Rheumatoid factor or interleukin-6 receptor inhibition predicts the long-term effectiveness of certolizumab pegol in Japanese patients with rheumatoid arthritis: A two-center retrospective study

doi:10.21203/rs.3.rs-5207468/v1

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Rheumatoid factor or interleukin-6 receptor inhibition predicts the long-term effectiveness of certolizumab pegol in Japanese patients with rheumatoid arthritis: A two-center retrospective study

https://doi.org/10.21203/rs.3.rs-5207468/v1

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Objectives

To assess long-term retention rates associated with effectiveness of certolizumab pegol (CZP) and identify determinants of its effectiveness in patients with rheumatoid arthritis (RA).

Methods

This retrospective observational study enrolled 107 patients with RA. Retention rates based on effectiveness were investigated using the Kaplan–Meier method. Cox regression analysis was used to identify predictors of CZP effectiveness. In subgroup analyses, patients were categorized according to history of biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) to detect the determinants of CZP effectiveness in each group. Receiver operating characteristic analysis was performed to detect the optimal cut-off point for rheumatoid factor (RF).

Results

During a median of 56.0 months, overall retention rates at 12, 24, 48, and 60 months were 65.0%, 55.8%, 46.4%, and 40.2%, respectively. Multivariate analysis revealed that a b/tsDMARD-naïve group exhibited lowest likelihood of non-response to CZP (hazard ratio [HR]: 0.38, 95% confidence interval [CI]: 0.19–0.73, P = 0.003). In the sub-analyses, RF titer (HR per 100 IU/mL increment: 1.25, 95% CI: 1.06–1.60, P = 0.009) and prior interleukin-6 receptor (IL-6R) blockade (HR: 2.46, 95% CI: 1.11–5.57, P = 0.027) were strong determinants for CZP ineffectiveness in the b/tsDMARD-naïve and b/tsDMARD-switched groups, respectively. Highest retention rate was observed in the b/tsDMARD-naive population with an RF of < 79.9 IU/mL.

Conclusions

Overall, b/tsDMRAD-naïve status was the strongest predictor of long-term CZP effectiveness. RF elevation in b/tsDMARD-naïve and preceding IL-6R inhibition in b/tsDMARD-switched populations are significantly associated with reduced therapeutic effects of CZP.

Certolizumab pegol

Rheumatoid factor

Interluekin-6 receptor inhibitors

Rheumatoid arthritis

Tumor necrosis factor inhibitors.

・No history of molecular-targeted therapies was the strongest contributor to long-term effectiveness of certolizumab pegol.

・Lower rheumatoid factor significantly decreased discontinuation of certolizumab pegol due to ineffectiveness in biologics-naïve population.

・Prior interleukin-6 receptor blockade strongly correlated with non-response to certolizumab pegol in biologics-switched population.

Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by persistent synovitis in multiple joints, resulting in bone and cartilage destruction [1]. If not adequately managed, irreversible structural damage can progress, leading to severe disability, necessitating a rapid and effective treatment approach [2]. The widespread introduction of molecular-targeted therapies with biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) has resulted in substantial improvements in disease activity and inhibition of joint destruction. Given that RA is chronic in nature and still challenging to cure, it is essential to investigate the long-term durability and definite biomarkers that can predict treatment response to individual agents, which remains an unmet need [3].

Certolizumab pegol (CZP) is a fragment crystallizable (Fc)-free, polyethyleneglycolylated, humanized Fab fragment targeting tumor necrosis factor-alpha (TNF-α) [4], which has fundamental roles in the pathogenesis of RA, such as inducing immune cells activation, enhancing osteoclast differentiation, and promoting matrix metalloproteinases production [1]. Several clinical trials have extensively demonstrated the marked ability of CZP to induce disease remission and prevent radiographic progression over 24–52 weeks [5–9]. Moreover, pooled data from 27 clinical trials that included 6927 patients have demonstrated that retention rate at five years was 39.7%, with age, disease duration, and previous use of TNF inhibitors (TNFis) associated with CZP retention [10]; however, controlled trials have recruited highly selected populations, which achieved better treatment response than non-eligible patients [11]. Thus, cohort studies enrolling unselected patients in routine clinical practice are crucial for complementing the pragmatic effectiveness of CZP.

