3.1. Study characteristics and quality scores
After the removal of duplicates and selection by viewing the abstracts and titles, a full-text review of 35 articles was performed. Six [9, 12-15, 21] and five [9, 13-15, 21] studies were included in the qualitative and quantitative analyses, respectively (Figure 1). The systematic review comprised a total of 319 patients (PFD+NAC group n=144, PFD alone group n=175). The studies were conducted in Europe (n=4), Japan (n=1) and China (n=2). One study was a controlled clinical trial (PANORAMA trial  by Behr et al), four were cohort studies [9, 13, 14, 21], and one was a case-control study . Of note, one RCT was excluded because only the conference abstract was available . A meta-analysis of observational real-world studies including 207 patients was performed. The general characteristics of the studies are shown in Table 1.
The average quality score for the included observational studies was 7.25 for cohort studies and 6 for the case-control study based on the NOS. The only RCT, which was conducted by Behr et al. , had high quality after being assessed according to the Cochrane Collaboration risk of bias assessment tool. The detailed quality characteristics are shown in the Supplement Table.
3.1 Effect of combined pirfenidone and acetylcysteine therapy on lung function parameters
The ΔFVC% predicted from baseline to week 24 was available in four studies with a total of 108 patients (PFD+NAC: n=48, PFD alone: n=60). Due to the lack of standard deviation values provided, the study by Sakamoto et al.  was excluded. Therefore, only three studies [9, 13, 21] were included in the meta-analysis. Given the premise of moderate heterogeneity (I2=62.5%, p=0.069), the random effects model was applied for the analysis. The results showed that PFD+NAC therapy had no additional benefit in reducing the decrease in lung function (SMD=-0.09, 95% CI -0.86-0.69, p=0.295, Figure 2-a) compared to PFD alone.
Similarly, the ΔDLco% predicted from baseline to week 24 was available in 3 studies [9, 13, 21] with a total of 76 patients (PFD+NAC: n=28, PFD alone: n=48). These studies had low heterogeneity (I2=30.1%, p=0.239). There was no difference in the ΔDLco% between the PFD+NAC group and the PFD group (SMD=0.13, 95% CI -0.34-0.61, p=0.580, Figure 2-b).
3.2 Safety and treatment tolerability of combined pirfenidone and acetylcysteine therapy
The number of patients who experienced at least one side effect was mentioned in five studies, including a total of 207 patients [9, 13-15, 21] (PFD+NAC: n=84, PFD alone: n=113). Moderate significant heterogeneity (I2=53.9%, p=0.070) was detected, and a random effects model was applied. The results suggested that the rate of at least one side effect in the PFD+NAC therapy group was similar (PFD+NAC vs PFD alone: 41 vs 57, OR=1.83, 95% CI 0.56-5.94, p=0.314, Figure 3-a) to that in the PFD alone group. No significant differences were observed in the rates of specific side effects (PFD+NAC vs PFD alone: gastrointestinal (GI): 26 vs 47, I2=30.9%, p=0.215, OR=1.08, 95% CI 0.56-2.08, p=0.811, Figure 4-a; skin side effects: 12 vs 17, I2=0%, p=0.769, OR=1.91, 95% CI 0.77-4.71, p=0.162, Figure 4-b) between the treatment groups in the subgroup analysis.
Intolerable side effects leading to treatment discontinuation were reported in three studies with a total of 100 patients [9, 15, 21] (PFD+NAC n=34, PFD alone n=66). There was no significant heterogeneity (I2=0%, p=0.762) observed among these studies. The results showed that combined PFD+NAC therapy did not increase the risk of intolerable side effects (OR=2.85, 95% CI 0.84-9.59, p=0.092, Figure 3-b) in comparison with PFD therapy. Patients receiving PFD+NAC therapy experienced intolerable side effects at a similar frequency as in those receiving PFD alone.
3.4 Qualitative analysis and sensitivity analysis
Funnel plots and Egger’s test could not be used to check for the existence of publication bias because our meta-analysis included fewer than 10 studies . In addition, the secondary meta-analysis with only oral NAC studies and sensitivity analysis excluding the case-control study resulted in p values of 0.249, 0.611 and 0.955 for gastrointestinal, skin and intolerable side effects, respectively, and the forest plots composed of only oral NAC studies can be found in the Supplement Material. (Supplement Figure 1-3). In the ensuing quantitative analysis comparing the results of the meta-analysis and Behrs’ RCT (Table 2), the safety, tolerability, and efficacy outcomes  were similar in the PFD+NAC treatment group and the PFD monotherapy group except for a significantly higher rate of skin adverse effects in the RCT (p values in meta vs RCT: 0.097/0.038). Other parameters, such as the six-minute walk distance (6MWD) and progression-free survival (PFS), were available in only one study. The 6MWD results were comparable between the observational study (-13.25±6.77 vs -16.59±4.65, p=0.159)  and Behr’s RCT (-4.3 vs -11.7, p=0.54). In addition, PFD+NAC treatment showed favourable results regarding the PFS (median survival days 304 d vs 168 d; p = 0.016) in the case-control study .