Www.research.manchester.ac.uk
Title: Calcinosis is associated with digital ulcers and osteoporosis in patients with Systemic Sclerosis: A Scleroderma Clinical Trials Consortium StudyAuthors Names, and Institutional Affiliation:Antonia Valenzuela1, Murray Baron2, the Canadian Scleroderma Research Group, Ariane L Herrick3, Susanna Proudman4,5, Wendy Stevens5, the Australian Scleroderma Interest Group, Tatiana S. Rodriguez-Reyna6, Alessandra Vacca7, Thomas A. Medsger Jr.8, Monique Hinchcliff9, Vivien Hsu10, Joy Y. Wu11, David Fiorentino12, Lorinda Chung11Department of Immunology and Rheumatology, Stanford University School of Medicine2Department of Rheumatology, Jewish General Hospital McGill University3Centre for Musculoskeletal Research, The University of Manchester, Manchester Academic Health Science Centre, Manchester4Rheumatology Unit, Royal Adelaide Hospital North Terrace5Discipline of Medicine, University of Adelaide, Department of Rheumatology, St. Vincent’s Hospital Melbourne6Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán7Unit and Chair of Rheumatology, University Hospital of Cagliari8Department of Medicine/Rheumatology, University of Pittsburgh School of Medicine9Department of Rheumatology, Northwestern University10Department of Medicine, Rutgers- Robert Wood Johnson Medical School11Department of Endocrinology, Stanford University School of Medicine12Department of Dermatology, Stanford University School of MedicineCorresponding author and reprint requests: Dr. Lorinda Chung, MD, MSStanford University School of MedicineDepartment of Immunology and Rheumatology1000 Welch RoadSuite 203 MC 5755Palo Alto, CA 94304Phone (650) 493-5000 X62042Fax (650) 849-1213shauwei@stanford.eduAbstract Objectives: We sought to identify the clinical factors associated with calcinosis in an international multicenter collaborative effort with the Scleroderma Clinical Trials Consortium (SCTC).Methods: This is a retrospective cohort study of 5218 patients with systemic sclerosis (SSc). Logistic regression was used to obtain odds ratios (OR) relating calcinosis to various clinical features in multivariate analyses.Results: A total of 1290 patients (24.7%) had calcinosis. In univariate analyses, patients with calcinosis were older than patients without calcinosis, more likely to be female, and had longer disease duration from the first non-Raynaud phenomenon symptom. Patients with calcinosis were more likely to have digital ulcers, telangiectasias, acro-osteolysis, cardiac disease, pulmonary hypertension, gastrointestinal involvement, arthritis, and osteoporosis, but less likely to have muscle disease. Anti-Scl-70, RNA-polymerase-III, and U1-RNP autoantibodies were significantly less common in patients with calcinosis, while anticentromere (ACA), anti-PM/Scl, and anticardiolipin antibodies were more frequent. In multivariate analysis, the strongest associations with calcinosis were digital ulcers (OR 3.9, 95%CI 2.7-5.5, p<0.0001) and osteoporosis (OR 4.2, 95%CI 2.3-7.9, p<0.0001).Conclusion: One quarter of patients with SSc have calcinosis at some time during their illness. Our data confirm a strong association of calcinosis with digital ulcers, and support a novel association with osteoporosis. Keywords: Systemic sclerosis, calcinosis, digital ulcers, osteoporosis Abbreviations: Systemic sclerosis: SScDermatomyositis: DMAnti-centromere antibody: ACA Odds ratios: ORRaynaud phenomenon: RPAntinuclear antibodies: ANABody mass index: BMIBone mineral density: BMDIntroduction Calcinosis is a rare disorder characterized by deposition of calcium in skin and subcutaneous tissues.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdXRpZXJyZXo8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy
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ADDIN EN.CITE.DATA (1) It is associated with connective tissue diseases including systemic sclerosis (SSc) and dermatomyositis (DM). Two general mechanisms of calcification in soft tissues have been described: 1) metastatic calcification, where the deposition of calcium occurs in normal cutaneous or subcutaneous tissue in the presence of elevated levels of serum calcium and/or phosphate, and 2) dystrophic calcification -the most common presentation of calcinosis occurring in association with SSc- where the deposition of calcified material happens in diseased tissues, and associated with normal serum calcium and phosphate levels. ADDIN EN.CITE <EndNote><Cite><Author>Valenzuela</Author><Year>2015</Year><RecNum>1244</RecNum><DisplayText>(2)</DisplayText><record><rec-number>1244</rec-number><foreign-keys><key app="EN" db-id="rte0z9av5rdz2kerwwuvzepoa99tdr9w5wzz">1244</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Valenzuela, A.</author><author>Chung, L.</author></authors></contributors><auth-address>Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, California, USA.</auth-address><titles><title>Calcinosis: pathophysiology and management</title><secondary-title>Curr Opin Rheumatol</secondary-title><alt-title>Current opinion in rheumatology</alt-title></titles><periodical><full-title>Curr Opin Rheumatol</full-title><abbr-1>Current opinion in rheumatology</abbr-1></periodical><alt-periodical><full-title>Curr Opin Rheumatol</full-title><abbr-1>Current opinion in rheumatology</abbr-1></alt-periodical><pages>542-8</pages><volume>27</volume><number>6</number><edition>2015/09/10</edition><dates><year>2015</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1531-6963 (Electronic)
1040-8711 (Linking)</isbn><accession-num>26352733</accession-num><urls><related-urls><url>;(2) Calcinosis is often painful and may be associated with recurrent episodes of local inflammation or infection, leading to considerable functional impairment. ADDIN EN.CITE <EndNote><Cite><Author>Boulman</Author><Year>2005</Year><RecNum>255</RecNum><DisplayText>(3)</DisplayText><record><rec-number>255</rec-number><foreign-keys><key app="EN" db-id="rte0z9av5rdz2kerwwuvzepoa99tdr9w5wzz">255</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Boulman, N.</author><author>Slobodin, G.</author><author>Rozenbaum, M.</author><author>Rosner, I.</author></authors></contributors><auth-address>Department of Rheumatology, Bnai Zion Medical Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.</auth-address><titles><title>Calcinosis in rheumatic diseases</title><secondary-title>Semin Arthritis Rheum</secondary-title><alt-title>Seminars in arthritis and rheumatism</alt-title></titles><periodical><full-title>Semin Arthritis Rheum</full-title><abbr-1>Seminars in arthritis and rheumatism</abbr-1></periodical><alt-periodical><full-title>Semin Arthritis Rheum</full-title><abbr-1>Seminars in arthritis and rheumatism</abbr-1></alt-periodical><pages>805-12</pages><volume>34</volume><number>6</number><edition>2005/06/09</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Calcinosis/drug therapy/ etiology/pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Rheumatic Diseases/ complications/pathology</keyword></keywords><dates><year>2005</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0049-0172 (Print)
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ADDIN EN.CITE.DATA (8) late nailfold videocapillaroscopy pattern ADDIN EN.CITE <EndNote><Cite><Author>Morardet</Author><Year>2016</Year><RecNum>1245</RecNum><DisplayText>(7)</DisplayText><record><rec-number>1245</rec-number><foreign-keys><key app="EN" db-id="rte0z9av5rdz2kerwwuvzepoa99tdr9w5wzz">1245</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Morardet, L.</author><author>Avouac, J.</author><author>Sammour, M.</author><author>Baron, M.</author><author>Kahan, A.</author><author>Feydy, A.</author><author>Allanore, Y.</author></authors></contributors><auth-address>Paris Descartes University, Sorbonne Paris Cite, Cochin Hospital, Paris, France.
