Previous studies have proposed a link between IBD and RA. However, whether there is an increased risk of RA among patients with IBD remains controversial. In this study, we systematically reviewed the published literature and analyzed the association between IBD and the risk of RA. Our results showed that there was a significantly increased risk of RA in patients with IBD (RR = 2.59, 95% CI: 1.93–3.48). Moreover, the increase in risk remained significant when CD and UC were separately analyzed (CD: RR = 3.14, 95% CI 2.46–4.01; UC: RR = 2.29, 95% CI 1.76–2.97).
Although there was a similar trend in the correlation between IBD and RA among almost all the datasets included in this study, the effect sizes varied greatly among studies and considerable heterogeneity was detected. We performed a subgroup analysis based on the study design, age of the recruited anticipants, and year of publication, but failed to identify the source of heterogeneity. The heterogeneity may be partly explained by the different studied populations, disease definition criteria, and covariate adjustment. However, these factors could not be effectively stratified due to limited datasets. To generate more conservative results, the random-effects model was applied in all scenarios. In cross-sectional studies, the IBD and RA were measured during the same timeframe and therefore provide weaker evidence than longitudinal studies for the causal relationship between IBD and RA. However, this issue did not affect the findings, since in the subgroup analysis stratified by study design, the correlations between IBD and the increased risk of RA were consistently significant in both cross-sectional and cohort studies.
There are a few potential mechanisms that may contribute to the association between IBD and RA. Genetic susceptibility plays a vital role in the pathogenesis of both IBD and RA and several susceptibility genes which code key modulators of immune and inflammatory response are shared by IBD and RA. It has been reported that polymorphisms in the IRF5 locus can confer susceptibility to UC, CD, and RA [28–30]. Meanwhile, studies have determined that IL2/IL21 and TNFRSF14 loci are common risk loci for RA and UC [31–34]. Likewise, the risk loci shared by CD and RA have been identified in two genome-wide association studies [35, 36]. It has been suggested that a chronically imbalanced mucosal immune response to gut microbiota in the genetically susceptible patients may play an important role in the pathogenesis of IBD [37–40]. A few studies indicated that there was a link between gut microbiota and RA as well. It has been reported that Bacteroides was decreased in amount in both CD and RA patients . Additionally, studies utilizing animal models demonstrated that RA could be rescued by eliminating the bacteria residing in the intestine, while treating sterile mice with a specific intestine-residing bacterium, segmented filamentous bacteria, led to the development of RA .
RA is a chronic and progressive disease; early diagnosis and intervention are essential for better prognosis. The management strategy of RA has focused on the early identification of high-risk patients [43, 44]. However, it might be difficult for clinicians to distinguish arthritis related to IBD and early RA due to the obscure signs and symptoms. Collaboration between gastroenterologists and rheumatologists and close follow-up are suggested for the management of IBD patients presenting with undifferentiated arthritis.
The results presented in this meta-analysis must be interpreted with caution due to the several limitations of the study. First, our results were based on cross-sectional, case-control, and retrospective cohort studies; no prospective cohort study was available. Second, only a few studies were included in our meta-analyses. However, this could be partly compensated for by the large number of patients as all the studies included were based on nationwide or large-scale databases. Third, while smoking is the most important environmental risk factor for RA, only 2 studies [10, 18] included in this meta-analysis adjusted for the smoking status between the IBD group and the non-IBD control group. Fourth, there was considerable heterogeneity in our meta-analysis and we failed to identify the source of heterogeneity in the subgroup and sensitivity analyses. Fifth, significant publication bias was observed in the meta-analysis of the association between CD and risk of RA. Sixth, only the studies from USA, Denmark, Finland, and Korea analyzed the risk of RA in patients with IBD, which may compromise the generalizability of the results for the populations of other countries.