 | 6 (10.3) |
| ACPA positive, n (%) | 58 | 44 (75.9) |
| ACPA level, U/mL | 58 | 67.4 (9.9–463.1) |
| Treatment history before TCZ-SC Q1W escalation | ||
| Duration of TCZ-SC Q2W treatment before escalation, months | 58 | 2.0 (1.0–12.8) |
| MTX use at escalation, n (%) | 58 | 24 (41.4) |
| MTX dose at escalation, mg/week | 58 | 0 (0–6) |
| MTX discontinued due to adverse events, n (%) | 58 | 33 (56.9) |
| MTX adverse event/intolerance history, n (%) | 58 | 45 (77.6) |
| csDMARD inadequate response, intolerance, or contraindication, n (%) | 58 | 58 (100.0) |
| Failed b/tsDMARDs before Q1W escalation, excluding ongoing TCZ-SC Q2W, n | 58 | 1.0 (0.0–1.8) |
| Failed b/tsDMARDs before Q1W escalation, including ongoing TCZ-SC Q2W, n | 58 | 2.0 (1.0–2.8) |
| Distinct failed mechanisms of action before Q1W escalation, including ongoing TCZ-SC Q2W, n | 58 | 2.0 (1.0–2.0) |
| ≥ 2 distinct failed mechanisms of action including ongoing TCZ-SC Q2W, n (%) | 58 | 40 (69.0) |
| D2T RA in the stricter classification, excluding ongoing TCZ-SC Q2W as a qualifying failure, n (%) | 58 | 5 (8.6) |
| Prior exposure by mechanism of action before Q1W escalation | ||
| TNF inhibitor exposure before Q1W escalation, n (%) | 58 | 36 (62.1) |
| IL-6 receptor inhibitor, including ongoing TCZ-SC Q2W, n (%) | 58 | 58 (100.0) |
| Non-TCZ IL-6 receptor inhibitor, n (%) | 58 | 2 (3.4) |
| Abatacept, n (%) | 58 | 6 (10.3) |
| JAK inhibitor, n (%) | 58 | 3 (5.2) |
| Disease activity and laboratory data at Q1W escalation | ||
| DAS28-ESR | 58 | 3.36 (2.19–4.41) |
| CDAI | 58 | 16.00 (9.52–22.61) |
| CDAI > 10, n (%) | 58 | 41 (70.7) |
| Tender joint count | 58 | 5.5 (2.0–12.5) |
| Swollen joint count | 58 | 3.5 (0.0–10.0) |
| CRP, mg/L | 58 | 0.3 (0.1–2.6) |
| ESR, mm/h | 58 | 6.0 (2.0–11.8) |
| MMP-3, ng/mL | 58 | 146.6 (76.8–311.5) |
| eGFR, mL/min/1.73 m² | 58 | 80.2 (66.6–94.6) |
| Serum creatinine, µmol/L | 58 | 59 (48–67) |
| Concomitant medications at Q1W escalation | ||
| PSL use, n (%) | 58 | 37 (63.8) |
| PSL dose, mg/day | 58 | 2.3 (0.0–4.9) |
| TAC use, n (%) | 58 | 10 (17.2) |
| IGU use, n (%) | 58 | 8 (13.8) |
| SASP use, n (%) | 58 | 20 (34.5) |
| BUC use, n (%) | 58 | 9 (15.5) |
| NSAID use, n (%) | 58 | 44 (75.9) |
Data are presented as n (%) or the median (IQR), as appropriate. Baseline was defined as the date of escalation from TCZ-SC Q2W to TCZ-SC Q1W. All patients received TCZ-SC 162 mg Q2W before escalation and 162 mg Q1W after escalation
Prior exposure by mechanism of action was assessed at any time before Q1W escalation. Prior b/tsDMARDs and mechanisms of action were re-adjudicated using individual-level treatment histories available before TCZ-SC Q1W escalation. TCZ-SC Q1W and all post-escalation therapies were not counted. In the main re-adjudication, inadequate clinical control during ongoing TCZ-SC Q2W was considered current IL-6R inhibitor failure. The stricter classification excluded the ongoing TCZ-SC Q2W regimen as a qualifying bDMARD failure and required csDMARD inadequate response, intolerance, or contraindication; failure of at least two b/tsDMARDs with different mechanisms of action; persistent active disease; and problematic management. The csDMARD criterion included a history of inadequate disease control under csDMARD-based therapy leading to initiation of b/tsDMARD therapy, intolerance, or contraindication; current tolerance of low-dose MTX at Q1W escalation was not considered to negate a prior csDMARD inadequate response