Jewish General Hospital, McGill University, Montreal, Quebec, Canada.</auth-address><titles><title>Late Nailfold Videocapillaroscopy Pattern Associated With Hand Calcinosis and Acro-Osteolysis in Systemic Sclerosis</title><secondary-title>Arthritis Care Res (Hoboken)</secondary-title><alt-title>Arthritis care & research</alt-title></titles><periodical><full-title>Arthritis Care Res (Hoboken)</full-title><abbr-1>Arthritis care & research</abbr-1></periodical><alt-periodical><full-title>Arthritis Care Res (Hoboken)</full-title><abbr-1>Arthritis care & research</abbr-1></alt-periodical><pages>366-73</pages><volume>68</volume><number>3</number><edition>2015/08/01</edition><dates><year>2016</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>2151-4658 (Electronic)
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ADDIN EN.CITE.DATA (10) These findings are primarily derived from small single-center studies, and the effects of confounding variables were not taken into account. We previously found an overall frequency of calcinosis of 22% in a multi-center international cohort of 7056 SSc patients (data unpublished). Given that calcinosis is a frequent, debilitating complication of SSc with no effective therapies, we sought to identify clinical associations of calcinosis that may shed light on the underlying pathogenesis, and provide novel therapeutic targets.MethodsStudy design This is a retrospective multicenter cohort study of 5218 patients with SSc from 9 cohorts within the US (Stanford University, University of Pittsburgh, Northwestern University, and Rutgers-RWJMS), Australia, Canada, United Kingdom, Italy, and Mexico. We collected information on demographics, clinical findings, internal organ involvement, co-morbid diseases (osteoporosis, renal disease), and serum autoantibodies. We defined diffuse cutaneous SSc as skin thickness proximal to elbows and knees or truncal involvement, and limited cutaneous SSc as skin thickness distal to elbows and knees without truncal involvement at any time during the disease course, following the classification proposed by LeRoy and Medsger. ADDIN EN.CITE <EndNote><Cite><Author>LeRoy</Author><Year>2001</Year><RecNum>1055</RecNum><DisplayText>(11)</DisplayText><record><rec-number>1055</rec-number><foreign-keys><key app="EN" db-id="rte0z9av5rdz2kerwwuvzepoa99tdr9w5wzz">1055</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>LeRoy, E. C.</author><author>Medsger, T. A., Jr.</author></authors></contributors><auth-address>Department of Medicine, Medical University of South Carolina, Charleston 29425, USA. leroyc@musc.edu</auth-address><titles><title>Criteria for the classification of early systemic sclerosis</title><secondary-title>J Rheumatol</secondary-title><alt-title>The Journal of rheumatology</alt-title></titles><periodical><full-title>J Rheumatol</full-title><abbr-1>The Journal of rheumatology</abbr-1></periodical><alt-periodical><full-title>J Rheumatol</full-title><abbr-1>The Journal of rheumatology</abbr-1></alt-periodical><pages>1573-6</pages><volume>28</volume><number>7</number><edition>2001/07/27</edition><keywords><keyword>Humans</keyword><keyword>Raynaud Disease/classification/diagnosis</keyword><keyword>Scleroderma, Systemic/ classification/ diagnosis</keyword></keywords><dates><year>2001</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0315-162X (Print)
0315-162X (Linking)</isbn><accession-num>11469464</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(11) We defined organ system involvement as described previously;PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb21zaWM8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (12) chronic renal disease as a creatinine>2 mg/dl, osteoporosis as a T-score ≤ - 2.5 SD on bone densitometry, or a clinical history of osteoporosis requiring medical treatment; digital ulcers as denuded areas with a defined border, loss of epithelialization and loss of epidermis and dermis on the volar aspect distal to the proximal interphalangeal joints, and acro-osteolysis as the resorption of the distal phalangeal tufts on physical examination and/or radiography. Calcinosis was defined as ever having evidence of subcutaneous calcium deposition on physical examination and/or radiography, or a clear history of calcium extruding from the skin as described by the patient. This study was designed in accordance with the general ethical principles outlined in the Declaration of Helsinki. Study PopulationWe included all patients diagnosed with SSc, mixed connective tissue disease, and other overlap connective tissue diseases who fulfilled 2013 revised ACR/EULAR criteria for SSc.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gZGVuIEhvb2dlbjwvQXV0aG9yPjxZZWFyPjIwMTM8
