Comparison of the Efficacy and Safety of TNFi, IL-6Ri, and CTLA4-Ig

A total of 203 patients with PMR which was resistant or intolerant to glucocorticoids and could be classified as RA were enrolled in the study. Out of these 203 patients, 142 had not previously received bDMARDs, while 61 had received some form of bDMARDs before this admission. To determine the features of patients with PMR which could be classified as RA, we compared them to patients who had introduced bDMARDs for RA. Cases in which bDMARDs were introduced for RA were extracted from our registry, the FIRST registry, a multicenter observational cohort of patients who met the 1987 ACR classification criteria for RA or the 2010 ACR/EULAR classification for RA and were enrolled in biologic/targeted synthetic DMARDs (b/tsDMARDs). Specifically, we identified 2669 patients who were administered their first b/tsDMARDs from the 4524 patients in the FIRST registry. A comparison of patients with PMR classifiable as RA and patients with RA revealed that patients with PMR classifiable as RA were older, had longer persistent morning stiffness, and had more impaired HAQ-DI than patients with RA (Table 1). In this study, we also evaluated how well each diagnostic criterion was met to ensure rigorous diagnosis. For the Bird criteria, 68% of patients met all or six items, with a mean score of 4.8 out of 6 points (5.4 out of 8 points), on the 2012 EULAR/ACR classification criteria. For the diagnosis of RA, 71% of patients diagnosed with the 1987 ACR classification criteria for RA met all or six of the criteria, and the 2010 ACR/EULAR classification for RA had a mean score of 7.6. Thus, only cases that strictly met the diagnostic criteria for both diseases were included. Approximately 14% of the data related to the primary endpoint were missing as a result of the discontinuation of bDMARDs. Since a complete case analysis may introduce bias, these cases were also included in the analysis by substituting missing data with the MICE procedure, regardless of the reason for censoring.

Table 1 Comparison of RA with PMR and RA without PMR in bDMARD-naïve cases in the study

The 203 patients were divided into the TNFi, IL-6Ri, and CTLA4-Ig groups. Patient characteristics, such as age and duration of RA, differed significantly among the three groups (Table 2). Nearly half of the cases showed both myalgia symptoms associated with PMR and joint symptoms associated with RA concurrently. In most of the remaining cases, myalgia symptoms associated with PMR developed after the joint symptoms associated with RA had already manifested over time. While there were no significant differences among the three groups in terms of the diagnostic/classification criteria used, we observed a trend toward more cases in the IL-6Ri group meeting the 2012 EULAR/ACR provisional classification criteria for PMR. The concomitant use of MTX and GC was also significantly different between the groups. Factors involved in disease activity, such as evaluator’s global assessment and pain visual analogue scale, were also significantly lower in the CTLA4-Ig group than in the TNFi and IL-6Ri groups; DAS28 and SDAI, which indicate RA disease activity, tended to be lower in the CTLA4-Ig group. PMR disease activity was not significantly different among the three groups. The continuation rate of bDMARDs did not differ between bDMARDs classes (TNFi, IL-6Ri, and CTLA4-Ig = 82.2%, 85.7%, and 77.3%, respectively) (Fig. 1).

Table 2 Baseline characteristics of patients with PMR and RA in the studyFig. 1

Retention rates up to 26 weeks after the introduction of biological disease-modifying antirheumatic drugs (bDMARDs). The tumor necrosis factor inhibitor (TNFi) is shown as a solid black line, interleukin-6 receptor inhibitor (IL-6Ri) as a solid gray line, and cytotoxic T lymphocyte-associated antigen-4-immunoglobulin (CTLA4-Ig) as a dashed line

The trends in PMR activity after bDMARD initiation are displayed in Fig. 2a. Clin-PMR-AS after 26 weeks of bDMARD introduction was significantly lower in the IL-6Ri group than in the CTLA4-Ig group (IL-6Ri 8.6 + 9.6; CTLA4-Ig 15.7 + 12.7; p < 0.001, q < 0.001). The percentage of patients with low disease activity was significantly higher in the IL-6Ri group than in the TNFi and CTLA4-Ig groups (Fig. 2b, c). PMR-AS, ESR-PMR-AS, and CRP-imp PMR-AS demonstrated similar trends, with the IL-6Ri group exhibiting significantly higher levels than the TNFi and CTLA4-Ig groups (Supplementary Fig. S1). Supplementary Fig. S2 displays the trend in disease activity in patients with RA.

Fig. 2

a Changes in clinical Polymyalgia Rheumatica Activity Score (Clin-PMR-AS) after the introduction of biological disease-modifying antirheumatic drugs (bDMARDs). b Percentage of patients reaching low disease activity (LDA) using C-reactive protein imputed Polymyalgia Rheumatica Activity Score (CRP-imp PMR-AS) after 26 weeks of the introduction of bDMARDs. c Percentage of patients reaching LDA using Polymyalgia Rheumatica Activity Score (PMR-AS) after 26 weeks of the introduction of bDMARDs. d Changes in glucocorticoids (GC) dose (prednisolone (PSL) equivalent) after the introduction of bDMARDs. The points denote the mean value and the bars indicate the standard deviation. TNFi tumor necrosis factor inhibitor, IL-6Ri interleukin-6 receptor inhibitor, CTLA4-Ig cytotoxic T lymphocyte-associated antigen-4-immunoglobulin

CDAI was significantly lower in the IL-6Ri group than in both the TNFi (p = 0.003, q = 0.008) and CTLA4-Ig (p = 0.005, q = 0.008) groups 26 weeks after bDMARD introduction (Supplementary Fig. S2A), as well as in other disease activity measures.