Abbreviations: ACPA, anti-citrullinated protein antibody; BUC, bucillamine; b/tsDMARDs, biological or targeted synthetic disease-modifying antirheumatic drugs; CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; csDMARDs, conventional synthetic disease-modifying antirheumatic drugs; DAS28-ESR, Disease Activity Score in 28 joints using erythrocyte sedimentation rate; D2T RA, difficult-to-treat rheumatoid arthritis; eGFR, estimated glomerular filtration rate; ESR, erythrocyte sedimentation rate; IGU, iguratimod; IL-6R, interleukin-6 receptor; IQR, interquartile range; JAK, Janus kinase; MMP-3, matrix metalloproteinase-3; MOA, mechanism of action; MTX, methotrexate; NSAID, non-steroidal anti-inflammatory drug; PSL, prednisolone; Q1W, once weekly; Q2W, every 2 weeks; SASP, salazosulfapyridine; TAC, tacrolimus; TCZ-SC, subcutaneous tocilizumab; TNF, tumor necrosis factor
MTX intolerance or limitations were common. At Q1W escalation, 24 patients (41.4%) were receiving MTX, the median MTX dose was 0 mg/week (IQR 0–6), 33 patients (56.9%) had discontinued MTX because of adverse events, and 45 patients (77.6%) had a recorded history of MTX adverse events or intolerance. All patients were considered to have an inadequate response to csDMARDs, intolerance, or contraindications.
Prior treatment exposure was re-adjudicated using individual treatment histories before TCZ-SC Q1W escalation. The median number of failed b/tsDMARDs before Q1W escalation was 1.0 (IQR 0.0–1.8) when the ongoing TCZ-SC Q2W regimen was excluded, and 2.0 (IQR 1.0–2.8) when the ongoing TCZ-SC Q2W regimen was considered as current IL-6 receptor inhibitor failure. Forty patients (69.0%) had at least two distinct failed mechanisms of action when TCZ-SC Q2W was included. In the stricter classification excluding ongoing TCZ-SC Q2W as a qualifying bDMARD failure, 5 patients (8.6%) fulfilled the D2T RA definition. The individual-level details of these 5 cases are provided in Supplementary Table S3.
At Q1W escalation, the median DAS28-ESR was 3.36 (IQR 2.19–4.41) and the median CDAI was 16.00 (IQR 9.52–22.61). Forty-one patients (70.7%) had CDAI scores > 10. Although CRP and ESR levels were low, with median values of 0.3 mg/L (IQR 0.1–2.6) and 6.0 mm/h (IQR 2.0–11.8), respectively, the median MMP-3 level was 146.6 ng/mL (IQR 76.8–311.5). Hypertension and diabetes mellitus were present in 18 (31.0%) and 6 (10.3%) patients, respectively.
Follow-up disposition and attrition analysis
Complete CDAI data at baseline and all four follow-up visits were available for 42 (72.4%) patients. One patient had week-52 CDAI data but lacked at least one interim assessment, and 15 (25.9%) lacked week-52 CDAI data. Among these 15 patients, 13 discontinued or interrupted Q1W treatment before complete follow-up because of primary inefficacy (n = 5), secondary inefficacy or inadequate control (n = 5), patient preference (n = 1), a switch to intravenous TCZ (n = 1), or a surgery-related interruption (n = 1). The remaining 2 patients transferred care.
In comparison to the complete-case group, the incomplete-case group had a higher baseline CDAI [22.85 (IQR, 17.16–32.62) vs. 12.50 (IQR, 8.71–17.60), P < 0.001], a higher baseline DAS28-ESR [4.21 (IQR, 3.77–5.32) vs. 3.21 (IQR, 2.13–3.85), P = 0.007], and a higher baseline PSL dose [3.0 mg/day (IQR, 1.6–8.1) vs. 2.0 mg/day (IQR, 0.0–3.5), P = 0.049]. Detailed follow-up disposition and comparisons between the complete-case and incomplete-case groups are presented in Supplementary Table S4.