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ADDIN EN.CITE.DATA (13) Statistical AnalysisTo characterize patients with and without calcinosis, we used student’s t-test for continuous variables and chi-square or Fisher’s exact test for categorical variables, as appropriate. P-values from univariate analysis were adjusted using the Bonferroni correction for multiple comparisons. We then developed stratified and non-stratified logistic multivariate regression models to obtain odds ratios (OR) for the association between calcinosis and significant risk factors, and to control for potential confounders (including chronic renal disease, body mass index (BMI), and steroids use for the association between calcinosis and osteoporosis). Multicollinearity and interactions among the candidate predictors were assessed. We used stepwise elimination to determine the final regression model, retaining those factors with a p-value < 0.05 in univariate analysis. Statistical tests of the regression estimates were based on the chi-squared approximation for the likelihood ratio statistic and 95% confidence intervals were based on Wald's test. Statistical significance was defined as p ≤ 0.05. All statistical analyses were performed using SAS statistical software, version 9.3 (SAS Institute Inc, Cary, NC). ResultsPatient characteristics and calcinosisOf 5218 patients with SSc, 4428 (84.9%) were female, and racial distribution was 81.7% Caucasian, 6.1% Hispanic, 2.6% Asian, and 0.9% African-American. 61.4% had limited cutaneous SSc, and 38.4% had diffuse cutaneous SSc. Mean age at last visit was 57.4 ± 13.3 years, and mean disease duration from first non-Raynaud phenomenon (RP) symptom was 9.4 ± 9.7 years. A total of 1290 patients (24.7%) had calcinosis. Patients with calcinosis were older than patients without calcinosis, more likely to be female, and had longer disease duration from first non-RP symptom, but there was no difference in cutaneous subtype. Patients with calcinosis were significantly more likely to have digital ulcers (65.5% vs. 34.4%, p<0.0001), telangiectasias, and acro-osteolysis, but less likely to have puffy fingers. Regarding internal organ involvement, patients with calcinosis more often had SSc-associated cardiac disease, pulmonary hypertension, gastrointestinal involvement, and arthritis, but less frequently had muscle disease. Osteoporosis was much more common in patients who had calcinosis (22.8% vs. 2.8%, p<0.0001)(Table 1). Autoantibodies and calcinosisAnti-Scl-70, RNA-polymerase-III, and U1-RNP autoantibodies were significantly less common in patients with calcinosis, while ACA, and anti-PM/Scl were more frequent. In the small subgroup of patients who had anticardiolipin antibodies tested, these were also more frequently found in patients with calcinosis. There were no statistically significant differences in antinuclear antibodies (ANA), lupus anticoagulant, and anti-beta-2-glycoprotein antibody frequency between patients with and without calcinosis (Table 2).Factors associated with calcinosis in univariate and multivariate analysisIn univariate analysis, the strongest associations with calcinosis were digital ulcers (OR 3.6, 95%CI 3.1-4.1), and osteoporosis (OR 10.2, 95%CI 6.9-15). In multivariate analysis, digital ulcers and osteoporosis remained the strongest significant associations with calcinosis (OR 3.9, 95%CI 2.7-5.5, and OR 4.2, 95%CI 2.3-7.9, respectively)(Table 3). Telangiectasias, and ACA also remained highly significant (p<.0001). After controlling for steroid use and BMI in the model, the association with osteoporosis persisted in stratified analyses in non-obese patients (OR 6.5, 95%CI 1.8-23.8, p=0.004).DiscussionCalcinosis is a common manifestation in patients with SSc, and has a substantial impact on quality of life. Our large database was able to confirm with high statistical certainty prior studies showing an association between calcinosis and digital ulcers, as well as other ischemic manifestations of SSc, including digital tip pitting scars, loss of digital pulp, nailfold capillary changes, and acro-osteolysis. One study of 103 patients with SSc found that a history of digital ulcers was a significant independent predictor for radiographic progression of calcinosis (HR 3.16, 95% CI 1.22-9.43).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bdm91YWM8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (8) More recently, a cross-sectional study that included 155 SSc patients from a single center showed that a history of and/or active digital ulcers was independently associated with calcinosis (OR 3.39, 95%CI 1.32-8.69). ADDIN EN.CITE <EndNote><Cite><Author>Morardet</Author><Year>2015</Year><RecNum>1228</RecNum><DisplayText>(14)</DisplayText><record><rec-number>1228</rec-number><foreign-keys><key app="EN" db-id="rte0z9av5rdz2kerwwuvzepoa99tdr9w5wzz">1228</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Morardet, L.</author><author>Avouac, J.</author><author>Sammour, M.</author><author>Baron, M.</author><author>Kahan, A.</author><author>Feydy, A.</author><author>Allanore, Y.</author></authors></contributors><auth-address>Paris Descartes University, Sorbonne Paris Cite, Rheumatology A department, Cochin Hospital, Paris, France.
Paris Descartes University, Sorbonne paris Cite, Radiology B department, Cochin Hospital, Paris, France.
