Comparing the effectiveness and safety of Abatacept and Tocilizumab in elderly patients with rheumatoid arthritis.

BACKGROUND: The number of biological DMARDs (bDMARDs) used in elderly patients with rheumatoid arthritis (RA) has increased in recent years. We aimed to compare the drug retention rates and safety of abatacept (ABT) and tocilizumab (TCZ) in elderly patients with RA.
METHODS: A total 125 elderly patients with RA (>65 years) who began therapy with either ABT (n = 47) or TCZ (n = 78) between 2014 and 2021 at our institute were enrolled. We compared the drug retention rate and clinical response at 24 weeks between elderly patients with RA treated with ABT and those treated with TCZ. Adverse events (AEs) and the reasons for drug discontinuation were assessed.
RESULTS: There was no significant difference in demographic characteristics except for the use of glucocorticoid between the ABT and TCZ groups. There was no significant difference in the drug retention rate between the ABT and TCZ groups. Furthermore, there was no significant difference in the discontinuation rates due to the lack of effectiveness between these two groups. The proportions of the patients archiving low disease activity at 24 weeks did not differ significantly between the two groups. Whereas, the discontinuation rates due to AEs, including interstitial lung disease (ILD), seemed higher in the TCZ group than in the ABT group. In TCZ-treated group, the concomitant use of methotrexate (MTX) significantly increased the incidences of AEs leading to the discontinuation of TCZ. Whereas these was no significant impact of concomitant use of MTX on the incidences of AEs leading to discontinuation in ABT-treated group.
CONCLUSIONS: In elderly patients with RA treated with ABT and TCZ, drug retention rates were equivalent between the two groups. There were some differences in safety profiles between ABT and TCZ, and the rates of discontinuation due to AEs, including ILD, seem to be lower with ABT than with TCZ in elderly patients with RA.

Background

The prevalence of elderly patient with rheumatoid arthritis (RA) in elderly patients has been increasing, and the peak age at disease onset was found to be 60–69 years in JAPAN [1]. Elderly patients with RA seem to have characteristic clinical features and biological profiles that differ from those of younger patients with RA [2]. The management of elderly patients with RA seems challenging, since treatment approaches must be balanced against adverse events due to the many comorbidities associated with old age, including chronic lung disease and chronic kidney disease [3]. Elderly patients with RA who may have different RA phenotypes, it seems important to know which biological disease-modifying antirheumatic drugs (bDMARDs) can efficiently improve the RA disease activity in elderly patients [4].

There are several cohort studies comparing the effectiveness of bDMARDs among elderly patients with RA [5]. Abatacept (ABT) selectively inhibits T cell co-stimulatory signals, resulting in the suppression of inflammatory cytokines [6]. The incidence of serious infections seems lower among patients receiving abatacept than among those receiving other biological agents such as tumor necrosis factor inhibitors (TNFi) or interleukin-6 (IL-6) receptor antibodies [7]. Furthermore, real-world data have demonstrated that ABT treatment is associated with a lower risk of infections than treatment with other bDMARDs [8]. In contrast, significantly higher serum levels of IL-6 and lower serum levels of TNF-α were detected in elderly-onset rheumatic arthritis (EORA) than in young-onset RA, suggesting that IL-6 might be an important inflammatory mediator in elderly patients with RA [9].

Therefore, it is interesting to compare the effectiveness and safety of TCZ and ABT in elderly patients with RA who are intolerant to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). However, real-world data on the effectiveness and safety of TCZ and ABT in elderly patients with RA are limited. Given that drug retention rates can be influenced by both the safety and effectiveness of bDMARDs, we hypothesized that comparisons of these two bDMARDs are reasonable to estimate their usefulness in elderly patients with RA. From this viewpoint, this study aimed to investigate drug retention and reasons for discontinuation of ABT and TCZ among elderly patients with RA taking these two agents in an observational cohort study.

Materials and methods

Patients and study design

We conducted a retrospective cohort study at the Department of Rheumatology, Fukushima Medical University Hospital and Japanese Red Cross Fukushima hospital and Ohta Nishinouchi Hospital. Among 1148 elderly patients (age ≥65 years; Female 796, Male 352) diagnosed with RA during the study period (between May, 2014 and July, 2021), 125 consecutive elderly (age ≥65 years) patients who were initiated with ABT or TCZ due to inadequate response to at least one or more csDMARDs were enrolled. All patients were diagnosed as having RA according to the 2010 American College of Rheumatology (ACR) /European League Against Rheumatism (EULAR) classification criteria for RA [10] and be continuously followed up until 24 weeks after initiation of ABT or TCZ. The study was approved by the Institutional Review Board of Fukushima Medical University (No.29281), and Japanese Red Cross Fukushima Hospital and Ohta Nishinouchi Hospital.