So far, several observational studies have reported survival rates of CZP of ≥ 2 years in real-world settings mainly in European countries [12–15]; however, data on long-term persistence focusing on only CZP in Japanese population is limited. Furthermore, considering the unique structure of CZP lacking the Fc portion, recent evidence have suggested substantial benefits for the clinical outcomes of high levels of rheumatoid factor (RF), which binds to the Fc region of anti-TNF-α monoclonal antibody [16] and might reduce serum half-lives via inhibiting the neonatal Fc receptor-mediated recycling of the antibody in patients with RA receiving CZP compared with other TNFis with Fc region [17, 18]; nevertheless, in investigations limited to CZP in routine care of Japanese patients, baseline predictors for long-term effectiveness remain undetermined [19, 20]. Particularly, it is important to ensure the most suitable population for the introduction of CZP to avoid unnecessary exposure to ineffective treatments.

In the current study, we aimed to examine the long-term drug survival of patients with CZP and clarify the baseline characteristics that enable the prediction of the sustained effectiveness of CZP by retrospectively evaluating real-world data from Japanese patients with RA to address these issues.

Study design and patient selection

This retrospective observational study was conducted at two tertiary referral centers in Japan: the Tohoku University and Osaki Citizen Hospitals. Consecutive patients aged ≥ 18 years who were diagnosed with RA according to the 2010 classification criteria [21] and initiated CZP treatment between March 2013 and September 2021 were enrolled in the study. These patients were followed-up until the end of the observation period (June 2022) or until CZP was discontinued. CZP was administered at an initial loading dose of 400 mg every two weeks for one month, and thereafter at 200 mg every two weeks or 400 mg every four weeks in accordance with the dosage approved for the treatment of patients with RA with inadequate response to existing antirheumatic drugs in Japan. However, the administration and regimen of CZP were decided based on shared decision-making between patients and treating physicians, considering the treat-to-target strategy, comorbidities, patient preference [22], and in accordance with the Japan College of Rheumatology guidelines for managing RA [23]. The primary objective of this study was to assess the proportion of CZP continuation attributable to its effectiveness during follow-up period after CZP administration. Secondary objective was to determine the factors associated with ineffectiveness of CZP discontinuation. First, after excluding patients with incomplete data available for analysis from the total enrolled population, the total analysis population was established. Patients who discontinued CZP, independent of effectiveness, were excluded from the total analysis to allow for a direct comparison between drug retention and CZP effectiveness. Finally, the effectiveness analysis population, which comprised only patients with a sustained response or non-response to CZP, was divided into two groups stratified according to drug survival to explore the predictors of CZP effectiveness (Supplementary Fig. 1). This study was conducted in compliance with the Declaration of Helsinki and was approved by the Ethics Committees of the respective institutions (Osaki Citizen Hospital, reference number: 20230313-36; Tohoku University Graduate School of Medicine, reference number: 2023–1–047)). The requirement for written consent from enrolled patients was waived according to local regulations.

Data collection

Baseline demographics and clinical information of patients with RA initiating CZP were retrospectively collected from electronic medical records: age, sex, disease duration, positivity and titer of anti-citrullinated protein antibody (ACPA) and RF, frequency and dose of concomitant methotrexate (MTX) and oral glucocorticoids (GCs) equivalent to prednisolone (PSL), number and class of b/tsDMARDs administered before starting CZP, values of C-reactive protein (CRP), tender joint count, swollen joint count, dose and duration of CZP, proportion of CZP initial loading, and reasons for CZP discontinuation.

Clinical evaluation

Reasons for CZP discontinuation included ineffectiveness, including primary or secondary non-response to CZP, adverse events, attainment of remission, and patient preference. Retention duration was defined as the period from CZP administration to withdrawal for all reasons in the total analysis population or non-response to CZP in the effective analysis population. As previously described [24], primary non-response was defined as no achievement of disease activity score 28 using CRP (DAS28-CRP) of ≤ 3.2 or clinical disease activity index (CDAI) of ≤ 10 without intensification of conventional synthetic DMARDs (csDMARDs) and/or GCs within 3–6 months after initiation of CZP. Furthermore, secondary non-response was defined as disease activity increased to DAS28-CRP of > 3.2, CDAI of > 10, or requirement of intensification of csDMARDs and/or GCs in patients who achieved DAS28-CRP of ≤ 3.2 or CDAI of ≤ 10. Predictive factors associated with ineffectiveness leading to CZP discontinuation were evaluated in the effectiveness analysis.