Department of Rheumatology, Jewish General Hospital, McGill University, Montreal, Canada.</auth-address><titles><title>Late nailfold videocapillaroscopy patterns associated with hand calcinosis and acro-osteolysis in systemic sclerosis</title><secondary-title>Arthritis Care Res (Hoboken)</secondary-title><alt-title>Arthritis care & research</alt-title></titles><periodical><full-title>Arthritis Care Res (Hoboken)</full-title><abbr-1>Arthritis care & research</abbr-1></periodical><alt-periodical><full-title>Arthritis Care Res (Hoboken)</full-title><abbr-1>Arthritis care & research</abbr-1></alt-periodical><dates><year>2015</year><pub-dates><date>Jul 20</date></pub-dates></dates><isbn>2151-4658 (Electronic)
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ADDIN EN.CITE.DATA (15) In the same line, vasodilator therapy has been tried for the management of calcinosis in patients with systemic sclerosis. Several case reports have shown positive results with diltiazem, the calcium channel blocker most frequently used for the medical treatment of calcinosis. More powerful vasodilatory therapies such as phosphodiesterase 5-inhibitors and prostacyclins may also play a role. Preliminary observations in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) registry have found improvement in calcinosis lesions with subcutaneous treprostinil for PAH. ADDIN EN.CITE <EndNote><Cite><Author>Valenzuela</Author><Year>2016</Year><RecNum>1246</RecNum><DisplayText>(16)</DisplayText><record><rec-number>1246</rec-number><foreign-keys><key app="EN" db-id="rte0z9av5rdz2kerwwuvzepoa99tdr9w5wzz">1246</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Valenzuela, Antonia</author><author>Chung, Lorinda</author></authors></contributors><titles><title>Management of Calcinosis Associated with Systemic Sclerosis</title><secondary-title>Current Treatment Options in Rheumatology</secondary-title></titles><periodical><full-title>Current Treatment Options in Rheumatology</full-title></periodical><pages>85-96</pages><volume>2</volume><number>1</number><dates><year>2016</year></dates><isbn>2198-6002</isbn><label>Valenzuela2016</label><work-type>journal article</work-type><urls><related-urls><url>*~hmac=cd1289569703f2677f62cb63aa1e8eb88c49a07e330bbc0d8e6a4ab8493b801c</url></related-urls></urls><electronic-resource-num>10.1007/s40674-016-0035-x</electronic-resource-num></record></Cite></EndNote>(16) These findings support a potential role for vasculopathy in the pathogenesis of calcinosis.We also found a significant association between osteoporosis and calcinosis, particularly in non-obese patients. There is a well-known association between osteoporosis and vascular calcification. ADDIN EN.CITE <EndNote><Cite><Author>Lampropoulos</Author><Year>2012</Year><RecNum>1227</RecNum><DisplayText>(17)</DisplayText><record><rec-number>1227</rec-number><foreign-keys><key app="EN" db-id="rte0z9av5rdz2kerwwuvzepoa99tdr9w5wzz">1227</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lampropoulos, C. E.</author><author>Papaioannou, I.</author><author>D'Cruz, D. P.</author></authors></contributors><auth-address>Department of Internal Medicine, General Hospital of Nafplio, Kolokotroni and Asklipiou Streets, 21100 Nafplio, Greece.</auth-address><titles><title>Osteoporosis--a risk factor for cardiovascular disease?</title><secondary-title>Nat Rev Rheumatol</secondary-title><alt-title>Nature reviews. Rheumatology</alt-title></titles><periodical><full-title>Nat Rev Rheumatol</full-title><abbr-1>Nature reviews. Rheumatology</abbr-1></periodical><alt-periodical><full-title>Nat Rev Rheumatol</full-title><abbr-1>Nature reviews. Rheumatology</abbr-1></alt-periodical><pages>587-98</pages><volume>8</volume><number>10</number><keywords><keyword>Animals</keyword><keyword>Cardiovascular Diseases/*complications</keyword><keyword>Humans</keyword><keyword>Osteoporosis/*complications/metabolism/physiopathology</keyword><keyword>Vascular Calcification/*complications/metabolism</keyword></keywords><dates><year>2012</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1759-4804 (Electronic)
1759-4790 (Linking)</isbn><accession-num>22890244</accession-num><urls><related-urls><url>;(17) Although poorly understood, proposed mechanisms have included inflammation, ADDIN EN.CITE <EndNote><Cite><Author>Fadini</Author><Year>2012</Year><RecNum>1224</RecNum><DisplayText>(18)</DisplayText><record><rec-number>1224</rec-number><foreign-keys><key app="EN" db-id="rte0z9av5rdz2kerwwuvzepoa99tdr9w5wzz">1224</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fadini, G. P.</author><author>Rattazzi, M.</author><author>Matsumoto, T.</author><author>Asahara, T.</author><author>Khosla, S.</author></authors></contributors><auth-address>Department of Medicine, University of Padova, Padova, Italy. gianpaolofadini@</auth-address><titles><title>Emerging role of circulating calcifying cells in the bone-vascular axis</title><secondary-title>Circulation</secondary-title><alt-title>Circulation</alt-title></titles><periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></periodical><alt-periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></alt-periodical><pages>2772-81</pages><volume>125</volume><number>22</number><keywords><keyword>Aging/physiology</keyword><keyword>Animals</keyword><keyword>Blood Vessels/cytology/physiology</keyword><keyword>Bone and Bones/cytology/physiology</keyword><keyword>Calcinosis/*physiopathology</keyword><keyword>Humans</keyword><keyword>Myeloid Cells/cytology/*physiology</keyword><keyword>Osteoporosis/*physiopathology</keyword><keyword>Signal Transduction/physiology</keyword><keyword>Vascular Calcification/*physiopathology</keyword></keywords><dates><year>2012</year><pub-dates><date>Jun 5</date></pub-dates></dates><isbn>1524-4539 (Electronic)