Clinical evaluations

At the start of treatment, baseline data were collected from medical records, including demographics, clinical data (disease duration, presence of the anti-citrullinated protein/peptide antibody [ACPA] antibody and rheumatoid factor [RF]), evaluations of disease activity (swollen joint count [SJC], tender joint count [TJC], patient global assessment [PtGA], physician global assessment [PGA]), and C-reactive protein [CRP], and information of treatments (current glucocorticoid and MTX doses, previous use of bDMARDs). Treatment was at the discretion of the attending physician, based on the clinical conditions and patient’s intentions. Disease activity were evaluated based on disease Activity Score-28 (DAS28)-CRP and clinical disease activity index (CDAI). We divided the patients into those at remission (DAS28-CRP < 2.6) and those in non-remission as follows, low disease activity (LDA): 2.6 ≤ DAS28-CRP < 3.2, moderate disease activity (MDA): DAS28-CRP 3.2–5.1, high disease activity (HDA): DAS28-CRP > 5.1 [11]. With respect to the CDAI disease activity categories, HDA is defined as a CDAI >22, MDA as a CDAI >10 and ≤22, LDA as a CDAI ≤10 and >2.8, and remission as a CDAI ≤2.8 [12].

Follow-up

Serial assessments of disease activity including laboratory and treatment-related information were collected at every 4 weeks after the initiation of ABT and TCZ. If treatment was discontinued, the reasons for discontinuations were recorded. Clinical response was evaluated based on disease activity after 24 weeks from the start of ABT and TCZ. We compared the proportions of archiving LDA or remission between elderly patients initiating with ABT or TCZ [13]. To evaluate the appropriate therapeutic effect of ABT and TCZ, patients who had discontinued due to adverse events until 24 weeks were excluded for the evaluation of clinical response, and those who discontinued due to inadequate response were classified as HDA cases. AEs that had caused ABT or TCZ discontinuation were record in detail. Decisions to discontinue of ABT and TCZ due to AEs were determined carefully by 2 rheumatologists based on the evaluation of clinical findings, laboratory data and radiological examinations. If there were obvious causal relationships between AEs and the use of these bDMARDs, the discontinuation was decided.

Statistical analysis

Continuous variables were showed as mean ± standard deviation or median (interquartile range) and categorical variables were sowed as frequency (percentage). The chi-squared test was used to compare categorical variables, and the Mann-Whitney U test was used to compare continuous variables. Drug retention was analyzed using Kaplan–Meier plots and assessed using the log-rank test. Cumulative incidences of discontinuation due to lack of effectiveness or adverse effects were compared using the Log-rank test for the Kaplan-Meier model. Statistical analyses were performed using the software of SPSS Statistics (version 25.0 for Windows, Chicago, IL, USA). Two–tailed p values <0.05 were considered indicative of statistical significance.

Results

Baseline characteristics of elderly RA patients

Among 1148 elderly (>65 years) RA patients registered in our cohort study, 125 (10.9%) who were on either ABT (n = 47) or TCZ (n = 78) during the observational period were enrolled (Fig 1). Relatively few patients were treated with ABT. The characteristics of the patients in each group are shown in Table 1. The proportion of patients treated with glucocorticoids (GCs) was significantly lower in the TCZ group than in the ABT group. Otherwise, there was no significant between-group difference between the two groups with respect to the other variables.

Fig 1

Flowchart of patient recruitment in our cohort.

Table 1

Baseline characteristics between ABT group and TCZ group in elderly RA patients.

	ABT (n = 47)	TCZ (n = 78)	p-Value
Age (years), median (IQR)	74 (68–78)	75 (70–81)	0.220
Female, n (%)	37 (78.7)	54 (69.2)	0.172
Intravenous/subcutaneous injection, n (%)	36 (76.6)/11 (23.4)	34 (43.6)/44 (56.4)	<0.001
Disease duration (years), median (IQR)	7 (0.9–15.0)	7 (1.0–14.0)	0.919
RF-positive, n (%)	39 (83.0)	55 (70.5)	0.092
ACPA-positive, n (%)	35 (74.5)	60 (76.9)	0.861
CRP (mg/dL), median (IQR)	1.93 (0.78–4.30)	1.17 (0.29–3.88)	0.289
SJC, median (IQR)	3 (1.5–5.5)	2 (0.0–6.0)	0.407
TJC, median (IQR)	2 (0.5–4.5)	3 (1.0–8.0)	0.204
PtGA (mm), median (IQR)	56.0 (30.5–80.0)	49.0 (31.8–66.3)	0.478
PGA (mm), median (IQR)	60.0 (33.5–72.5)	48.0 (37.0–58.0)	0.202
DAS28-CRP, median (IQR)	3.79 (2.80–4.29)	3.52 (2.45–4.76)	0.828
CDAI, median (IQR)	16.7 (8.6–31.0)	16.7 (7.6–26.0)	0.802
eGFR (mL/min), median (IQR)	71.0 (57.7–82.5)	75.5 (60.9–84.1)	0.522
CKD (eGFR<60), n (%)	13 (27.7)	19 (24.4)	0.732
Interstitial lung disease, n (%)	14 (29.8)	17 (21.8)	0.480
MTX use, n (%)	22(46.8)	31 (39.7)	0.439
MTX dose (mg/week)	6.0 (6.0–8.0)	7.0 (4.0–8.0)	0.941
Other csDEMARDs, n (%)	21 (44.7)	22 (28.2)	0.060
GC use, n (%)	29 (61.7)	32 (41.0)	0.025*
GC dose (mg/day)	5.0 (2.5–7.5)	5.0 (4.0–7.9)	0.371
Prior bDMARDs use, n (%)	12 (25.5)	25 (32.0)	0.439
Prior TNFi use, n (%)	11 (23.4)	25 (32.0)	0.301
Follow up periods (month), median (IQR)	28 (10–42)	24 (12–45)	0.661

