Study selection
The electronic literature search identified 20,124 publications. The titles and abstracts of 16,109 unique studies were screened using the selection criteria, leaving 35 papers. The full texts of these articles were carefully reviewed. Finally, 11 studies meeting the selection criteria were selected for further qualitative analysis, as shown in Fig. 1.
Study characteristics
The characteristics of these studies are outlined in tables 1 and 2. The studies were published between 2007 and 2019 and conducted in the USA [10, 11, 13, 17, 18], Korea [9, 14, 15], Denmark [12, 16], and Finland [19]. Three publications [15-17] were retrospective cohort studies, two [18, 19] were case-control studies and the other six [9-14] were cross-sectional studies. Six studies [9, 12, 14-16] were based on nationwide population-based databases, four [10, 11, 13, 17] were based on large administrative databases and the other one [18] was based on single-center biobank. Two cross-sectional studies [9, 14] and one cohort study [15] recruited an overlapping population from the Korean National Health Insurance Database; we only included the cohort study in the statistical analysis. Likewise, since two studies [12, 16] recruited overlapping samples from the Danish National Patient Database, we only included the cohort study in the meta-analysis. The cross-sectional study conducted by Cohen et al [13] utilized two independent datasets which were marked as Cohen-2008-1 and Cohen-2008-2, respectively. Dataset Cohen-2008-1 was only included in the meta-analysis of risk of RA in patients with CD or UC alone, as it shared an overlapping sample with the cohort study conducted by Aletaha et al [17] when investigated the risk of RA in patients with IBD.
The final datasets for evaluating the risk of RA among IBD consisted of 42,987,815 participants (193,200 nonoverlapping IBD patients). Besides, a cumulative total of 204,712 participants (46,575 nonoverlapping CD patients) and 356,745 participants (84,140 nonoverlapping UC patients) were included in the meta-analysis on the association between CD and RA, and between UC and RA, respectively. Regarding gender distribution, the proportion of male ranged from 27% to 70%. However, the gender information of 2 studies [16, 17], including the one [17] with the biggest sample size, was not reported. One study [11] focused on the children, five [13, 16-19] analyzed adult population, and the remaining studies [12, 15] recruited both children and adults.
Study quality
A summary of the methodological quality scores of the included studies is shown in Table 2 and the detailed information is presented in supplementary Table 2 (Additional file 2). With respect to the risk of RA among patients with IBD, 10 studies with 11 datasets showed “good quality”, with a median score of 7 (range: 6–9).
Risk of RA in patients with IBD
The combined evidence from eight studies (three cohort studies [15-17], two case-control studies [18, 19], and three cross-sectional studies [10-12]) showed a significant increased risk of RA among patients with IBD (RR=2.59, 95% CI: 1.93–3.48, I2=94.2%; Fig. 2). In addition, the pooled risk estimates of six datasets from five studies showed that the corresponding risks were both significantly increased in patients with CD (RR=3.14, 95% CI: 2.46–4.01, I2=74.9%; Fig. 3), and UC (RR=2.29, 95% CI: 1.76–2.97, I2=84.7%; Fig. 4).
Subgroup analyses stratified by study design, age of the targeted population, year of publication, and study duration were performed. Results showed that the risk of RA among patients with IBD was significantly increased in all subgroups except for the studies with case-control design (RR= 1.62, 95% CI: 0.32-8.07, I2=92.9%; Table 3) and those with shorter study duration (RR= 1.76, 95% CI: 0.31-9.92, I2=98.4%). The corresponding risk in CD remained significantly increased in all subgroups. The association between UC and the risk of RA was less significant in the pediatric group (RR=3.60, 95% CI: 0.80–16.10) and in the group comprised of both children and adults (RR=2.41, 95% CI: 0.94–6.14, I2=95.4%). However, we failed to identify the source of heterogeneity based on these factors.
Publication bias and Sensitivity analysis
No significant publication bias was found in the meta-analysis on the risk of RA among patients with IBD or UC. However, significant publication bias was detected in the meta-analysis on the association between CD and the risk of RA (Begg’s test: P=0.060; Egger’s test: P=0.048; Supplementary Fig. 1, Additional file 3).
The results of sensitivity analysis showed that the risk estimates of RA among patients with IBD, and with CD or UC alone, were stable (Supplementary Table 3, Additional file 4).