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ADDIN EN.CITE.DATA (20) and circulating cells with osteogenic/calcifying potential ADDIN EN.CITE <EndNote><Cite><Author>Fadini</Author><Year>2012</Year><RecNum>1224</RecNum><DisplayText>(18)</DisplayText><record><rec-number>1224</rec-number><foreign-keys><key app="EN" db-id="rte0z9av5rdz2kerwwuvzepoa99tdr9w5wzz">1224</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fadini, G. P.</author><author>Rattazzi, M.</author><author>Matsumoto, T.</author><author>Asahara, T.</author><author>Khosla, S.</author></authors></contributors><auth-address>Department of Medicine, University of Padova, Padova, Italy. gianpaolofadini@</auth-address><titles><title>Emerging role of circulating calcifying cells in the bone-vascular axis</title><secondary-title>Circulation</secondary-title><alt-title>Circulation</alt-title></titles><periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></periodical><alt-periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></alt-periodical><pages>2772-81</pages><volume>125</volume><number>22</number><keywords><keyword>Aging/physiology</keyword><keyword>Animals</keyword><keyword>Blood Vessels/cytology/physiology</keyword><keyword>Bone and Bones/cytology/physiology</keyword><keyword>Calcinosis/*physiopathology</keyword><keyword>Humans</keyword><keyword>Myeloid Cells/cytology/*physiology</keyword><keyword>Osteoporosis/*physiopathology</keyword><keyword>Signal Transduction/physiology</keyword><keyword>Vascular Calcification/*physiopathology</keyword></keywords><dates><year>2012</year><pub-dates><date>Jun 5</date></pub-dates></dates><isbn>1524-4539 (Electronic)
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ADDIN EN.CITE.DATA (22, 23) while another (43 SSc females) noted no effect of calcinosis on BMD. ADDIN EN.CITE <EndNote><Cite><Author>Di Munno</Author><Year>1995</Year><RecNum>518</RecNum><DisplayText>(24)</DisplayText><record><rec-number>518</rec-number><foreign-keys><key app="EN" db-id="rte0z9av5rdz2kerwwuvzepoa99tdr9w5wzz">518</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Di Munno, O.</author><author>Mazzantini, M.</author><author>Massei, P.</author><author>Ferdeghini, M.</author><author>Pitaro, N.</author><author>Latorraca, A.</author><author>Ferri, C.</author></authors></contributors><auth-address>Institute of Internal Medicine, University of Pisa, Italy.</auth-address><titles><title>Reduced bone mass and normal calcium metabolism in systemic sclerosis with and without calcinosis</title><secondary-title>Clin Rheumatol</secondary-title><alt-title>Clinical rheumatology</alt-title></titles><periodical><full-title>Clin Rheumatol</full-title><abbr-1>Clinical rheumatology</abbr-1></periodical><alt-periodical><full-title>Clin Rheumatol</full-title><abbr-1>Clinical rheumatology</abbr-1></alt-periodical><pages>407-12</pages><volume>14</volume><number>4</number><edition>1995/07/01</edition><keywords><keyword>Absorptiometry, Photon</keyword><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Bone Density</keyword><keyword>Calcinosis/complications/metabolism/ physiopathology</keyword><keyword>Calcium/ metabolism</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Middle Aged</keyword><keyword>Osteoporosis, Postmenopausal/complications/metabolism/physiopathology</keyword><keyword>Scleroderma, Systemic/complications/metabolism/ physiopathology</keyword></keywords><dates><year>1995</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0770-3198 (Print)
0770-3198 (Linking)</isbn><accession-num>7586976</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(24) One study that included 60 SSc patients showed that circulating levels of osteoprotegerin, but not RANKL, were higher in those with calcinosis. The authors suggested that this probably represented an inadequate compensatory response of osteoprotegerin as an inhibitor of calcification. PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb3ZpbzwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (26, 27) Notably, we found that SSc patients with calcinosis had a lower rate of steroid usage than those without calcinosis, yet have a higher frequency of osteoporosis. This is consistent with the previously mentioned systematic review by Omair et al. who concluded that the use of steroids did not have a significant effect on BMD in SSc patients.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PbWFpcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (4) and if any effect, would lead to underdiagnosis of osteoporosis. Finally, a recent article by Park et al. found that acro-osteolysis in patients with SSc was correlated with increased osteoclastogenesis and higher VEGF levels.(27) Interestingly, subjects with acro-osteolysis had more calcinosis than subjects without calcinosis, leading us to speculate that a similar hypoxia-induced process might also underlie calcinosis and lead to an increased risk for osteoporosis. Further research is needed to confirm the association between calcinosis and osteoporosis, and to determine its implication in the development of targeted therapies. Although historically calcinosis has been thought to be more common in patients with lcSSc, we did not find a difference in the distribution of calcinosis in the cutaneous subtypes, and this was also the case in a recent study aimed to determine whether calcinosis and acro-osteolysis were related to specific nailfold videocapillaroscopy features in SSc. ADDIN EN.CITE <EndNote><Cite><Author>Morardet</Author><Year>2015</Year><RecNum>1228</RecNum><DisplayText>(14)</DisplayText><record><rec-number>1228</rec-number><foreign-keys><key app="EN" db-id="rte0z9av5rdz2kerwwuvzepoa99tdr9w5wzz">1228</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Morardet, L.</author><author>Avouac, J.</author><author>Sammour, M.</author><author>Baron, M.</author><author>Kahan, A.</author><author>Feydy, A.</author><author>Allanore, Y.</author></authors></contributors><auth-address>Paris Descartes University, Sorbonne Paris Cite, Rheumatology A department, Cochin Hospital, Paris, France.
Paris Descartes University, Sorbonne paris Cite, Radiology B department, Cochin Hospital, Paris, France.