ABT: abatacept; TCZ: tocilizumab; RA: rheumatoid arthritis; IQR: interquartile range; RF: rheumatoid factor; ACPA: anti-citrullinated peptide antibody; CRP: c-reactive protein; SJC: swollen joint count; TJC: tender joint count; PtGA: patient global assessment; PGA: physican global assessment; DAS28: disease activity score 28; CDAI: clinical disease activity index; eGFR: estimated glomerular filtration rate; CKD: chronic kidney disease; csDMARDs: conventional synthetic disease modifying anti-rheumatic drugs; MTX: methotrexate; GC: glucocorticoid; bDMARDs: biological disease modifying anti-rheumatic drugs; TNFi: tumor necrosis factor inhibitors

* p<0.05.

Drug effectiveness at 24 weeks of follow-up

Proportions of patients who archived LDA or remission based on a DAS28-CRP or CDAI after 24 weeks were compared between elderly RA patterns initiated with ABT and TCZ. The proportion of disease activity categorized as remission, LDA, MDA and HDA at 24 weeks after initiation ABT or TCZ were shown in Fig 2. On week 24, there was no significant difference in the proportions of patients who achieved LDA or remission between the two groups (DAS28-CRP; ABT; 73.9% vs. TCZ; 80.5%, p = 0.396, CDAI; ABT; 69.6% vs. TCZ; 66.7%, p = 0.742). In the AMPLE study, the efficacy of ABT was shown to be higher in patients with RA with high titers of the ACPA [14]. Therefore, we compared the proportions of patients who achieved LDA or remission between elderly patients with RA with ACPA (>4.5 U/ml) or without ACPA in ABT-treated group. There was no significant difference in the proportions of patients who achieved LDA or remission between elderly patients with and without the positivity of ACPA in ABT-treated group (Fig 3A). Similarly, there was no significant difference in the proportions of patients who achieved LDA or remission between elderly patients with RA with or without the positivity of ACPA in TCZ-treated group (Fig 3A). In addition, we compared the proportions of patients achieving LDA or remission in the ABT and TCZ-treated group for elderly RA patients according to the use of MTX. There was no significant difference in the proportions of patients who achieved LDA or remission between elderly patients with and without MTX in ABT and TCZ-treated group (Fig 3B).

Fig 2

Proportions of patients who archived LDA or remission based on a DAS28-CRP or CDAI between elderly patients initiating with ABT and TCZ at 24 weeks.

Disease activity was classified into four categories as HDA, MDA, LDA, remission based on DAS28-CRP and CDAI. There was no significant difference in the proportions of archiving LDA or remission between elderly patients initiating with ABT or TCZ.

Fig 3

Proportions of patients who archived LDA or remission based on CDAI between elderly patients initiating with ABT or TCZ at 24 weeks according to the presence of ACPA or the concomitant use of MTX.

Disease activity was classified into four categories as HDA, MDA, LDA, remission based on CDAI. (A) There was no significant difference in the portions of archiving LDA or remission between elderly patients initiating with ABT or TCZ according to the presence of ACPA. (B) There was no significant difference in the portions of archiving LDA or remission between elderly patients initiating with ABT or TCZ according to the use of MTX.

Drug overall retention rates

The overall drug retention rates of ABT and TCZ are shown in Fig 4. In ABT group, the rates of reasons for drug discontinuation were lack of efficacy 12 (25.5%) and AEs 6 (12.8%). In TCZ group, the rates of reasons for drug discontinuation were lack of efficacy 14 (17.9%) and AEs 17 (21.8%). There was no significant difference in the drug retention rates between the two groups. The cumulative incidence of drug discontinuation due to lack of effectiveness was also compared between the two groups, and no significant difference in this parameter was found between the two groups (Fig 5).

Fig 4

Kaplan–Meier curve related to the overall cumulative drug retention rate of ABT and TCZ in elderly patients initiating these bDMARDs.

There was no significant between-group difference with respect to the drug retention rates.

Fig 5

The cumulative incidences of discontinuation of ABT or TCZ due to lack of effectiveness.

There were no significant differences in the incidences of drug discontinuation due to lack of effectiveness between ABT and TCZ groups.

Rates of discontinuation due to AEs

Among the 47 patients who initiated with ABT, 6 (12.8%) discontinued the drug due to AEs. Among the 78 patients initiated with TCZ, 17 (21.8%) discontinued the drug due to AEs. The patients experienced no severe or life-threatening AEs in both groups. The total rates of discontinuation due to AEs were higher in the TCZ group than in the ABT group in elderly patients with RA; however, there was no significant difference between these two groups (Table 2). These AEs leading to the discontinuation of bDMARDs included intestinal lung disease (ILD, n = 5), infections (n = 5) hematological disorders (n = 3), malignancy (n = 4), allergic reactions (n = 2), renal impairment (n = 1), liver dysfunction (n = 1), and cardiovascular event (n = 1). The most frequent AE leading to the discontinuation of TCZ in elderly RA patients was ILD. Among 5 patents complicated with ILD in TCZ group, 2 patients presented with the exacerbation of pre-existing ILD and 4 patients with the concomitant use of MTX. In contrast, ILD was not observed as an AE leading to the discontinuation of ABT in elderly RA patients. We compared the incidence of discontinuation due to AEs between the ABT and TCZ groups using the Kaplan-Meier curve. The incidence of discontinuation due to AEs was higher in the TCZ group than in the ABT group; however, there was no statistically significant difference in this parameter between the two groups (Fig 6).