Longitudinal changes in the disease activity indices and inflammatory markers
The primary outcome, overall longitudinal change in CDAI, was significant in the complete-case Friedman test (complete n = 42, P < 0.001). The median CDAI decreased from 16.00 (IQR 9.52–22.61; n = 58) at baseline to 9.75 (IQR 5.30–15.62; n = 56) at week 12, 9.06 (IQR 5.00–11.98; n = 46) at week 24, 8.80 (IQR 4.60–12.00; n = 43) at week 36, and 8.20 (IQR 3.20–12.10; n = 43) at week 52 (Fig. 1 and Supplementary Table S1).
Fig. 1.
Longitudinal changes in DAS28-ESR, CDAI, and MMP-3 after escalation from TCZ-SC Q2W to Q1W. Median values are shown as solid black lines, and shaded areas indicate the interquartile ranges at baseline (week 0) and weeks 12, 24, 36, and 52 after escalation from TCZ-SC Q2W to Q1W. The number of patients with available data at each time point is shown below the x-axis. Overall longitudinal changes were assessed using complete-case Friedman tests; the complete-case sample size and P value are shown in each panel. Analyses were performed without imputation of missing values. Detailed summary statistics and data availability are provided in Supplementary Table S1.(A) DAS28-ESR. (B) CDAI. (C) MMP-3. Abbreviations: CDAI, Clinical Disease Activity Index; DAS28-ESR, Disease Activity Score in 28 joints using erythrocyte sedimentation rate; IQR, interquartile range; MMP-3, matrix metalloproteinase-3; Q1W, once weekly; Q2W, every 2 weeks; TCZ-SC, subcutaneous tocilizumab
The DAS28-ESR also decreased over time in the complete-case Friedman test (complete n = 42, P < 0.001), from a median of 3.36 (IQR 2.19–4.41; n = 58) at baseline to 1.74 (IQR 0.94–2.54; n = 43) at week 52. MMP-3 decreased from 146.6 ng/mL (IQR 76.8–311.5; n = 58) at baseline to 79.8 ng/mL (IQR 58.5–106.2; n = 43) at week 52, with a significant overall longitudinal change in the complete-case Friedman test (complete n = 42, P < 0.001). CRP and ESR levels remained low throughout the follow-up period, although both showed significant overall longitudinal changes in the complete-case analyses (Supplementary Table S1).
In the mixed-effects sensitivity analyses using all available observations, the model-estimated week-52 changes from baseline were − 5.89 points for CDAI (95% CI, − 8.15 to − 3.63), − 1.29 points for DAS28-ESR (95% CI, − 1.63 to − 0.95), and − 45.8% for MMP-3 (95% CI, − 54.9% to − 34.7%). These estimates were directionally consistent with the complete-case analyses (Supplementary Table S5).
The individual CDAI trajectories and CDAI disease activity categories are shown in Fig. 2. At baseline, 2 of the 58 patients (3.4%) were in CDAI remission, 15 (25.9%) had low disease activity, 26 (44.8%) had moderate disease activity, and 15 (25.9%) had high disease activity. At week 52, among the 43 patients with available CDAI data, 7 (16.3%) were in remission, 20 (46.5%) had low disease activity, 14 (32.6%) had moderate disease activity, and 2 (4.7%) had high disease activity.
Fig. 2.
Individual CDAI trajectories and disease activity categories after escalation from TCZ-SC Q2W to Q1W. (A) Individual CDAI trajectories from baseline (week 0) to week 52 after escalation from TCZ-SC Q2W to Q1W. Thin gray lines indicate individual patient trajectories, and the bold black line indicates the median CDAI at each time point. Horizontal dashed lines indicate CDAI disease activity thresholds. The number of patients with available CDAI data at each time point is shown below the x-axis. Missing values were not imputed.(B) Distribution of the CDAI disease activity categories at each time point. CDAI categories were defined as remission (REM, ≤2.8), low disease activity (LDA, >2.8 to 10), moderate disease activity (MDA, >10 to 22), and high disease activity (HDA, >22). Abbreviations: CDAI, Clinical Disease Activity Index; HDA, high disease activity; LDA, low disease activity; MDA, moderate disease activity; Q1W, once weekly; Q2W, every 2 weeks; REM, remission; TCZ-SC, subcutaneous tocilizumab
Q2W continuation contextual comparator
During the same study period, 242 patients continued TCZ-SC Q2W and did not overlap with the Q1W escalation cohort based on patient identifiers. The Q2W continuation landmark analysis and patient selection and follow-up disposition flowchart are shown in Supplementary Figures S1 and S2, respectively. Among them, 215 patients had CDAI data at week 12 after TCZ-SC Q2W initiation, which was used as the pseudo-index for the contextual comparator analysis. Of these, 66 patients had residual disease activity at week 12, defined as CDAI > 10, and 54 had paired CDAI data at both weeks 12 and 24.