Statistical analysis

Data are expressed as medians with interquartile ranges (IQR) for continuous variables, and as numbers (%) for categorical variables. Continuous variables were compared using the Mann–Whitney U test, and categorical variables were compared using the chi-square test or Fisher’s exact test, as appropriate. Kaplan–Meier curves were constructed to calculate the retention rate of CZP associated with drug effectiveness, and the log-rank test was used to compare the curves. The optimal cutoff value for the RF titer to differentiate between the retention and discontinuation groups was determined using receiver operating characteristic (ROC) curve analysis. Cox proportional hazards models were used to determine the predictors of CZP discontinuation owing to ineffectiveness. Variables with P < 0.1 by univariate Cox regression analysis, as well as potential confounders (initial loading, concomitant MTX use, MTX dose, and treatment line) that could influence the effectiveness of CZP [12, 13, 25–27] were applied to the multivariate model. The adjusted hazard ratio (HR) with a 95% confidence interval (CI) was calculated. With regard to continuous variables, the increment of units for HR was based on that of 1 year for age at CZP initiation and disease duration, 100 U/mL for ACPA titer, 100 IU/mL for RF titer, 1 mg/week for MTX dose, 1 mg/day for PSL dose, 1 mg/dL for CRP levels, and 1 count for tender or swollen joints. All statistical analyses were performed using JMP version 10.2 Software (SAS Institute, Japan) and GraphPad Prism 7.03 (GraphPad Software, La Jolla, CA, USA). Statistical significance was set at P < 0.05.

Patient selection

Of the 107 patients, nine were excluded because of a lack of available data, and 98 patients were finally analyzed. During the observational period (median: 56.0 months, IQR: 36.0–76.0 months), 12 patients completely discontinued CZP treatment for the following reasons: patient preference, three; injection site reaction, two; angina pectoris, two; urinary tract infection, one; peritonsillar abscess, one; malignant lymphoma, one; depression, one; and drug rash, one. The median duration until withdrawal occurred was 17.5 (IQR: 5.3–45.5) months after CZP initiation. After excluding the 12 patients from the total analysis population, the effectiveness analysis population was identified (n = 86), of which 45 (52.3%) and 41 (47.7%) patients were divided into continuation and discontinuation groups, respectively. During the median follow-up duration of 56.0 (IQR: 36.0–76.0) months, 17 (41.5%) and 24 (58.5%) patients discontinued CZP because of primary and secondary failures, respectively.

Baseline demographics and clinical features

As shown in Table 1, majority of patients were females (87.8%). Median age at CZP initiation and disease duration were 56.0 (42.5–64.0) and 5.0 (2.0–8.2) years, respectively. Seventy-three (74.5%) patients had positive ACPA with median titers of 115.0 (44.6–500.0) U/mL, and 74 (75.5%) patients had positive RF with median titers of 137.7 (50.8–334.5) IU/mL. MTX was simultaneously administered to 60 (61.2%) patients at a median dose of 8.0 (8.0–10.0) mg/week. Frequency and median dose of concomitant PSL were 43.9% and 5.0 (2.6–7.8) of mg/day, respectively. Initial loading was administered in 73 (74.5%) patients. CZP was introduced as 1-, 2-, and ≥ 3-line biologics in 43 (43.9%), 31 (31.6%), and 24 (24.5%) patients, respectively. Distribution of b/tsDMARDs before CZP use was TNFi in 48 (50.0%) patients, interleukin-6 receptor inhibitor (IL-6Ri) in 18 (18.4%), T-cell co-stimulation modulator (abatacept) in 12 (12.2%), and Jak kinase inhibitor (JAKi) in 2 (2.0%). Median level of CRP was 1.2 (0.4–3.0) mg/dL. Median tender and swollen joint counts were 3.0 (2.0–6.0) and 3.0 (1.0–6.0), respectively. Additionally, patients who discontinued CZP for reasons other than ineffectiveness had a significantly higher proportion of b/tsDMARD failure than the effective analysis population (58.3% vs. 27.9%; P = 0.047); however, other baseline demographics and clinical features did not statistically differ between the two groups.