Table 2

All adverse events and adverse events lead to drug discontinuation in ABT group and TCZ group.

	AEs with drug discontinuation (Whole AEs)
	ABT (n = 47)	TCZ (n = 78)	p-Value
Intestinal lung disease	0 (0)	5 (5)	0.090
Infection	2 (9)	3 (8)	0.910
Malignancy	1 (1)	3 (3)	0.516
Renal impairment	1 (1)	0 (0)	0.376
Liver dysfunction	0 (0)	1 (2)	0.624
Hematological disorder	1 (3)	2 (3)	0.684
Allergic reaction	0 (0)	2 (2)	0.387
Cardiovascular event	0 (0)	1 (2)	0.624
Hypothyroidism	1 (1)	0 (0)	0.376
Total	6 (15)	17 (25)	0.207

AEs: adverse events; ABT: abatacept; TCZ: tocilizumab

* p<0.05.

Fig 6

The cumulative incidences of discontinuation of ABT or TCZ due to adverse.

There were no significant differences in the incidences of drug discontinuation due to AEs between ABT and TCZ groups.

Rates of discontinuation due to AEs according to the use of MTX

We compared the demographic data between elderly RA patients who did and did not discontinue bDMARDs due to AEs (Table 3). We found that the use of MTX seems to be higher in patients discontinued bDMARDs due to AEs, however, there was no significant difference. The rates of combination use of MTX plus TCZ were significantly higher in patients who discontinued bDMARDs due to AE. We compared the incidence of discontinuation due to AEs according to the use of MTX using the Kaplan-Meier curve. As show in Fig 7A, the incidences of discontinuation of TCZ due to AEs were significantly higher in elderly RA patients with the use of MTX compared to those without use of MTX. Whereas there was no significant difference in the incidences of discontinuation of ABT between elderly RA patients with or without use of MTX (Fig 7B). We also compared the rates of each adverse event leading to the discontinuation of bDMARDs according to the use of MTX. In ABT group, there was no significant difference in the rates of each adverse events between elderly RA patients with and without use of MTX. In TCZ group, the rates of ILD were higher in elderly RA patients with the use of MTX compared to those without use of MTX, however, there was no statistical difference.

Table 3

Baseline characteristics of elderly RA patients with the discontinuation of bDMARDs due to AEs.

	AEs (n = 23)	Non-AEs (n = 102)	p-Value
Age (years), median (IQR)	70 (66–77)	73 (68–78)	0.531
Female, n (%)	15 (65.2)	76 (74.5)	0.366
Disease duration (years), median (IQR)	7 (3–12)	7 (1–16)	0.958
RF-positive, n (%)	19 (82.6)	77 (75.5)	0.521
ACPA-positive, n (%)	14 (60.9)	80 (78.4)	0.145
CRP (mg/dL), median (IQR)	2.11 (0.76–3.85)	1.43 (0.49–3.95)	0.461
DAS28-CRP, median (IQR)	3.12 (2.67–3.72)	3.89 (2.58–4.80)	0.370
CDAI, median (IQR)	16.7 (9.4–26.0)	16.8 (12.0–42.4)	0.787
eGFR (mL/min), median (IQR)	60.0 (46.0–83.0)	72.4 (61.5–82.6)	0.157
Interstitial lung disease, n (%)	7 (30.4)	24 (23.5)	0.505
bDMARDs use
ABT, n (%)	6 (26.1)	41 (40.2)	0.207
TCZ, n (%)	17 (73.9)	61 (59.8)	0.207
ABT/MTX, n (%)	3 (13.0)	19 (18.6)	0.525
TCZ/MTX, n (%)	11 (47.8)	21 (20.6)	0.007*
MTX use, n (%)	14 (60.8)	40 (39.2)	0.058
GC use, n (%)	13 (56.5)	48 (47.1)	0.412

RA: rheumatoid arthritis; bDMARDs: biological disease modifying anti-rheumatic drugs; AEs: adverse events; IQR: interquartile range; RF: rheumatoid factor; ACPA: anti-citrullinated peptide antibody; CRP: c-reactive protein; DAS28: disease activity score 28; CDAI: clinical disease activity index; eGFR: estimated glomerular filtration rate; ABT: abatacept; TCZ: tocilizumab; MTX: methotrexate; GC: glucocorticoid

* p<0.05.

Fig 7

The cumulative incidence of the discontinuation of ABT or TCZ due to AEs were compared in elderly RA patients group according to the concurrent MTX use.

(A) The incidences of the discontinuation of TCZ due to AEs were significantly higher in elderly RA patients with the use of MTX compared to those without the use of MTX. (B) There were no significant differences in the incidences of the discontinuation of ABT due to AEs between elderly RA patients group according to the concurrent MTX use.