The Q2W continuation analytical cohort (n = 215) had lower disease activity at the pseudo-index than the Q1W escalation cohort, with a median CDAI of 6.91 (IQR 4.00–11.80). In contrast, the Q2W week-12 residual-activity subgroup had a median CDAI of 15.43 (IQR 13.13–19.63), which was similar to the baseline CDAI of the Q1W escalation cohort. Compared with the Q2W residual-activity subgroup, the Q1W escalation cohort had a higher burden of prior b/tsDMARD exposure before TCZ-SC initiation and was less likely to have received TCZ-SC as the first b/tsDMARD (Supplementary Table S2).
Among the 54 patients in the Q2W residual-activity subgroup with paired CDAI data, the median CDAI decreased from 15.18 at week 12 to 11.62 at week 24 (exploratory Wilcoxon signed-rank test, P = 4.15 × 10⁻⁵; Supplementary Figure S1). In the direct exploratory comparison, the median 12-week ΔCDAI was − 2.85 (IQR, − 9.52 to 0.03) in the Q1W escalation cohort (n = 56) and − 3.40 (IQR, − 6.40 to 0.14) in the Q2W residual-activity subgroup (n = 54), with no significant between-group difference (P = 0.754; Supplementary Table S2 and Supplementary Figure S3). Because this comparison was nonrandomized and unmatched, the absence of a significant difference should not be interpreted as evidence of equivalence.
Safety, concomitant medications, and renal outcomes
The laboratory safety parameters and concomitant medications during follow-up are summarized in Supplementary Table S1. No serious infections or treatment discontinuations due to adverse events were documented during the 52-week follow-up. White blood cell and platelet counts decreased over time in the complete-case analyses, whereas hemoglobin, AST, ALT, γGTP, and total cholesterol did not show significant overall longitudinal changes.
At the individual patient level, 7 of 58 patients (12.1%) had documented regular systemic treatment intensification during weeks 0–12: PSL was initiated or increased in 4 patients, MTX in 2, and another csDMARD in 1; no TAC initiation or dose increase or NSAID initiation was documented during this period. At any prespecified visit through week 52, 15 of 58 patients (25.9%) had documented regular systemic treatment intensification, including PSL initiation or dose increase in 7 patients, MTX in 3, another csDMARD in 4, and TAC in 6; drug-specific categories could overlap. After excluding the 7 patients with early regular systemic treatment intensification, the median CDAI decreased from 14.70 (IQR, 9.50–20.90) at baseline to 8.81 (IQR, 4.20–13.20) at week 12 among 49 patients with paired data, with a median ΔCDAI of − 3.00 (IQR, − 10.20 to − 0.60; P < 0.001). At the group level, PSL use, PSL dose, and MTX use decreased during follow-up, whereas NSAID use remained similar over time (Supplementary Tables S1 and S6).
eGFR decreased modestly over 52 weeks, from a median of 80.2 mL/min/1.73 m2 (IQR 66.6–94.6; n = 58) at baseline to 75.3 mL/min/1.73 m2 (IQR 60.8–89.3; n = 43) at week 52, with a significant overall longitudinal change in the complete-case Friedman test (complete n = 42, P = 0.001; Fig. 3 and Supplementary Table S1). Among 43 patients with paired baseline and week-52 eGFR data, the median ΔeGFR was − 6.4 mL/min/1.73 m2 (IQR − 9.9 to 0.5), and 18 patients (41.9%) had a ≥ 10% decline in eGFR. In the exploratory mixed-effects sensitivity analysis using all available observations, the model-estimated week-52 change in eGFR was − 4.79 mL/min/1.73 m2 (95% CI, − 7.65 to − 1.92; P = 0.001), which was directionally consistent with the complete-case analysis (Supplementary Table S5).