The use of GCs 26 weeks after the introduction of bDMARDs did not differ among the three groups (Fig. 2d). The proportion of patients who were able to discontinue GC was also similar among the three groups (31.3%, 26.4%, and 36.0%, respectively). The adverse events during the observation period are displayed in Supplementary Table S1. There were no significant differences in overall or serious adverse events. On the other hand, severe infections were less common in the IL-6Ri group. One death due to cardiovascular disease occurred in the IL-6Ri group, but the patient had been on hemodialysis for 2 years before the introduction of IL-6Ri as a result of diabetic nephropathy and had also suffered an acute myocardial infarction 6 months before its introduction, suggesting that the combined use of GC was more influential than IL-6Ri.

Factors Associated with Clin-PMR-AS After 26 Weeks of bDMARD Introduction

As the patient characteristics varied widely, the factors involved in Clin-PMR-AS at 26 weeks were examined using single and multiple regression analyses (Table 3). In the single regression analysis, factors such as previous use of bDMARDs, tender joint count, morning stiffness, DAS28-ESR, PMR-AS, and BMI were identified as factors associated with Clin-PMR-AS at 26 weeks after bDMARD introduction. Multiple regression analysis, using explanatory variable factors (p < 0.05) in the single regression analysis and factors considered clinically important and excluding factors with multicollinearity, showed that the introduction of IL-6Ri was involved, along with the previous use of bDMARDs, BMI, and morning stiffness.

Table 3 Univariate and multivariate multiple regression analysis with Clin-PMR-AS after treatment as the objective variablePatient Characteristics After Adjustment by PS-Based IPTW

As IL-6Ri use was associated with Clin-PMR-AS 26 weeks after bDMARD introduction, we minimized the selection bias using PS-based IPTW and compared the results. Patient characteristics before PS-based IPTW adjustment were very different, as presented in Table 2, including the concomitant use of MTX and GC, BMI, and laboratory results (CRP and anti-CCP antibody). After the PS-based IPTW adjustment, as displayed in Table 2, there were no significant differences in any of the patient characteristics, and the standardized mean differences were all less than 0.1.

Comparison of Efficacy and Safety Among Three Groups After Adjustment by PS-Based IPTW

The persistence rate after bDMARD initiation, adjusted by PS-based IPTW, was not significantly different (TNFi, IL-6Ri, and CTLA4-Ig = 81.0%, 82.7%, and 70.0%, respectively) (Supplementary Fig. S3). In terms of PMR activity trends, the IL-6Ri group had significantly lower Clin-PMR-AS scores than the TNFi (p = 0.033, q = 0.042) and CTLA4-Ig (p = 0.001, q = 0.004) groups at 26 weeks after bDMARD introduction (Fig. 3a). The percentage of patients with low disease activity in the CRP-imp PMR-AS group was significantly different (33.1%, 60.0%, and 29.9%, respectively; p < 0.001), and in multiple testing of each group, the IL-6Ri group was significantly higher than that in the TNFi (p = 0.004, q = 0.006) and CTLA4-Ig (p = 0.003, q = 0. 010) (Fig. 3b). The residual analysis also demonstrated that the IL-6Ri group had a significantly higher proportion of patients with low disease activity (p = 0.002, q = 0.006) as compared to the other groups. The percentage of patients with low disease activity in the PMR-AS group was significantly higher in the IL-6Ri group compared to the TNFi and CTLA4-Ig groups. PMR-AS, ESR-PMR-AS, and CRP-imp PMR-AS at 26 weeks after bDMARD initiation were significantly lower in the IL-6Ri group than in the other two groups (Supplementary Fig. S4). Regarding RA disease activity, the CDAI, SDAI, and DAS28-ESR were significantly lower in the IL-6Ri group than in the other two groups after 26 weeks of bDMARD introduction (Supplementary Fig. S5). The overall trend of GC use was not significantly different between the two groups (Supplementary Fig. S6), but there was a significant difference in the percentage of patients who were able to reduce GC (58.5%, 77.7%, and 47.6%, respectively; p = 0.003); and multiple testing revealed that the IL-6Ri group was significantly lower than the TNFi (p = 0. 016, q = 0.025) and CTLA4-Ig group (p = 0.003, q = 0.009) (Fig. 3d). Supplementary Table S2 displays the adverse events during the observation period after adjusting for PS-based IPTW. There were no significant differences in overall or serious adverse events. Significantly fewer serious infections were observed in the IL-6Ri group than in the control group.

Fig. 3

a Change in clinical Polymyalgia Rheumatica Activity Score (Clin-PMR-AS) after biological disease-modifying antirheumatic drugs (bDMARDs) introduction adjusted by propensity score-based inverse probability of treatment weighting (PS-based IPTW). b Percentage of patients reaching low disease activity (LDA) using C-reactive protein imputed Polymyalgia Rheumatica Activity Score (CRP-imp PMR-AS) after 26 weeks of the introduction of bDMARDs adjusted for PS-based IPTW. c Percentage of patients reaching LDA using PMR-AS after 26 weeks of the introduction of bDMARDs adjusted for PS-based IPTW. d Percentage of patients who were able to reduce the dose of glucocorticoids (GC) after 26 weeks of bDMARD introduction. The points denote the mean value and the bars indicate the standard deviation. TNFi tumor necrosis factor inhibitor, IL-6Ri interleukin-6 receptor inhibitor, CTLA4-Ig cytotoxic T lymphocyte-associated antigen-4-immunoglobulin