Table 1

Baseline demographics and clinical characteristics of 98 patients with rheumatoid arthritis who were administered CZP
	Total analysis population (n = 98)	Others^¶ (n = 12)	Effective analysis population (n = 86)		p value^†
	Total analysis population (n = 98)	Others^¶ (n = 12)	Continuation (n = 45)	Discontinuation (n = 41)	p value^†
Age at CZP initiation, years	56.0 (42.5–64.0)	62.0 (54.3–70.0)	56.0 (41.0–61.5)	55.0 (40.0–65.5)	0.39
Female, n (%)	86 (87.8%)	11 (91.7%)	39 (86.7%)	36 (87.8%)	> 0.99
Disease duration, years	5.0 (2.0–8.2)	2.2 (1.8–6.9)	4.0 (1.7–6.8)	5.0 (2.0–8.8)	0.34
ACPA positive, n (%)	73 (74.5%)	11 (91.7%)	32 (71.1%)	30 (73.2%)	> 0.99
ACPA titer, U/mL	115.0 (44.6–500.0)	78.7 (46.2–115.0)	105.6 (35.7–428.9)	241.2 (49.4–668.9)	0.21
RF positive, n (%)	74 (75.5%)	9 (75.0%)	33 (73.3%)	32 (78.1%)	0.14
RF titer, IU/mL	137.7 (50.8-334.5)	109.4 (30.0-608.0)	84.0 (43.0–207.0)	206.6 (95.3–439.5)	0.004
MTX use, n (%)	60 (61.2%)	7 (58.3%)	32 (71.1%)	21 (51.2%)	0.077
MTX dose, mg/week	8.0 (8.0–10.0)	8.0 (6.0–10.0)	10.0 (8.0–12.0)	8.0 (7.0–10.0)	0.22
PSL use, n (%)	43 (43.9%)	4 (33.3%)	19 (42.2%)	20 (48.8%)	0.67
PSL dose, mg/day	5.0 (2.6–7.8)	5.8 (2.1–15.4)	5.0 (2.5–5.0)	5.5 (3.1–8.0)	0.17
Initial loading, n (%)	73 (74.5%)	9 (75.0%)	37 (82.2%)	27 (65.9%)	0.091
Number of b/tsDMARDs used prior to CZP
0, n (%)	43 (43.9%)	3 (25.0%)	28 (62.2%)	12 (29.3%)	0.003
1, n (%)	31 (31.6%)	7 (58.3%)	11 (24.4%)	13 (31.7%)	0.48
≥ 2, n (%)	24 (24.5%)	2 (16.7%)	6 (13.3%)	16 (39.0%)	0.012
Class of b/tsDMARDs used prior to CZP
TNFi, n (%)	48 (50.0%)	7 (58.3%)	14 (31.1%)	27 (65.9%)	0.002
IL-6Ri, n (%)	18 (18.4%)	1 (8.3%)	4 (8.9%)	13 (31.7%)	0.013
CTLA4-Ig, n (%)	12 (12.2%)	2 (16.7%)	3 (6.7%)	7 (17.1%)	0.18
JAKi, n (%)	2 (2.0%)	0 (0.0%)	0 (0.0%)	2 (4.9%)	0.22
CRP, mg/dL	1.2 (0.4–3.0)	2.7 (0.5–4.7)	0.91 (0.4–3.2)	1.4 (0.2–2.9)	0.54
Tender joint count	3.0 (2.0–6.0)	2.0 (2.0–5.3)	3.0 (1.0–5.8)	4.0 (1.5–7.5)	0.11
Swollen joint count	3.0 (1.0–6.0)	2.0 (1.0–5.3)	3.0 (1.0–6.0)	3.0 (2.0–8.0)	0.12
Data are presented as median (interquartile range) or number (%).
^¶Others include patients who discontinued CZP due to reasons other than non-response to CZP.
^†The continuation group versus the discontinuation group by the Mann-Whitney U test, the chi-square test or the Fisher’s exact test, as appropriate.
ACPA, anti-citrullinated protein antibody; CRP, C-reactive protein; CTLA4-Ig, cytotoxic T lymphocyte-associated antigen-4-Ig; CZP, certolizumab pegol; b/tsDMARDs, biological/targeted synthetic disease-modifying antirheumatic drugs; IL-6Ri, interleukin-6 receptor inhibitor; JAKi, Jak kinase inhibitor; MTX, methotrexate; PSL, prednisolone; RF, rheumatoid factor; TNFi, tumor necrosis factor inhibitor.