Fig. 3.
eGFR changes and exploratory renal subgroup analyses after TCZ-SC Q1W escalation. (A) Longitudinal changes in eGFR from baseline (week 0) to week 52 after escalation from TCZ-SC Q2W to Q1W. The median values are shown as a solid black line, and shaded areas indicate interquartile ranges. The number of patients with available eGFR data at each time point is shown below the x-axis. Overall longitudinal change was assessed using a complete-case Friedman test.(B) Change in eGFR from baseline to week 52 (ΔeGFR), stratified by concomitant tacrolimus (TAC) use during follow-up, among 43 patients with paired baseline and week-52 eGFR data.(C) Change in eGFR from baseline to week 52 according to hypertension and diabetes mellitus among patients with paired baseline and week-52 eGFR data. Box plots show medians and interquartile ranges; whiskers indicate 1.5 times the interquartile range, and dots indicate individual patients. P values in panels B and C were calculated using Mann–Whitney U tests. These subgroup analyses were exploratory and were not adjusted for multiple comparisons. Missing values were not imputed. Abbreviations: DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HTN, hypertension; IQR, interquartile range; Q1W, once weekly; Q2W, every 2 weeks; TAC, tacrolimus; TCZ-SC, subcutaneous tocilizumab
In exploratory subgroup analyses, the median ΔeGFR was − 4.0 mL/min/1.73 m2 (IQR − 8.8 to 1.4) in patients without TAC use during follow-up and − 9.9 mL/min/1.73 m2 (IQR − 14.3 to − 5.4) in patients with TAC use during follow-up (Mann–Whitney U test, P = 0.068). ΔeGFR did not differ significantly according to hypertension (P = 0.343) or diabetes mellitus (P = 0.504), although these subgroup analyses were limited by small sample sizes, particularly for patients with diabetes mellitus.
Discussion
In this retrospective real-world study, disease activity decreased over 52 weeks after escalation from TCZ-SC Q2W to Q1W in selected patients with RA who had inadequate clinical control during Q2W dosing. The decreases in CDAI, DAS28-ESR, and MMP-3 levels observed in the complete-case analyses were directionally consistent with the mixed-effects sensitivity analyses using all available observations. Although 7 patients had documented regular systemic treatment intensification during the first 12 weeks, the 12-week decrease in CDAI remained after excluding these patients. However, the 12-week change in CDAI did not differ significantly between the Q1W escalation cohort and the Q2W residual-activity subgroup. Collectively, these descriptive findings do not establish an incremental or causal benefit of Q1W dose escalation.
The interpretation of disease activity during TCZ therapy requires caution because IL-6 receptor blockade suppresses acute-phase reactants. In the present cohort, CRP and ESR were already low at the time of Q1W escalation, despite residual clinical disease activity based on CDAI. This finding supports the use of CDAI as a complementary outcome measure during TCZ treatment, because CDAI does not include CRP or ESR and has been validated as a clinical disease activity score in which acute-phase reactants add little additional information [22]. The observed decrease in MMP-3 levels should be interpreted as a change in an inflammatory or synovial biomarker rather than as evidence of reduced structural damage, because radiographic progression was not assessed in this study.
Our findings are broadly consistent with those of previous studies, including the SHINOBI and SUMMACTA studies, which reported clinical benefits or non-inferior efficacy with TCZ-SC Q1W dosing in selected patients [6, 12]. However, unlike randomized clinical trials, the present study reflects routine clinical decision-making in which escalation was determined by treating rheumatologists without protocol-defined disease activity thresholds. Therefore, the observed longitudinal changes should be interpreted as descriptive real-world outcomes rather than as confirmatory evidence of a treatment effect.
To address the absence of a formal control group, we performed an exploratory contextual analysis using patients who continued TCZ-SC Q2W treatment during the same study period. The Q2W continuation analytical cohort (n = 215) had lower disease activity at the week-12 pseudo-index than the Q1W escalation cohort, indicating that many patients who continued Q2W dosing had already achieved adequate disease control. In contrast, the CDAI values at the week-12 pseudo-index in the Q2W residual-activity subgroup were comparable to those at Q1W escalation in the Q1W escalation cohort. Over the subsequent 12 weeks, the median ΔCDAI was − 2.85 in the Q1W escalation cohort and − 3.40 in the Q2W residual-activity subgroup, with no significant between-group difference (P = 0.754). Because this comparison was nonrandomized and unmatched, the absence of a significant difference should not be interpreted as evidence of equivalence. Rather, the improvement observed with continued Q2W dosing suggests that natural fluctuations, delayed response to ongoing Q2W therapy, and regression to the mean may have contributed to the within-patient changes observed after Q1W dose escalation [23]. Thus, the contextual comparison did not establish the incremental benefit of Q1W escalation.