Department of Rheumatology, Jewish General Hospital, McGill University, Montreal, Canada.</auth-address><titles><title>Late nailfold videocapillaroscopy patterns associated with hand calcinosis and acro-osteolysis in systemic sclerosis</title><secondary-title>Arthritis Care Res (Hoboken)</secondary-title><alt-title>Arthritis care & research</alt-title></titles><periodical><full-title>Arthritis Care Res (Hoboken)</full-title><abbr-1>Arthritis care & research</abbr-1></periodical><alt-periodical><full-title>Arthritis Care Res (Hoboken)</full-title><abbr-1>Arthritis care & research</abbr-1></alt-periodical><dates><year>2015</year><pub-dates><date>Jul 20</date></pub-dates></dates><isbn>2151-4658 (Electronic)
2151-464X (Linking)</isbn><accession-num>26223810</accession-num><urls><related-urls><url>;(14) The present study confirmed the association between calcinosis and ACA and anti-PM/Scl autoantibodies. A previous study of 95 patients with lcSSc found that 60% of those who were ACA positive had calcinosis in any location compared with 26% of those who were ACA negative. ADDIN EN.CITE <EndNote><Cite><Author>Steen</Author><Year>1984</Year><RecNum>750</RecNum><DisplayText>(9)</DisplayText><record><rec-number>750</rec-number><foreign-keys><key app="EN" db-id="rte0z9av5rdz2kerwwuvzepoa99tdr9w5wzz">750</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Steen, V. D.</author><author>Ziegler, G. L.</author><author>Rodnan, G. P.</author><author>Medsger, T. A., Jr.</author></authors></contributors><titles><title>Clinical and laboratory associations of anticentromere antibody in patients with progressive systemic sclerosis</title><secondary-title>Arthritis Rheum</secondary-title><alt-title>Arthritis and rheumatism</alt-title></titles><periodical><full-title>Arthritis Rheum</full-title><abbr-1>Arthritis and rheumatism</abbr-1></periodical><alt-periodical><full-title>Arthritis Rheum</full-title><abbr-1>Arthritis and rheumatism</abbr-1></alt-periodical><pages>125-31</pages><volume>27</volume><number>2</number><edition>1984/02/01</edition><keywords><keyword>Adult</keyword><keyword>Antibodies, Antinuclear/ analysis</keyword><keyword>Calcinosis/complications/immunology</keyword><keyword>Centromere/ immunology</keyword><keyword>Chromosomes/ immunology</keyword><keyword>Female</keyword><keyword>Gastrointestinal Diseases/complications/immunology</keyword><keyword>HLA-DR1 Antigen</keyword><keyword>Histocompatibility Antigens Class II/analysis</keyword><keyword>Humans</keyword><keyword>Lung Diseases/complications/immunology</keyword><keyword>Male</keyword><keyword>Rheumatoid Factor/analysis</keyword><keyword>Scleroderma, Systemic/complications/ immunology</keyword><keyword>Syndrome</keyword><keyword>Telangiectasis/complications/immunology</keyword><keyword>Time Factors</keyword></keywords><dates><year>1984</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0004-3591 (Print)
0004-3591 (Linking)</isbn><accession-num>6607734</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(9) The positive association between calcinosis and anti-PM/Scl antibody was also described by D’Aoust et al. in a study of 763 SSc patients, where 58% of patients with positive anti-PM/Scl antibodies had calcinosis vs. 30% in patients without these antibodies.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EJmFwb3M7QW91c3Q8L0F1dGhvcj48WWVhcj4yMDE0PC9Z
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ADDIN EN.CITE.DATA (10) However, muscle disease was less frequent in our calcinosis group. The discrepancy between the higher frequency of anti-PM/Scl and lower frequency of muscle disease in the calcinosis group may partially be explained by the fact that muscle involvement in our study included the spectrum of non-inflammatory myopathy as well as myositis. In the subgroup of patients who had anticardiolipin antibodies assessed, we found they were more frequent in the calcinosis group. This variable was not included in the multivariate model given that results were only available in 18% of patients. The association between anticardiolipin antibodies and calcinosis suggests the possibility that these antibodies might play a role in the development of vascular injury in SSc with subsequent development of calcinosis. ADDIN EN.CITE <EndNote><Cite><Author>Katayama</Author><Year>1990</Year><RecNum>1180</RecNum><DisplayText>(28)</DisplayText><record><rec-number>1180</rec-number><foreign-keys><key app="EN" db-id="rte0z9av5rdz2kerwwuvzepoa99tdr9w5wzz">1180</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Katayama, I.</author><author>Otoyama, K.</author><author>Kondo, S.</author><author>Nishioka, K.</author><author>Nishiyama, S.</author></authors></contributors><auth-address>Department of Dermatology, Kitasato University School of Medicine, Kanagawa, Japan.</auth-address><titles><title>Clinical manifestations in anticardiolipin antibody-positive patients with progressive systemic sclerosis</title><secondary-title>J Am Acad Dermatol</secondary-title><alt-title>Journal of the American Academy of Dermatology</alt-title></titles><periodical><full-title>J Am Acad Dermatol</full-title><abbr-1>Journal of the American Academy of Dermatology</abbr-1></periodical><alt-periodical><full-title>J Am Acad Dermatol</full-title><abbr-1>Journal of the American Academy of Dermatology</abbr-1></alt-periodical><pages>198-201</pages><volume>23</volume><number>2 Pt 1</number><edition>1990/08/01</edition><keywords><keyword>Autoantibodies/ analysis</keyword><keyword>Cardiolipins/ immunology</keyword><keyword>Enzyme-Linked Immunosorbent Assay</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Rheumatoid Factor/immunology</keyword><keyword>Scleroderma, Systemic/classification/ immunology</keyword><keyword>Thrombocytopenia/immunology</keyword></keywords><dates><year>1990</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0190-9622 (Print)