Comparison between patients who continued or discontinued CZP due to ineffectiveness

We assessed differences in clinical parameters between patients continuing and discontinuing CZP due to lack of effectiveness (Table 1). The continuation group had significantly lower RF titer than the discontinuation group (84.0 [IQR: 43.0–207.0] vs. 206.6 [IQR: 95.3–439.5], P = 0.004), although no significant difference in the rate of RF positivity was observed between the two groups (73.3% vs. 78.1%, P = 0.14). The proportion of b/tsDMARDs-naïve population was significantly higher in the continuation group than that in the discontinuation group (62.2% vs. 29.3%, P = 0.003). Moreover, the continuation group was significantly lower in patients with history of ≥ 2 b/tsDMARDs, TNFi, and IL-6Ri than those in the withdrawal group (13.3% vs. 39.0%, P = 0.012; 31.1% vs. 65.9%, P = 0.002; 8.9% vs. 31.7%, P = 0.013, respectively). Although there was a trend towards a higher prevalence of MTX use (71.1% vs. 51.2%, P = .077) and initial loading (82.2% vs. 65.9%, P = .091) in the continuation group than that in the withdrawal group, the differences were not statistically significant.

Drug survivals in the overall population

Drug survival rates at 12, 24, 48, and 60 months in the total analysis population (n = 98) were 65.0%, 55.8%, 46.4%, and 40.2%, respectively, which were comparable to those in the effective analysis population (n = 86), excluding the 12 patients who withdrew CZP for reasons other than non-response (66.0% at 12, 59.3% at 24, 51.9% at 48, and 47.2% at 60 months) (Supplementary Fig. 2). Next, we analyzed the retention rates of CZP among groups divided according to different clinical features possibly associated with its effectiveness [12, 13, 25–27] in the effective analysis population. Drug survivals with and without MTX at 12, 24, and 60 months were 73.4% vs. 54.0%, 71.4% vs. 38.9%, and 55.6% vs. 34.6%, respectively (HR: 0.51, 95% CI: 0.27–0.98, P = 0.024) (Fig. 1a). Retention rates in patients with MTX of ≥ 8 mg/week were significantly longer than those in MTX of < 8 mg/week (73.5% vs. 58.8% at 12 months, 71.0% vs. 47.8% at 24 months, and 58.9% vs. 34.8% at 60 months, respectively) (HR: 0.53, 95% CI: 0.28–0.99, P = 0.047) (Fig. 1b). Patients receiving initial loading showed significantly lower discontinuation rates at 12, 24, and 60 months (71.5%, 64.4%, and 53.6%, respectively) than those who did not (50.0%, 44.4%, and 28.6%, respectively) (HR: 0.43, 95% CI: 0.20–0.92, P = 0.030) (Fig. 1c). Furthermore, retention rates in the b/tsDMARD-naïve groups were significantly higher than those in the b/tsDMARD-switch groups, with 79.1% and 54.3% at 12 months, 72.9% and 47.4% at 24 months, and 66.3% and 32.2% at 60 months, respectively, (HR: 0.39, 95% CI: 0.21–0.72, P = 0.003) (Fig. 1d).

Predictive factors for effectiveness associated with long-term continuation of CZP

The HR with 95% CI of the baseline variables when administering CZP was calculated using the Cox regression analysis to detect independent factors associated with CZP persistence attributable to its effectiveness in the effective analysis population. As shown in Table 2, the univariate analysis revealed that concomitant MTX use (HR: 0.50, 95% CI: 0.27–0.94, P = 0.031), MTX dose (HR: 0.92, 95% CI: 0.86–0.98, P = 0.013), initial loading (HR: 0.50, 95% CI: 0.26–0.98, P = 0.045), and no b/tsDMARDs exposure (HR: 0.38, 95% CI: 0.19–0.73, P = 0.003) were statistically significant variables associated with CZP retention. Because a negative correlation between the history and class of b/tsDMARDs was observed, the class of b/tsDMARDs was not applied to the multivariate analysis, considering collinearity. The multivariate model adjusted with ACPA and RF titer, concomitant MTX use, MTX dose, and initial loading demonstrated b/tsDMARD-naive as the most influential factor related to CZP discontinuation due to ineffectiveness (HR: 0.46, 95% CI: 0.22–0.90, P = 0.024). Next, the Cox regression analysis was performed to explore the predictive factors for effectiveness leading to CZP continuation in each group with or without a b/tsDMARD-naïve background. The multivariate analysis identified that IL-6Ri exposure was most associated with CZP discontinuation in the b/tsDMARD-switched population (HR: 2.46, 95% CI: 1.11–5.57, P = 0.027) (Supplementary Table 1). Furthermore, in the b/tsDMARD-naïve patients, multivariate analysis revealed that RF titer was the strongest predictor of CZP ineffectiveness (HR per 100 IU/mL increment: 1.25, 95% CI: 1.06–1.60, P = 0.009) (Supplementary Table 2).