The completeness of the follow-up also affected the interpretation. Patients with incomplete follow-up had higher baseline CDAI and DAS28-ESR values and a higher baseline PSL dose than the complete-case group, raising concerns regarding attrition bias because the complete-case estimates may preferentially reflect patients with lower baseline disease activity. The mixed-effects sensitivity analyses incorporated all available observations and yielded directionally consistent estimates; however, they could not fully eliminate bias if missingness was related to the clinical course. Similarly, the sensitivity analysis excluding 7 patients with documented early regular systemic treatment intensification supported the direction of the 12-week CDAI change. However, residual confounding remains possible because episodic intra-articular corticosteroid injections and short-term systemic corticosteroid interventions between the prespecified visits were not systematically captured.
D2T RA status was carefully re-adjudicated at the individual-patient level using treatment histories available before TCZ-SC Q1W escalation. This distinction was important because dose escalation within the same drug and therapies introduced after Q1W escalation should not be counted as failures of distinct b/tsDMARD mechanisms. When inadequate clinical control during ongoing TCZ-SC Q2W was considered current IL-6 receptor inhibitor failure, 40 patients had at least two distinct failed mechanisms of action. In contrast, in a stricter classification that excluded ongoing TCZ-SC Q2W as a qualifying bDMARD failure, only 5 patients fulfilled the D2T RA definition. Therefore, the present cohort should not be interpreted as predominantly D2T RA. Instead, it represents a selected real-world population with inadequate clinical control during TCZ-SC Q2W, frequent MTX intolerance or limitation, and variable prior b/tsDMARD exposure.
Renal outcomes and laboratory parameters were evaluated descriptively. The eGFR decreased over 52 weeks in both the complete-case and mixed-effects analyses, and 18 of 43 patients with paired baseline and week-52 data had a ≥ 10% decline in eGFR. ΔeGFR was numerically more negative among patients receiving concomitant TAC, although the between-group difference was not statistically significant, and no significant differences were observed according to the presence of hypertension or diabetes mellitus. These subgroup analyses were underpowered, particularly for diabetes mellitus, and the observed renal changes cannot be attributed to Q1W escalation or interpreted as establishing renal safety. Other laboratory findings did not indicate a major new toxicity signal, and no serious infections or treatment discontinuations due to adverse events were documented in the study. However, mild or transient adverse events may have been underreported in this retrospective study.
This study had some limitations. First, this was a retrospective single-center study, and the decision to escalate from TCZ-SC Q2W to Q1W was made at the discretion of the treating rheumatologist without predefined DAS28-ESR or CDAI thresholds; therefore, selection bias and confounding by indication cannot be excluded. Second, the Q2W continuation comparator was neither randomized nor matched. The absence of a significant difference in the 12-week ΔCDAI does not demonstrate equivalence, and natural fluctuations, delayed responses to ongoing Q2W therapy, and regression to the mean may have contributed to the observed changes. Third, follow-up was incomplete, and patients with incomplete follow-up had higher baseline disease activity than those in the complete-case group. No missing values were imputed in the analysis. Although mixed-effects sensitivity analyses using all available observations were directionally consistent with the complete-case analyses, informative attrition may have biased the results. Fourth, regular concomitant treatment changes were assessed only at the prespecified visits. Although the 12-week CDAI decrease persisted after excluding patients with documented early treatment intensification, episodic intra-articular corticosteroid injections and short-term systemic corticosteroid interventions were not systematically captured, and residual confounding could not be excluded. Fifth, the sample size was modest, particularly for the renal and comorbidity subgroup analyses; multivariable adjustment was not performed, and exploratory P values were not adjusted for multiple comparisons. Sixth, serum TCZ concentrations, IL-6 levels, and IL-6 receptor saturation were not measured, precluding pharmacokinetic or mechanistic interpretation. Seventh, radiographic progression and synovitis on ultrasound or magnetic resonance imaging were not evaluated, and changes in MMP-3 levels should not be interpreted as direct evidence of structural benefit. Finally, adverse events were retrospectively ascertained from medical records, which may have underestimated mild or transient events.