Finally, we performed the same analysis subjected the selected EORA (more than 60 years) RA patients (n = 85). Similarly, there was no significant difference in the overall cumulative drug retention rates of ABT and TCZ in these EORA patients initialing these biologics (Fig 8). The rates of discontinuation of these biologics due to AEs were significantly higher in TCZ group compared to those in ABT group (Fig 9). There was no difference in the rates of ABT discontinuation due to AEs between these EORA patients with or without use of MTX. Whereas, the rates of TCZ discontinuation due to AEs were significantly higher in these EORA patients with the use of MTX compared to those without the use of MTX (Fig 10).

Fig 8

Kaplan–Meier curve related to the overall cumulative drug retention rate of ABT and TCZ in EORA (more than 60 years) patients initiating these bDMARDs.

There was no significant between-group difference with respect to the drug retention rates.

Fig 9

The cumulative incidences of discontinuation of ABT or TCZ in EORA patients due to adverse.

The rates of discontinuation of these biologics due to AEs were significantly higher in TCZ group compared to those in ABT group.

Fig 10

The cumulative incidence of the discontinuation of ABT or TCZ due to AEs were compared in EORA group according to the concurrent MTX use.

(A) The incidences of the discontinuation of TCZ due to AEs were significantly higher in EORA patients with the use of MTX compared to those without the use of MTX. (B) There were no significant differences in the incidences of the discontinuation of ABT due to AEs between EORA patients group according to the concurrent MTX use.

Discussion

The proportion of elderly patients with RA has increased, and these patients often have multiple comorbidities, which makes it difficult to treat them using bDMARDs [15]. In clinical trials, ABT has shown similar efficacy to other bDMARDs [16]. Furthermore, ABT treatment has been shown to be is efficacious in the treatment of elder patients with RA [17]. In contrast, previous reports have demonstrated that elderly patients with RA have higher serum levels of interleukin (IL-6), suggesting that IL-6-targeting therapy could be one of the viable therapeutic options in elderly patients with RA [18]. However, elderly patients may not be likely to participate in clinical trials of bDMARDs, which explains the scarcity of evidence of the effectiveness of TCZ or ABT in the elderly patients with RA. In this observational study involving the elderly (aged >65 years) patients with RA, we compared the effectiveness and safety of ABT and TCZ in the elderly patients with RA. Our study demonstrated the equivalent drug relation rates of ABT and TCZ in elderly patients with RA on these bDMARDs. In terms of the disease activity, our findings demonstrated that the degree of clinical response was comparable between elderly patients with RA taking ABT and those taking TCZ. Biological factors, including seropositivity for autoantibodies, may affect the effectiveness of bDMARDs in patients with RA [19]. It has been demonstrated that the titers of the ACPA influence the effectiveness of ABT in clinical trials [14]. However, our data demonstrated that the effectiveness of ABT and TCZ groups were not significantly influenced by the ACPA positivity in elderly patients with RA.

Previous studies reported that the drug retention rates for TCZ and the rates of discontinuation due to AEs were shown to be similar between elderly (≧65 years) patients and non-elderly (<65 years) patients [20]. In our data, elderly patients with RA treated with TCZ experienced higher rates of discontinuation of TCZ due to AEs compared to those with ABT in our study. Our data do not allow us to give any causal explanation for the higher rates of discontinuation of TCZ due to AEs. In our data, elderly patients with RA receiving MTX tend to have higher rates of discontinuation of TCZ due to AEs. Among the AEs leading to the discontinuation of TCZ, ILD was the most frequent.

The risk of AEs may influence therapeutic decision-making, including the choice of bDMARDs [21]. Our data demonstrated the rates of discontinuation due to lack of effectiveness were comparable between elderly patients with RA initiated with ABT and TCZ. However, the rates of discontinuation due to AEs were relatively higher in the TCZ group than in the ABT group. Recent real-world data indicated that the rates for TCZ discontinuation due to the loss of efficacy and AEs were similar between TCZ monotherapy and combination therapy with MTX [22]. However, our data indicated that the rates of discontinuation due to AEs were significantly higher in elderly RA patients receiving TCZ plus MTX compared to those receiving TCZ monotherapy. In accord to our data, recent meta-analysis demonstrated that TCZ in combination with MTX is associated with a small but significantly increased risks with AEs [23]. It is possible that the comorbidities associated with elderly RA patients, may explaine the high rates of discontinuation due to AEs in our patients receiving MTX and TCZ.

The bDMARDs have been proposed to be a potential triggering factor for the acceleration of pre-existing ILD [24]. Among bDMARDs, TNFi and TCZ have been more commonly implicated in the pathogenesis of RA-related ILD than ABT and RTX [25]. In line with these reports, our data suggest that the use of ABT seems to be safe regarding the risk of worsening ILD in elderly RA patients. However, the precise mechanism by which ABT influences the ILD worsening in patients with RA has not yet been elucidated. Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) blockers have been reported to induce immune-mediated pneumonitis [26]. The current evidence suggests the effectiveness and safety of ABT treatment in patients with RA with ILD [27]. A recent large-scale multicenter study on patients with RA with ILD demonstrated that ABT seems to be an effective and safe treatment option for these patients [28, 29]. Further studies are needed to determine whether ABT has a protective effect against RA-related ILD in elderly patients with RA.

