Vivien M Hsu1, Eszter Kozák2, Qiaoli Li3, Márta Bocskai4, Naomi Schlesinger1, Ann Rosenthal5, Scott T McClure6,7, László Kovács4, László Bálint8, Szilvia Szamosi9, Gabriella Szücs9, Mary Carns10, Kathleen Aren10, Isaac Goldberg10, András Váradi2, John Varga10,11. 1. Rheumatology Division, Department of Medicine, Rutgers-RWJ Medical School, New Brunswick, NJ, USA. 2. Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences Centre of Excellence, Budapest, Hungary. 3. The Sidney Kimmel Medical College, The PXE International Center of Excellence in Research and Clinical Care, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA. 4. Department of Rheumatology and Immunology, University of Szeged, Szeged, Hungary. 5. Rheumatology Division, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI. 6. Department of Statistics, Shenandoah University, Winchester, VA. 7. Rebel Analytics, LLC, Laguna Hills, CA, USA. 8. Genomic Medicine and Bioinformatic Core Facility, Department of Biochemistry and Molecular Biology, University of Debrecen, Hungary University of Szeged, Szeged. 9. Division of Rheumatology, University of Debrecen, Debrecen, Hungary. 10. Divisions of Rheumatology and Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University, Chicago, IL. 11. Rheumatology Division, Department of Medicine, University of Michigan, Ann Arbor, MI, USA.
Abstract
OBJECTIVE: The pathogenesis of calcinosis cutis, a disabling complication of SSc, is poorly understood and effective treatments are lacking. Inorganic pyrophosphate (PPi) is a key regulator of ectopic mineralization, and its deficiency has been implicated in ectopic mineralization disorders. We therefore sought to test the hypothesis that SSc may be associated with reduced circulating PPi, which might play a pathogenic role in calcinosis cutis. METHODS: Subjects with SSc and age-matched controls without SSc were recruited from the outpatient rheumatology clinics at Rutgers and Northwestern Universities (US cohort), and from the Universities of Szeged and Debrecen (Hungarian cohort). Calcinosis cutis was confirmed by direct palpation, by imaging or both. Plasma PPi levels were determined in platelet-free plasma using ATP sulfurylase to convert PPi into ATP in the presence of excess adenosine 5' phosphosulfate. RESULTS: Eighty-one patients with SSc (40 diffuse cutaneous, and 41 limited cutaneous SSc) in the US cohort and 45 patients with SSc (19 diffuse cutaneous and 26 limited cutaneous SSc) in the Hungarian cohort were enrolled. Calcinosis was frequently detected (40% of US and 46% of the Hungarian cohort). Plasma PPi levels were significantly reduced in both SSc cohorts with and without calcinosis (US: P = 0.003; Hungarian: P < 0.001). CONCLUSIONS: Circulating PPi are significantly reduced in SSc patients with or without calcinosis. Reduced PPi may be important in the pathophysiology of calcinosis and contribute to tissue damage with chronic SSc. Administering PPi may be a therapeutic strategy and larger clinical studies are planned to confirm our findings.
OBJECTIVE: The pathogenesis of calcinosis cutis, a disabling complication of SSc, is poorly understood and effective treatments are lacking. Inorganic pyrophosphate (PPi) is a key regulator of ectopic mineralization, and its deficiency has been implicated in ectopic mineralization disorders. We therefore sought to test the hypothesis that SSc may be associated with reduced circulating PPi, which might play a pathogenic role in calcinosis cutis. METHODS: Subjects with SSc and age-matched controls without SSc were recruited from the outpatient rheumatology clinics at Rutgers and Northwestern Universities (US cohort), and from the Universities of Szeged and Debrecen (Hungarian cohort). Calcinosis cutis was confirmed by direct palpation, by imaging or both. Plasma PPi levels were determined in platelet-free plasma using ATP sulfurylase to convert PPi into ATP in the presence of excess adenosine 5' phosphosulfate. RESULTS: Eighty-one patients with SSc (40 diffuse cutaneous, and 41 limited cutaneous SSc) in the US cohort and 45 patients with SSc (19 diffuse cutaneous and 26 limited cutaneous SSc) in the Hungarian cohort were enrolled. Calcinosis was frequently detected (40% of US and 46% of the Hungarian cohort). Plasma PPi levels were significantly reduced in both SSc cohorts with and without calcinosis (US: P = 0.003; Hungarian: P < 0.001). CONCLUSIONS: Circulating PPi are significantly reduced in SSc patients with or without calcinosis. Reduced PPi may be important in the pathophysiology of calcinosis and contribute to tissue damage with chronic SSc. Administering PPi may be a therapeutic strategy and larger clinical studies are planned to confirm our findings.
Authors: Daniel Aletaha; Tuhina Neogi; Alan J Silman; Julia Funovits; David T Felson; Clifton O Bingham; Neal S Birnbaum; Gerd R Burmester; Vivian P Bykerk; Marc D Cohen; Bernard Combe; Karen H Costenbader; Maxime Dougados; Paul Emery; Gianfranco Ferraccioli; Johanna M W Hazes; Kathryn Hobbs; Tom W J Huizinga; Arthur Kavanaugh; Jonathan Kay; Tore K Kvien; Timothy Laing; Philip Mease; Henri A Ménard; Larry W Moreland; Raymond L Naden; Theodore Pincus; Josef S Smolen; Ewa Stanislawska-Biernat; Deborah Symmons; Paul P Tak; Katherine S Upchurch; Jirí Vencovský; Frederick Wolfe; Gillian Hawker Journal: Arthritis Rheum Date: 2010-09
Authors: Qiaoli Li; Joshua Kingman; Koen van de Wetering; Sami Tannouri; John P Sundberg; Jouni Uitto Journal: J Invest Dermatol Date: 2017-01-19 Impact factor: 8.551
Authors: Matthew J Budoff; Leslee J Shaw; Sandy T Liu; Steven R Weinstein; Tristen P Mosler; Philip H Tseng; Ferdinand R Flores; Tracy Q Callister; Paolo Raggi; Daniel S Berman Journal: J Am Coll Cardiol Date: 2007-04-20 Impact factor: 24.094
Authors: Robert S Jansen; Aslı Küçükosmanoglu; Marcel de Haas; Sunny Sapthu; Jon Andoni Otero; Ilse E M Hegman; Arthur A B Bergen; Theo G M F Gorgels; P Borst; Koen van de Wetering Journal: Proc Natl Acad Sci U S A Date: 2013-11-25 Impact factor: 11.205
Authors: Flora Szeri; Stefan Lundkvist; Sylvia Donnelly; Udo F H Engelke; Kyu Rhee; Charlene J Williams; John P Sundberg; Ron A Wevers; Ryan E Tomlinson; Robert S Jansen; Koen van de Wetering Journal: PLoS Genet Date: 2020-07-08 Impact factor: 5.917