Anti-RNA polymerase III antibodies in systemic sclerosis: prevalence and clinical associations from a systematic review and meta-analysis

Abstract

Objectives: Anti-RNA polymerase III antibodies (ARA) are frequent in systemic sclerosis (SSc). However, the reported prevalence is variable among studies and some clinical associations are debated. We aimed (i) to update the recent data on overall ARA prevalence in SSc and heterogeneity between centres; and (ii) to describe their clinical associations.

Methods: A systematic review of the literature available up to June 2024 was carried out in Pubmed and Embase. Meta-analyses were performed to assess the prevalence and clinical associations of ARA in SSc, combined with meta-regressions in case of heterogeneity to identify potential cofactors.

Results: Ninety-three studies corresponding to a total of 23 038 SSc patients were included in the meta-analysis. In this population, the overall seroprevalence of ARA was 9% (95% CI: 8-10) with a high degree of heterogeneity (I2 = 88%, P < 0.001). ARA positivity was significantly associated with diffuse cutaneous subset (OR: 2.20 [1.91-2.53]), joint manifestations (OR: 1.29 [1.01-1.66]), gastric antral vascular ectasia (GAVE) (OR: 2.70 [1.52-4.81]), heart involvement (OR: 1.93 [1.18-3.18]), scleroderma renal crisis (OR: 7.82 [5.79-10.57]), interstitial lung disease (ILD) (OR: 1.10 [1.00-1.20]) and cancer (OR: 1.86 [1.33-2.59]).

Conclusion: This study provides an overall seroprevalence of ARA of 9% [8-10] and confirms that SSc patients with ARA are at higher risk of severe skin extension and renal crisis. It also highlights a positive association with cancer, GAVE, heart, joint involvement and ILD. ARA positive SSc patients could therefore benefit from an appropriate screening of these potentially severe complications.

Keywords: RNA-polymerase; SSc; autoantibodies; meta-analysis; prevalence; systematic review.

Graphical abstract

Figure 1.

Flow chart illustrating the search strategy used to identify publications included in the meta-analysis. ARA: anti-RNA polymerase III antibodies

Figure 2.

(A) Estimation of the worldwide prevalence of ARA in SSc according to countries of studies included in the meta-analysis. With the available data in the meta-analysis, the variable ‘country’ was associated with the prevalence of ARA. Grey areas = no data. (B) Prevalence of ARA in SSc patients, according to the method of detection. Diamonds represent the pooled prevalence for each detection method. ARA: anti-RNA polymerase III antibodies

Figure 3.

Association between ARA seropositivity and SSc features. Secondary analyses provided alternative odds ratio (OR) regarding: ^aCardiac involvement excluding studies in which the definition comprised right heart involvement or pericardial effusion, ^bInterstitial lung disease diagnosed exclusively on high resolution computed tomography or chest X-ray, ^cPulmonary arterial hypertension (PAH) confirmed by right heart catheterization, ^dCancer diagnosed within five years before or after disease onset. P het: P-value for heterogeneity, NS: non-significant, ARA: anti-RNA polymerase III antibodies, GAVE: gastric antral vascular ectasia, GI involvement: gastrointestinal involvement, PBC: primary biliary cholangitis. Statistically significant associations are represented in bold

Figure 4.

(A) Forest plot showing the association between heart involvement and ARA in SSc patients, in all studies, according to the publication year. Each square represents an individual odds ratio, with the size of the square being proportional to the weight given to the study. Lines represent the 95% confidence interval. Diamonds represent the pooled odds ratio for each publication time frame. (B) Forest plot showing the association between ILD and ARA in SSc patients, in all studies, according to the method used to define ILD. Each square represents an individual odds ratio, with the size of the square being proportional to the weight given to the study. Lines represent the 95% confidence interval. Diamonds represent the pooled prevalence for each diagnostic method. HRCT: high resolution CT

Figure 5.

Sensitivity analysis of the association between ARA seropositivity and SSc features, using only studies published between 2010 and 2024. GI involvement: gastrointestinal involvement, GAVE: gastric antral vascular ectasia