Calcinosis in Systemic Sclerosis: Updates in Pathophysiology, Evaluation, and Treatment
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SCLERODERMA (J VARGA, SECTION EDITOR)
Calcinosis in Systemic Sclerosis: Updates in Pathophysiology, Evaluation, and Treatment Carrie Richardson 1,2 & Anna Plaas 1 & John Varga 3
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose of Review Calcinosis is a common complication of systemic sclerosis with no known effective pharmacologic therapy. We reviewed the literature regarding systemic sclerosis-related calcinosis as well as other disorders of biomineralization in order to identify targets of future study for calcinosis. Recent Findings Patients with systemic sclerosis-related calcinosis demonstrate systemic abnormalities in mineralization pathways, including decreased levels of the mineralization inhibitor inorganic pyrophosphate. Insights from other mineralization disorders suggest that local and systemic phosphate metabolism pathways involving the ABCC6, ENPP1, and NT5E genes play a critical role in regulation of ectopic calcification. Knockout models of these genes may lead to an appropriate murine model for study of calcinosis. Poly(ADP-ribose) polymerase (PARP) enzymes may also play a critical role in hydroxyapatite nucleation and warrant future study in systemic sclerosis. Summary Study of local and systemic mineralization pathways, particularly phosphate metabolism pathways and PARP enzymes, should provide greater insight into the pathogenesis of systemic sclerosis-related calcinosis. Keywords Systemic sclerosis . Calcinosis
Introduction Calcinosis, which is characterized by ectopic soft tissue deposition of apatite, is a disfiguring complication that affects 1 in 3 patients with systemic sclerosis (SSc) [1, 2]. Deposits commonly ulcerate, which may lead to bacterial superinfection [2]. SSc-related calcinosis most commonly affects the fingers, particularly the thumb of the dominant hand [3], suggesting that mechanical stimulation may play an important role in the This article is part of the Topical Collection on Scleroderma * Carrie Richardson [email protected] Anna Plaas [email protected] John Varga [email protected] 1
Rush University Medical Center, Chicago, IL, USA
2
Chicago, USA
3
Northwestern University, Chicago, IL, USA
pathogenesis of calcinosis [4]. Longer disease duration and ischemic digital ulcers are also associated with calcinosis, indicating that cumulative disease damage and hypoxic tissue injury may contribute to calcinosis [5–8]. In addition, previous studies have demonstrated lower bone density in SSc patients with calcinosis compared with those without calcinosis, demonstrating that systemic abnormalities of bone and mineral metabolism accompany calcinosis [9, 10]. A more recent study has identified decreased serum levels of the mineralization inhibitor inorganic pyrophosphate (PPi) in patients with SSc-related calcinosis [11], supporting the role of a systemic imbalance of mineralization inhibitors and promotors in SSc patients with calcinosis. Nevertheless, the cellular pathways underpinning the pathophysiology of cal
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