Conclusions
In this single-center retrospective real-world cohort of selected patients with RA who had inadequate clinical control during TCZ-SC Q2W, CDAI, DAS28-ESR, and MMP-3 decreased over 52 weeks after escalation to TCZ-SC Q1W, and mixed-effects sensitivity analyses using all available observations were directionally consistent. However, the 12-week change in CDAI did not differ significantly between the Q1W escalation cohort and the Q2W residual-activity subgroup. Individual-level re-adjudication identified only a small subset of patients who fulfilled the stricter D2T RA definition. These descriptive findings do not establish an incremental or causal benefit of Q1W escalation. Prospective controlled studies are needed to determine whether Q1W escalation provides additional benefit over continued Q2W dosing and, if so, which patients are most likely to benefit.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors thank all patients and staff of the Niigata Rheumatic Center for their contributions to clinical data collection and care. The authors also thank Japan Medical Communication for English-language editing.
Abbreviations
- ACPA
Anti-citrullinated protein antibody
- ALT
Alanine aminotransferase
- AST
Aspartate aminotransferase
- bDMARD
biological Disease-modifying antirheumatic drug
- b/tsDMARD
biological or targeted synthetic disease-modifying antirheumatic drug
- BUC
Bucillamine
- CDAI
Clinical disease activity index
- CI
Confidence interval
- CRP
C-reactive protein
- csDMARD
conventional synthetic Disease-modifying antirheumatic drug
- D2T RA
Difficult-to-treat rheumatoid arthritis
- DAS28-ESR
Disease activity score in 28 joints using erythrocyte sedimentation rate
- DM
Diabetes mellitus
- DMARD
Disease-modifying antirheumatic drug
- eGFR
estimated glomerular filtration rate
- ESR
Erythrocyte sedimentation rate
- γGTP
Gamma-glutamyl transpeptidase
- HDA
High disease activity
- HTN
Hypertension
- IGU
iguratimod
- IL-6
Interleukin-6
- IL-6R
Interleukin-6 receptor
- IQR
Interquartile range
- JAKi
Janus kinase inhibitor
- LDA
Low disease activity
- MDA
Moderate disease activity
- MMP-3
Matrix metalloproteinase-3
- MOA
Mechanism of action
- MTX
Methotrexate
- MZR
Mizoribine
- NSAID
Non-steroidal anti-inflammatory drug
- PSL
Prednisolone
- Q1W
Once weekly
- Q2W
Every 2 weeks
- RA
Rheumatoid arthritis
- REM
Remission
- SASP
Salazosulfapyridine
- TAC
Tacrolimus
- TCZ
Tocilizumab
- TCZ-SC
Subcutaneous tocilizumab
- TNFi
Tumor necrosis factor inhibitor
- tsDMARD
targeted synthetic Disease-modifying antirheumatic drug
Author contributions
MS designed the study, collected and analyzed the data, interpreted the results, and drafted the manuscript. ST, AA, HI, DK, KN, and AM contributed to data collection and clinical interpretation. SY and SI supervised the study and contributed to interpretation of the findings. All authors critically reviewed and revised the manuscript, approved the final version, and agree to be accountable for all aspects of the work.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Data availability
The data underlying this study cannot be shared publicly because of patient privacy and institutional ethical restrictions. De-identified data may be made available from the corresponding author upon reasonable request and subject to institutional approval by the relevant institutional ethics committee.
Declarations
Ethics approval and consent to participate
This study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Institutional Ethics Committee of the Niigata Rheumatic Center (approval number: 2025-025). Given the retrospective nature of the study, the requirement for written informed consent was waived by the Ethics Committee. Information about the study and the opportunity to opt out were made available through the hospital website and institutional bulletin board.
Consent for publication
Not applicable.
Competing interests
MS received an honorarium from Chugai Pharmaceutical Co., Ltd. for participation in a local scientific meeting at which preliminary work related to the topic of this manuscript was presented. Chugai Pharmaceutical Co., Ltd. provided no funding or other support for this study and had no role in the study design, data collection, statistical analyses, interpretation of the results, manuscript preparation, or the decision to submit the manuscript. The other authors declare that they have no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
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Supplementary Materials
Data Availability Statement
The data underlying this study cannot be shared publicly because of patient privacy and institutional ethical restrictions. De-identified data may be made available from the corresponding author upon reasonable request and subject to institutional approval by the relevant institutional ethics committee.