Literature search results and study selection

A total of 113 records were initially identified through the search process. Following the screening of titles and abstracts, 31 articles were deemed eligible for full-text review. Ultimately, three studies were included in the meta-analysis [1, 2, 13]. Additionally, a manual review of the references from the included studies did not yield any further articles for inclusion. The study selection process is illustrated in the PRISMA flow diagram presented in Fig. 1.

Fig. 1

PRISMA flow diagram of the included studies

Characteristics of included studies and participants

A total of 355 patients from the three randomized controlled trials (RCTs) were included in the analysis. These studies were conducted in both Japan and the USA, although they had a multinational scope. The treatment groups comprised participants receiving either ziltivekimab or a placebo. Detailed characteristics of the studies are presented in Tables 1, 2 and 3, while the baseline characteristics of the patients are provided in Table 4.

Table 1 Summary 1.1 of the included studiesTable 2 Summary 1.2 of the included studiesTable 3 Summary 1.3 of the included studiesTable 4 Baseline characteristics of the patients in the included studiesRisk of bias and quality of evidence

The risk of bias for each outcome included in the quantitative analysis was assessed using the Cochrane RoB2 tool, which examines five domains. One study raised some concerns [2], while the other two studies [1, 13] were evaluated as having a low risk of bias (Fig. 2). Based on the GRADE system, all primary outcomes were rated as providing low-quality evidence. Further details and explanations are provided in Table S2.

Fig. 2

RoB-2 of the included studies

Efficacy outcomesHs-CRP

The pooled estimate showed a significant reduction in hs-CRP with high doses of ziltivekimab, and there was significant heterogeneity (MD = − 56.73, 95% CI [− 112.47; − 1.00], P value = 0.05, I2 = 98%), intermediate doses of ziltivekimab (MD = − 79.96, 95% CI [− 98.21; − 61.71], P value < 0.00001, I2 = 51%), and low doses of ziltivekimab (MD = − 28.50, 95% CI [− 51.68; − 5.32], P value = 0.02, I2 = 96%) compared to control. Finally, the overall analysis showed  a significant reduction (MD = − 51.64, 95% CI [− 73.73; − 29.56], P value < 0.00001, I2 = 97%) (Fig. 3). The sensitivity analysis did not resolve the heterogeneity.

Fig. 3

Forest plot for hs-CRP. RR: risk ratio, CI: confidence interval

Fibrinogen

The pooled estimate showed a significant reduction in fibrinogen with high doses of ziltivekimab, and there was significant heterogeneity (MD = − 67.15, 95% CI [− 97.515; − 36.76], P value < 0.00001, I2 = 95%), intermediate doses of ziltivekimab (MD = − 29.96, 95% CI [− 39.65; − 20.26], P value < 0.00001, I2 = 70%), and low doses of ziltivekimab (MD = − 89.36, 95% CI [− 173.34; − 5.38], P value = 0.04, I2 = 94%) compared to control. Finally, the overall analysis showed a significant reduction (MD = − 48.23, 95% CI [− 61.73; − 34.72], P value < 0.00001, I2 = 92%) (Fig. 4). The sensitivity analysis did not resolve the heterogeneity.

Fig. 4

Forest plot for fibrinogen

SAA

The pooled estimate showed a significant improvement in SAA with high doses of ziltivekimab (MD = − 33.86, 95% CI [− 56.29; − 11.44], P value = 0.003, I2 = 82%), lower doses of ziltivekimab (MD = − 35.07, 95% CI [− 43.59; − 26.56], P value = 0.00001, I2 = 2%),  and non-significant improvement with intermediate doses of ziltivekimab (MD = − 12.74, 95% CI [− 39.85; 14.36], P value = 0.36, I2 = 85%) compared to control. Finally, the overall analysis showed a significant reduction (MD = − 26.34, 95% CI [− 38.63; − 14.04], P value < 0.00001, I2 = 78%). There was significant heterogeneity, except in the low-dose ziltivekimab group (Fig. 5). The sensitivity analysis did not resolve the heterogeneity.

Fig. 5LDL

The pooled estimate showed a significant increase in LDL with high doses of ziltivekimab (MD = 7.26, 95% CI [0.83; 13.70], P value = 0.03, I2 = 0%), intermediate doses of ziltivekimab (MD = 6.32, 95% CI [1.03; 11.60], P value = 0.02, I2 = 0%), and non-significant improvement with low doses of ziltivekimab (MD = 4.19, 95% CI [− 1.89; 10.27], P value = 0.18, I2 = 0%) compared to control. Finally, the overall analysis showed a significant increase (MD = 5.92, 95% CI [2.53; 9.31], P value = 0.0006, I2 = 0%). There was no significant heterogeneity (Fig. 6). The sensitivity analysis did not resolve the heterogeneity.

Fig. 6HDL

The pooled estimate showed a significant increase in HDL with high doses of ziltivekimab (MD = 7.28, 95% CI [3.80; 10.77], P value < 0.00001, I2 = 31%), lower doses of ziltivekimab (MD = 4.98, 95% CI [2.31; 7.64], P value = 0.08, I2 = 27%), and non-significant increase with intermediate doses of ziltivekimab (MD = 5.04, 95% CI [− 0.58; 10.65], P value = 0.0003, I2 = 0%) compared to control. Finally, the overall analysis showed a significant increase (MD = − 5.73, 95% CI [3.75; 7.71], P value < 0.00001, I2 = 0%). There was no significant heterogeneity (Fig. 7).

Fig. 7Safety outcomesInfection

The pooled estimate showed a non-significant decrease in infection with high doses of ziltivekimab (OR = 0.64, 95% CI [0.33; 1.25], P value = 0.19, I2 = 0%), intermediate doses of ziltivekimab (OR = 1.13, 95% CI [0.57; 2.24], P value = 0.72, I2 = 0%), and low doses of ziltivekimab (OR = 0.92, 95% CI [0.49; 1.73], P value = 0.80, I2 = 0%) compared to control. Finally, the overall analysis showed a non-significant decrease (OR = 0.87, 95% CI [0.60; 1.28], P value = 0.48, I2 = 0%). There was no significant heterogeneity (Fig. 8).

Fig. 8

Forest plot for infection

Adverse effects(AEs)

The pooled estimate showed a non-significant decrease in AEs with high doses of ziltivekimab (OR = 1.53, 95% CI [0.67; 3.47], P value = 0.31, I2 = 26%), intermediate doses of ziltivekimab (OR = 1.85, 95% CI [0.26; 13.11], P value = 0.54, I2 = 64%), and low doses of ziltivekimab (OR = 1.90, 95% CI [0.52; 6.95], P value = 0.33, I2 = 57%) compared to control. Finally, the overall analysis showed a non-significant decrease (OR = 1.43, 95% CI [0.85; 2.38], P value = 0.18, I2 = 33%). Significant heterogeneity was observed in the intermediate- and low-dose groups (Fig. 9).

Fig. 9 Meta-regression analysis (dose–response correlation)

In our meta-regression analysis, we found a significant correlation between the dose of ziltivekimab and the effect size on hs-CRP, but no significant association with the other outcomes (p-value > 0.1). The omnibus p-values for hs-CRP, SAA, LDL, and HDL were 0.081, 0.76, 0.33, 0.5, and 0.16, respectively. (Fig. 10).

Fig. 10

Meta-regressions analysis