0190-9622 (Linking)</isbn><accession-num>2212115</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(28)A noteworthy strength of our study is that it is the largest to examine specific clinical associations with calcinosis including multiple centers throughout the world. However, we recognize some limitations. Our study is retrospective in design, thus missing data were unavoidable. Since not all patients had radiographs available, we cannot exclude the possibility of subclinical calcinosis. Likewise, densitometry for the assessment of osteoporosis was not performed systematically on all patients. Another limitation is that patients with overlap disease were included in this study, and we do not know how many of these patients had dermatomyositis overlap, which certainly might affect the prevalence of calcinosis. However, given that we did not find an association between muscle disease and calcinosis, the number of patients with classical DM (as opposed to amyopathic) overlap was likely small. Finally, we did not have information on the localization or severity of calcifications in this study, but we are currently performing a prospective cohort study that will provide more details regarding the distribution and quantity of calcinosis using the novel radiographic scoring system.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaHVuZzwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (29) Nonetheless, our data support a strong association of calcinosis with digital ulcers as well as osteoporosis, which may shed light on the pathogenesis of calcinosis and guide the development of future therapies. Acknowledgments Investigators of the Canadian Scleroderma Research Group: J. Pope, London, Ontario; M. Baron, Montreal, Quebec; J. Markland, Saskatoon, Saskatchewan; D. Robinson, Winnipeg, Manitoba; N. Jones, Edmonton, Alberta; N. Khalidi, Hamilton, Ontario; P. Docherty, Moncton, New Brunswick; E. Kaminska, Calgary, Alberta; A. Masetto, Sherbrooke, Quebec; E. Sutton, Halifax, Nova Scotia; J-P. Mathieu, Montreal, Quebec; M. Hudson, Montreal, Quebec; S. Ligier, Montreal, Quebec; T. Grodzicky, Montreal, Quebec; S. LeClercq, Calgary, Alberta; C. Thorne, Newmarket, Ontario; G. Gyger, Montreal, Quebec; D. Smith, Ottawa, Ontario; P.R. Fortin, Quebec, Quebec; M. Larché, Hamilton, Ontario; M. Fritzler, Mitogen Advanced Diagnostics Laboratory, Calgary, Alberta.Australian Scleroderma Interest Group: Mandana Nikpour (St Vincent's Hospital Melbourne VIC), Jo Sahhar (Monash Medical Centre, Clayton VIC), Peter Youssef (Royal Prince Alfred Hospital, Sydney NSW), Peter Nash (Rheumatology Research Unit, Sunshine Coast QLD), Jane Zochling (Menzies Research Unit, Hobart, TAS), Janet Roddy (Royal Perth Hospital, WA), Jenny Walker (Flinders Medical Centre, SA), Catherine Hill (The Queen Elizabeth Hospital, SA), Kathie Tymms (Canberra, ACT), Allan Sturgess (St George Hospital, Sydney, NSW), Les Schrieber (Royal North Shore Hospital, Sydney, NSW), Gabor Major (John Hunter, Newcastle, NSW), Vivek Thakkar (Liverpool Hospital, NSW)We thank Shufeng Li for statistical support.References ADDIN EN.REFLIST 1.Gutierrez A, Jr., Wetter DA. Calcinosis cutis in autoimmune connective tissue diseases. Dermatologic therapy. 2012;25(2):195-206.2.Valenzuela A, Chung L. 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Demographic characteristics and clinical features in SSc patients with and without calcinosisSample sizen (%)Without calcinosisn (%)With calcinosisn (%)p-valueTotal5218 (100)3928/5218 (75.3)1290/5218 (24.7)-Age at last visit (mean years ± SD)4929 (94.5)56.8 ± 13.459.4 ± 12.8<0.0001Female 5218 (100)3279/3928 (83.5)1149/1290 (89.1)<0.0001Race Caucasian Asian African-American Hispanic Other or unknown5022 (96.2)3220/3787 (85)108/3787 (2.9)33/3787 (0.9)232/3787 (6.1)194/3787 (5.1)1047/1235 (84.8)30/1235 (2.4)12/1235 (1)86/1235 (7)60/1235 (4.9)0.7584Smoking Never Ever5057 (96.9)2023/3811 (53.1)1788/3811 (46.9)678/1246 (54.4)568/1246 (45.6)0.4136SSc Subtype Diffuse Limited5211 (99.9)1511/3922 (38.5)2411/3922 (61.5)495/1289 (38.4)794/1289 (61.6)0.6200mRSS at first visit (mean ± SD)4978 (95.4)10.0 ± 10.510.7 ± 9.80.0635mRSS≥11 at first visit 4978 (95.4)1275/3745 (34.1)454/1233 (36.8)0.0758Maximum mRSS (mean ± SD)3838 (73.6)12.3 ± 11.913.6 ± 11.40.0071Disease duration from RP symptom (mean years ± SD) 4915 (94.2)10.4 ± 11.717.1 ± 13.8<0.0001Disease duration from first non-RP symptom (mean years ± SD)5052 (96.8)8.3 ±9.212.9 ± 10.4<0.0001BMI3473 (66.6)26.0 ± 6.625.4 ± 24.90.006Obese 3473 (66.6)557/2561 (21.8)163/912 (17.9)0.0131Steroid use ever3509 (67.2)1292/2565 (50.4)392/938 (41.8)<0.0001Chronic renal disease3736 (71.6)88/2963 (3.0)20/773 (3.8)0.2665Raynaud phenomenon5199 (99.6)3773/3912 (96.5)1271/1287 (98.8)<0.0001Digital ulcers4992 (95.7)1293/3764 (34.4)804/1228 (65.5)<0.0001Digital pitting scars5182 (99.3)1477/3898 (37.9)835/1284 (65)<0.0001Loss of