Elderly patients with RA seem to have a characteristic pattern with a more acute onset, systemic involvement, and worse functional outcomes [30]. However, concerns about AEs may influence therapeutic decisions with clinicians often preferring a less aggressive approach in elderly patients [31]. Our data suggest that either ABT or TCZ could be an appropriate therapeutic choice for elderly patients with RA disease activity; however, risk-benefit profiles should be carefully assessed. Further large-scale clinical studies in elderly patients with RA are needed to elucidate the more detailed risk-benefit profiles of ABT and TCZ.

Nevertheless, our study has several limitations. First, this was a retrospective observational study, and the study design may have might have affected the evaluation of treatment effectiveness. Second, the choice of treatment and decision to discontinue were made at the discretion of each rheumatologist, with no standardized protocol. Third, the sample size was relatively small. Fourth, marked reductions in the erythrocyte sedimentation rate and CRP levels were observed during TCZ treatment, which may or may not have corresponded to changes in other clinical signs and symptoms.

Conclusions

The results of our study demonstrated that ABT and TCZ have similar clinical responses and drug retention rates in elderly patients in a real-world setting. Whereas, the rates of discontinuation due to AEs, including ILD, seem to be lower in elderly patients with RA taking ABT than in those taking TCZ. Furthermore, large-scale prospective studies are necessary to determine whether ABT exerts more protective effects against ILD than other bDMARDs in elderly patients with RA.

(XLSX)

Click here for additional data file.

14 Jul 2022

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Masataka Kuwana, MD, PhD

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: No

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors compared the efficacy and safety between abatacept (ABT) and tocilizumab (TCZ) in elderly patients with rheumatoid arthritis (RA). The focusing point of this study is important and interesting in the era of ageing society. The authors concluded that drug retention rates were equivalent between ABT and TCZ, but the rates of discontinuation due to adverse event (AE) seemed to be lower with ABT than TCZ in elderly patients with RA. However, this study contains several serious concerns.

major

1. The authors should make a strict distinction between the terms of “Elderly-onset RA” and “Elderly RA”. These two terms refer to different population of RA (i.e the former refers to RA diagnosed at age of 65 or older, and the latter refers to patients who are currently 65 years or older regardless of the age of RA onset.) and which population should be targeted depends on the aim of the study, however, the authors use these terms confusingly. Therefore, the authors should review the design of the study and definition of patients depending on the aim of this study and revise the manuscript.

2. The authors showed all AEs leading to the discontinuation of ABT or TCZ in Table 2, but some AEs (ILD, liver dysfunction, renal dysfunction, cardiovascular disease, hypothyroidism) are generally unlikely to be associated with ABT or TCZ administration. Thus, it is questionable whether those AEs are due to these drug administrations and discontinuation of ABT or TCZ were necessary. Thus, the author should add explanations about detailed situation of each AE.

3. The authors highlighted the risk of ILD in the TCZ group, but it is not well verified or described. First, it is necessary to describe whether the ILDs were new occurrences after the initiation of TCZ or exacerbations of already diagnosed. Also, effect of MTX should be considered.

4. Regarding efficacy, the authors only showed achieving rate of low disease activity according to CDAI and DAS28-CRP at 24 weeks. When I read the method (P7L2-5), it seems that this did not include remission. It is desirable to analyze it including remission to evaluate effectiveness of the treatments. The authors should also show the longitudinal changes of score of CDAI and DAS28-CRP, proportion of the category of each disease activity (remission, low-, moderate-, high-disease activity), each component of composite measures, if possible.

5. Please describe summary of rate of reasons for drug discontinuation in ”Drug overall retention rates” section in P11.

6. AEs should be listed as a whole AE and then divided into AEs that led to drug discontinuation and AEs that did not.

7. The author excluded patients with no history of csDMARDs in Figure 1. What is the reason for excluding these patients?

8. The authors should add more detail clinical characteristics at the time of initiation of ABT or TCZ in Table 1. Each component of composited measures (SJC, TJC, PtGA, PGA), concomitant use of csDMARDs other than MTX, proportion of chronic kidney disease (eGFR<60), dose of glucocorticoid, types of used bDMARDs should be added.

9. Table 1 showed 12 patients with ABT group and 25 patients with TCZ group have ever used prior bDMARDs use. Is that mean are all prior bDMARDs TNF inhibitors? If not, it is necessary to describe the person who used both ABT and TCZ during the period.

Minor

1. Please correct abbreviations in the manuscript and figures. Abbreviations should be defined at first mention and used consistently thereafter, but it has not complied with frequently (ex. Adverse event (AE), low disease activity (LDA), abatacept (ABT, ABA) etc.).

2. “In the matched analysis,・・・・(P2L12, in abstract)” is not appropriate sentence because it may mislead that background were adjusted by using Propensity score matching etc.

3. In P8-9, check and correct the results for the rate of glucocorticoid use, as the results are opposite in the text and in Table 1.

