Background/Purpose: Calcinosis is a high-burden, key manifestation of systemic sclerosis (SSc), with a challenging therapeutic management. Yet, its precise prevalence and association with SSc charcateristics remain poorly defined. This study aimed to (i) assess the overall prevalence of calcinosis in SSc, and (ii) describe its association with clinical and serological phenotypes of SSc, through a systematic review of the literature with meta-analysis.

Methods: A systematic review of the literature available from inception to September 2024 was carried out in Pubmed, Embase and Web of Science databases. Meta-analyses were performed using collected data on demographic, clinical, biological and imaging characteristics of SSc patients with and without calcinosis.

Results: Eighty-one studies corresponding to a total of 18,643 SSc patients from 37 different countries were included in the meta-analysis. In this population, the overall prevalence of calcinosis was 24% (95% confidence interval [CI]: 21-27), with a high degree of heterogeneity (I² = 90.4%, p het < 0.001). Meta-regression revealed that the publication date (p = 0.02) and country (p = 0.001) of each report, could partially explain this observed disparity across studies. Calcinosis screening method also influenced its prevalence. When calcinosis diagnosis was based exclusively on clinical examination, its prevalence was 21% (95%CI: 16-27), whereas it increased to 28% (95%CI: 21-35) when the diagnosis was radiographic, alone or combined with clinical examination (p = 0.04) (Figure 1). Calcinosis was positively associated with female gender (OR: 1.43 [1.17; 1.76]), a longer disease duration (14.5 years vs 11.1 years, p = 0,03), pulmonary hypertension (OR: 1.76 [1.25-2.49]), digital ulcerations (OR: 2.29 [1.48; 3.54]), telangiectasia (OR: 2.79 [1.35; 5.79], an active nailfold capillaroscopy pattern (OR: 2.78 [1.11-7.01]), anti-centromere antibodies (ACA) (OR: 2.39 [1.65; 3.45] and, negatively associated with anti-topoisomerase I antibodies (OR: 0.86 [0.75; 0.99]). A positive association was also found between calcinosis and heart (OR: 1.69 [1.40; 2.05] or gastro-intestinal involvement (OR: 2.62 [1.24; 5.55]), but with a small number of studies (Figure 2). No statistically significant association was found between calcinosis and other available clinical features, including cutaneous subset.

Conclusion: Calcinosis is a highly prevalent clinical finding in SSc, occurring in almost one out of four SSc patients. Our work confirmed that, across multiple centers worldwide, calcinosis preferentially develops in female patients, with ACA, and a predominantly vascular phenotype. These findings also highlight the potential clinical relevance of a more systematic radiological evaluation of calcinosis, both to prevent a destructive local evolution, and to identify SSc patients who require closer monitoring of vascular complications, especially pulmonary hypertension. Further studies are needed to decipher the precise implication of vascular involvement in this manifestation, with the prospect of new therapeutic opportunities.

Figure 1. Prevalence of calcinosis in SSc patients, according to the diagnostic method. Diamonds represent the pooled prevalence for each diagnostic method and the overall prevalence.

Figure 2. Association between calcinosis and SSc features. p asso: p-value for association, p het: p-value for heterogeneity, LcSSc: limited cutaneous systemic sclerosis, GI involvement: gastrointestinal involvement, Ab: antibodies, NVC: nailfold video capillaroscopy. Statistically significant associations are represented in bold.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-overall-prevalence-and-associated-disease-characteristics-of-calcinosis-in-systemic-sclerosis-a-systematic-review-and-meta-analysis/