digital pulp3452 (66.1)735/2365 (31.1)619/1087 (57)<0.0001Nailfold capillary changesa3826 (73.3)1365/3051 (44.7)534/775 (68.9)<0.0001Puffy fingers4922 (94.3)2531/3726 (67.9)770/1196 (64.4)0.0232Sclerodactyly5204 (99.7)3420/3917 (87.3)1181/1287 (91.8)<0.0001Acro-osteolysis1156 (22.1)82/871 (9.4)76/285 (26.7)<0.0001Telangiectasias4888 (93.7)2392/3701 (64.6)1048/1187 (88.3)<0.0001Tendon friction rub4869 (93.3)627/3676 (17.1)219/1193 (18.4)0.3030Osteoporosis2127 (40.8)51/1816 (2.8)71/311 (22.8)<0.0001SRC5176 (99.2)188/3891 (4.8)60/1285 (4.7)0.8132Cardiac disease Pericardial involvement Myocardial involvement Conduction abnormalities4907 (94)1986 (38)1986 (38)2076 (40)463/3709 (12.5)73/1292 (5.7)48/1292 (3.7)188/1486 (12.7)217/1198 (18.1)72/694 (10.4)60/694 (8.7)79/590 (13.4)<0.0001<0.0001<0.00010.6503PAH4990 (95.8)517/3757 (13.8)202/1233 (16.4)0.0229Pulmonary fibrosis3860 (74)1081/3070 (35.2)283/790 (35.8)0.7486GI disease GERD symptoms Esophageal dysmotility Esophageal stricture Use of antibiotics for SIBO Malabsorption GAVE5179 (99.3)3343331634233440209819972477/3920 (63.2)1663/2299 (73.3)753/2277 (33.1)148/2360 (6.3)111/2372 (4.7)89/1518 (5.9)69/1320 (5.2)938/1259 (74.5)837/1044 (80.2)397/1039 (38.2)165/1063 (15.5)112/1068 (10.5)58/580 (10)45/677 (6.7)<0.0001<0.00010.0039<0.0001<0.00010.00090.1955Muscle diseaseb4580 (87.8)410/3325 (12.3)111/1255 (8.8)0.0009Arthritisc4606 (88.3)936/3504 (26.7)329/1102 (29.9)0.0415Use of vasodilators everd5218 (100)2079/3928 (52.93)825/1290 (63.95)<0.0001Use of biphosphonates ever2395 (45.9)69/1987 (3.47)48/408 (11.76)<0.0001Abbreviations: mRSS=modified Rodnan skin score, RP= Raynaud phenomenon, BMI=Body mass index, SRC=Scleroderma renal crisis, PAH=pulmonary artery hypertension, GI=gastrointestinal, GERD= gastroesophageal reflux, SIBO= small intestine bacterial overgrowth, GAVE=gastric antral vascular ectasia. a Nailfold capillary changes included pericapillary hemorrhages, dilated loops, and drop-outs. b Muscle disease was defined as proximal muscle weakness on physical examination and any of the following: muscle biopsy showing myositis, electromyogram showing a myopathic pattern, or elevated serum enzymes reflecting muscle disease. c Arthritis was defined as radiologic evidence of erosive arthritis or clinical synovitis, defined by tender and swollen jointsdVasodilators included calcium channel blockers, endothelin-1 receptor antogonists, phosphodiesterase inhibitors, and prostanoids.Table 2. Autoantibodies in SSc patients with and without calcinosis Sample sizen (%)Without calcinosisn (%)Withcalcinosisn (%)p-valuePositive ANA 4689 (89.9)3316/3494 (94.9)1123/1195 (94)0.2164Positive Scl-704578 (87.7)698/3409 (20.5)166/1169 (14.2)<0.0001Positive ACA3370 (64.6)717/2651 (27.1)277/719 (38.5)<0.0001Positive anti-PM/Scl 1825 (35)87/1365 (6.4)49/460 (10.7)0.0025Positive RNA-polymerase-III2414 (46.3)481/1772 (27.1)143/642 (22.3)0.0157Positive U1-RNP4286 (82.1)238/3174 (7.5)47/1112 (4.2)0.0002Positive Lupus anticoagulant1637 (31.4)44/1118 (3.9)28/519 (5.4)0.1803Positive Anti-Beta-2-glycoprotein588 (11.3)105/401 (26.2)46/187 (24.6)0.6819Positive Anticardiolipin949 (18.2)200/653 (30.6)125/296 (42.2)0.0005Abbreviations: ANA=antinuclear, ACA=anticentromere, RNP= RibonucleoproteinTable 3. Univariate and multivariate analysesUnivariate analysisMultivariate analysisOR95%CIp-valueOR95%CIp-valueAge at last visit1.021.01 – 1.02<0.0001*Disease duration1.051.04 – 1.05<0.0001*---Female1.61.3 – 2<0.0001*3.11.5 – 6.20.0016Obese0.80.6 – 0.90.0133Steroids use ever 0.70.6 – 0.8<0.0001*mRSS >111.10.98 – 1.30.0759---Puffy fingers0.80.7-0.90.0232Sclerodactyly1.61.3-2.0<0.0001*Raynaud phenomenon2.91.7-4.9<0.0001*Digital ulcers3.63.2 – 4.2<0.0001*3.92.7-5.5<0.0001Digital pitting scars3.02.7-3.5<0.0001*Loss of digital pulp2.92.5-3.4<0.0001*Nailfold capillary changes2.72.3-3.2<0.0001*Acro-osteolysis3.52.5 – 4.9<0.0001*Telangiectasias4.13.4 – 4.9<0.0001*3.62.2 – 5.8<0.0001Osteoporosis10.26.9 – 15<0.0001*4.22.3 – 7.9<0.0001Cardiac disease1.61.3 – 1.9<0.0001*1.81.1 – 2.90.0181PAH1.21.0 – 1.50.0231GI disease1.71.5 – 2<0.0001*1.71.1 – 2.60.0128Muscle disease0.70.6 – 0.90.001*---Arthritis1.21.0 – 1.40.0416Scl-700.60.5-0.8<0.0001*Anticentromere1.71.4 – 2<0.0001*2.21.5 – 3.2<0.0001Anti-PM/Scl1.81.2 – 2.50.0028RNA polymerase III0.80.6-0.90.0159U1-RNP0.50.4-0.80.0002*Anticardiolipin1.71.2 – 2.20.0005*Vasodilators use1.61.4-1.8<0.0001*Abbreviations: mRSS=modified Rodnan skin score, PAH=pulmonary artery hypertension, GI=gastrointestinal, ACA=anticentromere, RNP= Ribonucleoprotein* Adjusted p-value <0.05**Multivariate model included: disease duration from first non-RP symptoms, gender, mRSS, digital ulcers, telangiectasias, osteoporosis, cardiac disease, GI disease, muscle disease, and anticentromere antibody. ***Age at last visit was correlated with disease duration. Although not significant in univariate analysis, we retained mRSS in the model given its clinical relevance. RP, digital pitting scars, loss of digital pulp, nailfold capillary changes, acro-osteolyisis, vasodilators use, and PAH were excluded given correlation with digital ulcers. Scl-70, PM-1, RNA-polymerase-III, and U1-RNP were excluded because they are essentially mutually exclusive. Anticardiolipin was excluded because the low number of patients tested for this antibody. ................
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