4. In Table 3, the number of MTX users in the AE group is incorrect.

Reviewer #2: This study compared efficacy and safety of Abatacept and Tocilizumab in elderly patients with rheumatoid arthritis and showed comparable efficacy between both agents. On the other hand, the rates of discontinuation due to AEs, including ILD, seem to be lower with ABT than with TCZ in elderly patients with RA.

Major comments

The reviewer has a concern with the inclusion criteria.

#1 This study enrolled elderly (age ≥65 years) patients, irrespective of onset age with a mean of 7 years. Onset age is one of the important factors to determine clinical features including therapeutic responses. The reviewer is afraid that the authors confuse clinical features of elderly RA patients with those of elderly onset RA (EORA) patients. For example, the author described “Elderly patients with RA seem to have a characteristic pattern with a more acute onset, systemic involvement, and worse functional outcomes” (P19, L14-15), but this report compared EORA patients with young onset RA patients. The reviewer suggests analyzing the data by stratifying onset age or focusing those in patients having onset age over 60 years old.

#2 This study applied the 1987 ACR classification, but not 2010 ACR/EULAR, in spite of the study duration from 2014 to 2021. The reviewer is afraid that the inclusion criteria missed some of elderly onset RA patients. The reviewer suggests adding the data when the patients are enrolled based on the 2010 ACR/EULAR criteria.

Minor comments

#3 The reviewer suggests showing the administration routes and the standard dose of ABT and TCZ, because the standard dose of TCZ is different among countries. In addition, the interval of subcutaneous injection with TCZ can be shortened to one week. The reviewer is also interested in how often the interval is shortened because of the insufficient efficacy.

#4 Table 1 shows 25.5% of patients treated with ABT and 31.3% of those with TCZ have received prior bDMARD The reviewer is afraid it is hard to interpret the data in patients who had a switch from ABT to TCZ or TCZ to ABT. To avoid the complexity, the reviewer suggests showing the data in patients who received ABT or TCZ as the first bDMARD.

#5 spelling error

“the ACPA possibilities” (P17, L15) => positivity

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Mitsuhiro Takeno

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

28 Aug 2022

Reviewer #1: The authors compared the efficacy and safety between

abatacept (ABT) and tocilizumab (TCZ) in elderly patients with

rheumatoid arthritis (RA). The focusing point of this study is important

and interesting in the era of ageing society. The authors concluded that

drug retention rates were equivalent between ABT and TCZ, but the rates

of discontinuation due to adverse event (AE) seemed to be lower with ABT

than TCZ in elderly patients with RA. However, this study contains

several serious concerns.

major

1. The authors should make a strict distinction between the terms of “

Elderly-onset RA” and “Elderly RA”. These two terms refer to different

population of RA (i.e the former refers to RA diagnosed at age of 65 or

older, and the latter refers to patients who are currently 65 years or

older regardless of the age of RA onset.) and which population should be

targeted depends on the aim of the study, however, the authors use these

terms confusingly. Therefore, the authors should reviewthe design of the

study and definition of patients depending on the aim of this study and

revise the manuscript.

We appreciate your critical comments. According to your important comments, we discriminate “Elderly RA” and EORA and corrected these descriptions in the revived manuscript. We also performed the same analysis using the selected elderly-onset RA patients as requested by Reviewer #2. We presented these new data in the revised manuscript.

2. The authors showed all AEs leading to the discontinuation of ABT or

TCZ in Table 2, but some AEs (ILD, liver dysfunction, renal dysfunction,

cardiovascular disease, hypothyroidism) are generally unlikely to be

associated with ABT or TCZ administration. Thus, it is questionable

whether those AEs are due to these drug administrations and

discontinuation of ABT or TCZ were necessary. Thus, the author should

add explanations about detailed situation of each AE.

We appreciate your critical comments. According to your important comments, we described the detailed situations concerting the discontinuation of TCZ or ABT due to AEs in the revised manuscript.

3. The authors highlighted the risk of ILD in the TCZ group, but it is

not well verified or described. First, it is necessary to describe

whether the ILDs were new occurrences after the initiation of TCZ or

exacerbations of already diagnosed. Also, effect of MTX should be

considered.

We appreciate your critical comments. According your comments, we described the detailed information concerning the occurrence of ILD and the effects of MTX in TCZ group in the revised manuscript.

4. Regarding efficacy, the authors only showed achieving rate of low

disease activity according to CDAI and DAS28-CRP at 24 weeks. When I read

the method (P7L2-5), it seems that this did not include remission. It is

desirable to analyze it including remission to evaluate effectiveness of

the treatments. The authors should also show the longitudinal changes of

score of CDAI and DAS28-CRP, proportion of the category of each disease

activity (remission, low-, moderate-, high-disease activity), each

component of composite measures, if possible.

We appreciate your critical comments. According to your precise comments, we presented these important data in the new Figure in the revised manuscript.

5. Please describe summary of rate of reasons for drug discontinuation

in ”Drug overall retention rates” section in P11.

According to your important comments, we described the rates of reasons for drug discontinuation in this section of the revised manuscript.

6. AEs should be listed as a whole AE and then divided into AEs that led

to drug discontinuation and AEs that did not.

According to your important comments, we listed whole AEs dividing into AEs leading to or not-leading to drug discontinuation in the revised Table 2.

7. The author excluded patients with no history of csDMARDs in Figure 1.

What is the reason for excluding these patients?