Table 2

Predictive factors for ineffectiveness associated with CZP discontinuation in the effective analysis population
	Univariate		Multivariate
	HR (95% CI)	p value	HR (95% CI)	p value
Age at CZP initiation (years)	1.01 (0.99–1.04)	0.29
Female	1.10 (0.47–3.21)	0.83
Disease duration (years)	1.01 (0.96–1.04)	0.77
ACPA positivity	1.09 (0.56–2.28)	0.79
ACPA titer (×10² U/mL)	1.06 (0.991–1.12)	0.085	1.03 (0.96–1.09)	0.39
RF positivity	1.73 (0.82–4.26)	0.16
RF titer (×10² IU/mL)	1.06 (0.995–1.11)	0.067	1.04 (0.97–1.10)	0.27
MTX use	0.50 (0.27–0.94)	0.031	0.94 (0.23–3.46)	0.93
MTX dose (mg/week)	0.92 (0.86–0.98)	0.013	0.95 (0.82–1.10)	0.50
PSL use	1.03 (0.56–1.92)	0.90
PSL dose (mg/day)	1.04 (0.96–1.11)	0.33
Initial loading	0.50 (0.26–0.98)	0.045	0.77 (0.38–1.58)	0.47
b/tsDMARDs naïve	0.38 (0.19–0.73)	0.003	0.46 (0.22–0.90)	0.024
CRP (mg/dL)	1.12 (0.97–1.27)	0.11
Tender joint count	1.06 (0.98–1.14)	0.12
Swollen joint count	1.06 (0.97–1.13)	0.16
ACPA, anti-citrullinated protein antibody; b/tsDMARDs, biological/targeted synthetic disease-modifying antirheumatic drugs; CI, confidence interval; CRP, C-reactive protein; CZP, certolizumab pegol; HR, hazard ratio; MTX, methotrexate; PSL, prednisolone; RF, rheumatoid factor.
Supplementary Table 1. Predictive factors for ineffectiveness leading to CZP discontinuation in patients with previous b/tsDMARD exposure

Lower retention rate of CZP in b/tsDMARD-switch patients with previous IL-6Ri therapy

Because IL-6Ri exposure was the strongest contributor to CZP discontinuation in patients who failed first-line b/tsDMARDs, retention rates were stratified according to IL-6Ri to assess the extent to which it could influence CZP effectiveness. Patients with previous IL-6Ri treatment had significantly higher discontinuation rate compared to those without IL-6Ri (HR: 2.40, 95% CI: 1.04–5.57, P = 0.041). Median retention durations in the IL-6Ri and non-IL-6Ri groups were 5 and 39 months, respectively (Fig. 2a). Among the 46 patients treated with b/tsDMARDs, the proportion of history of ≥ 2 b/tsDMARDs was markedly significantly higher in the IL-6Ri group than that in the non-IL-6Ri group (15/17, 88.2% vs. 7/29, 24.1%; P < 0.0001) (Supplementary Table 3); however, among 22 patients with a history of ≥ 2 b/tsDMARDs, no significant differences in the discontinuation rates were observed between the IL-6Ri and non-IL-6Ri groups (11/15, 73.3% vs. 5/7, 71.4%; P > 0.99), indicating no correlation between increasing treatment line and CZP effectiveness in those populations.

Comparison of drug survivals by an optimal cut-off value of RF in the b/tsDMARDs-naive population

As the RF titer was an outstanding determinant of CZP effectiveness in patients taking b/tsDMARDs, an ROC curve analysis was performed to determine the optimal cut-off value of the RF titer demonstrating the highest sensitivity and specificity for predicting long-term CZP effectiveness. The cut-off value was determined to be 79.9 IU/mL (area under the curve, 0.76; P = 0.003). Finally, we calculated retention rates, stratified according to RF titer of 79.9 IU/mL. As shown in Fig. 2b, ≥ 79.9 IU/mL groups demonstrated significantly lower retention rate of CZP compared with < 79.9 IU/mL groups (HR: 6.09, 95% CI: 1.95–19.0, P = 0.007) in the b/tsDMARDs-naïve population. The retention rates in ≥ 79.9 vs. <79.9 IU/mL groups at 12, 24, and 60 months were 63.2% vs. 95.2%, 57.4% vs. 88.9%, and 44.7% vs. 88.9%, respectively. There were no statistical differences except for positivity and RF titer between patients with ≥ 79.9 and < 79.9 IU/mL (Supplementary Table 4).

This study revealed the long-term (median, 56.0 months) drug survival of CZP and identified the predictive factors of CZP effectiveness, leading to its continuation in clinical practice among Japanese patients with RA using real-world data. In the overall population, no history of b/tsDMARDs was associated with a better response to CZP, which displayed a 61% (HR: 0.39) reduced risk of CZP discontinuation due to ineffectiveness. More importantly, when patients were divided into two groups according to b/tsDMARD use, distinct factrs significantly affected the retention rates of CZP in each group. Prior IL-6Ri therapy increased the probability of treatment failure by more than two-fold (HR: 2.40) compared to those without a history of IL-6Ri in the population treated with b/tsDMARDs. In contrast, an RF of ≥ 79.9 IU/mL demonstrated approximately a six-fold (HR: 6.09) higher risk of discontinuing CZP compared with < 79.9 IU/mL in the population treated without b/tsDMARDs. These results could enable physicians to detect optimal features suitable for CZP administration in Japanese patients with RA.

Generally, drug efficacy in RA is prospectively estimated using composite measures, such as DAS28-CRP and CDAI. In recent years, retention rates have been frequently used as surrogate markers to evaluate the effectiveness of certain molecular-targeted DMARDs [28, 29]. Our multivariate analysis employing drug retention-related variables based on effectiveness in the overall population identified b/tDMARD-naïve status as an independent predictor, and among the b/tsDMARD-naïve patients, majority (> 65%) showed sustained retention of > 5 years. Previous studies also demonstrated that biologics-naïve predicted significantly better outcomes of CZP in European population [12–14, 27]. In a study [14], the retention curve in biologics-naïve patients was almost similar to our results; however, in other studies [12, 13], retention rates of 2 years after CZP initiation as the first biologic ranged between 40.1–60%, which was lower than that in the present study. This discrepancy is likely because retention rates in a real-world setting are affected by various factors, including adverse events, disease remission, patient preferences, and drug effectiveness. Moreover, treatment responses may be attributable to racial and ethnic differences [30]. Nevertheless, one of the conditions suitable for implementing CZP is biologic-naïve, as with other TNFis [31].

Multivariate analysis adjusted for concomitant MTX use, dose, and initial loading identified prior IL-6R blockade as the sole predictor of subsequent CZP discontinuation due to ineffectiveness (HR: 2.46). Paucity of real-world data are available to date for comparing TNFi effectiveness and individual non-TNFi following first-line IL-6Ri failure, and recent European Alliance of Associations for Rheumatology recommendations for the management of RA have not clearly stated which drugs should be administered after inadequate response to IL-6Ri [2]. In an observational multicenter registry in Japan, continuation rates due to ineffectiveness over 24 months were significantly higher for abatacept (82.2%) and JAKi (84.3%) than those for TNFi (59.5%) in tocilizumab-switched cases [32]. Furthermore, the incidence rates of treatment failure after first-line tocilizumab were lower for tofacitinib and abatacept than those for TNFi, except for etanercept, in a nationwide Korean study [33]. The current study did not compare CZP with other agents in patients who failed IL-6Ri; however, given the above findings, TNF inhibition with CZP may be insufficient to regulate the inflammatory processes of RA following IL-6R blockade in some patients.

RF has not been consistently shown to be predictive of the clinical response to TNFi in previous studies in which CZP was not evaluated [34, 35]. Recent accumulating evidence suggests that CZP exerts better outcomes than other TNFi in populations with high RF titers, but not in those with low titers [17, 18]. Although post-hoc analysis from six clinical trials focusing only on CZP demonstrated steady efficacy across baseline RF quartiles, remission rates at week 24 were likely to be numerically lower in early and established RA patients with the highest RF than in those with lower RF levels [36]. Moreover, in an observational study limited to b/tsDMARD-naïve status, median duration until CZP discontinuation was shorter in a higher RF group than that in a lower RF group (2.5 vs. 7.5 years, respectively) [18], which is consistent with our results. Collectively, these findings suggest that elevated RF could attenuate CZP effectiveness, but to a lesser extent than its effect on other TNFis.