We appreciate your important comments.

These patients were excluded from the analysis due to the following reasons:

Since the pre-existing serious complications (progressing ILD, renal insufficiency, hematological disorders, advanced disability), which limit the use of MTX and may affect the clinical course in these patents.

8. The authors should add more detail clinical characteristics at the time of initiation of ABT or TCZ in Table 1. Each component of composited measures (SJC, TJC, PtGA, PGA), concomitant use of csDMARDs other than MTX, proportion of chronic kidney disease (eGFR<60), dose of glucocorticoid, types of used bDMARDs should be added.

We appreciated your critical comments. According to your comments, we presented this important information in new Table 1 in the revised manuscript.

9. Table 1 showed 12 patients with ABT group and 25 patients with TCZ group have ever used prior bDMARDs use. Is that mean are all prior bDMARDs TNF inhibitors? If not, it is necessary to describe the person who used both ABT and TCZ during the period.

We appreciate your important comments. According to your comment, we added these important information in revised Table1.

Minor

1. Please correct abbreviations in the manuscript and figures.

Abbreviations should be defined at first mention and used consistently thereafter, but it has not complied with frequently (ex. Adverse event (AE), low disease activity (LDA), abatacept (ABT, ABA) etc.).

We corrected these abbreviations in the revised manuscript.

2. “In the matched analysis,・・・・(P2L12, in abstract)” is not

appropriate sentence because it may mislead that background were

adjusted by using Propensity score matching etc.

We appreciate your critical comments. We deleted these sentences in the revised manuscript.

3. In P8-9, check and correct the results for the rate of glucocorticoid

use, as the results are opposite in the text and in Table 1.

We corrected these mistakes in the revised manuscript.

4. In Table 3, the number of MTX users in the AE group is incorrect.

We corrected these mistakes in the revised manuscript.

Reviewer #2: This study compared efficacy and safety of Abatacept and

Tocilizumab in elderly patients with rheumatoid arthritis and showed

comparable efficacy between both agents. On the other hand, the rates of

discontinuation due to AEs, including ILD, seem to be lower with ABT

than with TCZ in elderly patients with RA.

Major comments

The reviewer has a concern with the inclusion criteria.

#1 This study enrolled elderly (age ≥65 years) patients, irrespective of

onset age with a mean of 7 years. Onset age is one of the important

factors to determine clinical features including therapeutic responses.

The reviewer is afraid that the authors confuse clinical features of

elderly RA patients with those of elderly onset RA (EORA)patients. For

example, the author described “Elderly patients with RA seem to have a

characteristic pattern with a more acute onset, systemic involvement,

and worse functional outcomes” (P19, L14-15), but this report compared

EORA patients with young onset RA patients. The reviewer suggests

analyzing the data by stratifying onset age or focusing those in

patients having onset age over 60 years old.

We appreciate your critical comments. According to your important comments, we analyzed the same analysis subjected RA patients with the onset age over 60 years old. We presented these new results in the revised manuscript.

#2 This study applied the 1987 ACR classification, but not 2010 ACR/

EULAR, in spite of the study duration from 2014 to 2021. The reviewer is

afraid that the inclusion criteria missed some of elderly onset RA

patients. The reviewer suggests adding the data when the patients are

enrolled based on the 2010 ACR/EULAR criteria.

We appreciate your critical comments. According to your comments, we applied the 2010 ACR/EULAR classification criteria, in the revised manuscript. However, we could not expand the number of the elderly RA patients.

Minor comments

#3 The reviewer suggests showing the administration routes and the

standard dose of ABT and TCZ, because the standard dose of TCZ is

different among countries. In addition, the interval of subcutaneous

injection with TCZ can be shortened to one week. The reviewer is also

interested in how often the interval is shortened because of the

insufficient efficacy.

We appreciate your critical comments. According to your comments, the administration ruts of ABT and TCZ in the revised manuscript.

#4 Table 1 shows 25.5% of patients treated with ABT and 31.3% of those

with TCZ have received prior Bdmard. The reviewer is afraid it is hard to

interpret the data in patients who had a switch from ABT to TCZ or TCZ

to ABT. To avoid the complexity, the reviewer suggests showing the data

in patients who received ABT or TCZ as the first bDMARD.

We appreciated your critical comments. According to your important comments, we added the important information concerning the prior Biologics in the revised Table 1.

#5 spelling error

“the ACPA possibilities” (P17, L15) => positivity

According to your precise comments, we corrected these mistakes in the revised manuscript.

Submitted filename: Reviewer response new.docx

Click here for additional data file.

6 Sep 2022

Comparing the effectiveness and safety of Abatacept and Tocilizumab in elderly patients with rheumatoid arthritis

PONE-D-22-17384R1

Dear Dr. Migita,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Masataka Kuwana, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors responded appropriately to reviewer's comments.

Please correct the abbreviation of abatacept in Figure 7 and 10 (ABA→ABT).

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Satoshi Takanashi

**********

9 Sep 2022

PONE-D-22-17384R1

Comparing the effectiveness and safety of Abatacept and Tocilizumab in elderly patients with rheumatoid arthritis

Dear Dr. Migita:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Prof. Masataka Kuwana

Academic Editor

PLOS ONE