Because the effect of autoantibodies on the pathogenesis of RA is an area under intensive study [37], it is valuable to speculate on the mechanisms by which RF affects CZP efficacy. This may be explained by involvement of the type I interferon (IFN-I) pathway. The IFN-I gene signature was higher in TNFi non-responders than that in TNFi-responders, with persistent post-treatment [38]. Furthermore, a strong positive correlation between serum IFN-α concentrations and RF titers was observed in early RA [39]. Importantly, the concept of cross-regulation between IFN-I and TNF-α in pathological conditions or in the course of disease progression has been currently proposed [40]. Taken together, increased RF, possibly indicating an immune state with a pathophysiological predominance of IFN signaling over TNF pathways, could lead to resistance to TNF inhibition.

This study has several limitations. First, this study was retrospective, and the sample size was small. Therefore, undetected confounding factors might have influenced the results, and we cannot exclude the possibility that it was underpowered to detect statistical differences, especially in the sub-analyses. Second, we did not evaluate analgesics, intra-articular injection of GCs, csDMARDs other than MTX, or adjustments in both PSL and DMRADs doses during the observational periods. Third, only two patients who received JAKi were included. Further studies are warranted to assess whether previous JAK inhibition affects subsequent treatment response to CZP. Nevertheless, this study is the first to identify the distinct determinants of sustained effectiveness of CZP based on the presence or absence of previously utilized b/tsDMARDs. These findings may help select patients suitable for CZP, resulting in personalized therapeutic strategies for RA.

In conclusion, our study demonstrated the long-term persistence of CZP in clinical practice among Japanese patients with RA and confirmed that no molecular-targeted therapies before CZP initiation were the strongest contributors to the increasing retention rates of CZP associated with effectiveness. Moreover, a high titer of RF (> 79.9 IU/mL) in the b/tsDMARD-naïve population or prior IL-6R inhibition in the b/tsDMARD-switch population showed significant correlations with non-response to CZP. Our findings would provide additional evidence for the optimal situation in which CZP is administered to improve disease outcomes.

Funding: None

Conflicts of interest:

The authors declare that they have no conflicts of interest.

Acknowledgement:

The authors thank Editage (www.editage.jp) for English language editing.

Author contributions:

TM conceived the study design. TM and OS contributed to acquisition, analysis, or interpretation of data. TM drafted the manuscript. All authors critically reviewed the manuscript and approved the submitted manuscript.

TM had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Ethics statement:

This study design was approved by the Ethics Committee of Osaki Citizen Hospital (reference number: 20230313-36) and Tohoku University Graduate School of Medicine (reference number: 2023–1-047). Written informed consent was waived due to the retrospective nature of the study.

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The authors declare no competing interests.

SupplementaryFig1.tif
Supplementary Figure 1 Patient selection flowchart in this study Among 107 patients with rheumatoid arthritis who initiated CZP (total enrolled population), total analysis population (n = 98) was established, excluding nine patients with missing data. Subsequently, 12 patients who discontinued CZP irrespective of drug efficacy were excluded to allow for a direct comparison between drug retention and CZP effectiveness, and an effectiveness analysis population (n = 86) was identified. CZP, certolizumab pegol.
SupplementaryFig2.tif
Supplementary Figure 2 Kaplan–Meier curves for retention rate of CZP in total patients included in this study or those excluded who withdrew CZP except for drug efficacy CZP, certolizumab pegol.
SupplementaryTables.docx

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Rheumatoid factor or interleukin-6 receptor inhibition predicts the long-term effectiveness of certolizumab pegol in Japanese patients with rheumatoid arthritis: A two-center retrospective study

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Abstract

Objectives

Methods

Results

Conclusions

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Main Points

INTRODUCTION

METHODS

Study design and patient selection

Data collection

Clinical evaluation

Statistical analysis

RESULTS

Patient selection

Baseline demographics and clinical features

Comparison between patients who continued or discontinued CZP due to ineffectiveness

Drug survivals in the overall population

Predictive factors for effectiveness associated with long-term continuation of CZP

Lower retention rate of CZP in b/tsDMARD-switch patients with previous IL-6Ri therapy

Comparison of drug survivals by an optimal cut-off value of RF in the b/tsDMARDs-naive population

DISCUSSION

Declarations

References

Additional Declarations

Supplementary Files

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