Calcinosis is associated with digital ulcers and osteoporosis in patients with systemic sclerosis: A Scleroderma Clinical Trials Consortium study

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Abstract

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.

Introduction

Calcinosis is a rare disorder characterized by deposition of calcium in skin and subcutaneous tissues [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 [2]. Calcinosis is often painful and may be associated with recurrent episodes of local inflammation or infection, leading to considerable functional impairment [3].

Calcinosis in patients with SSc is a late manifestation, most often occurring more than 7.5 years after the diagnosis [1]. It typically involves the hands and feet, particularly the fingers [4]. Calcinosis in SSc has been associated with male gender [5], digital ulcers [5], [6], [7], digital tip pitting scars [6], acro-osteolysis [8], late nailfold videocapillaroscopy pattern [7], anticentromere antibody (ACA) [9], and anti-PM/Scl antibody [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 multicenter 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.

Section snippets

Study design

This is a retrospective multicenter cohort study of 5218 patients with SSc from 9 cohorts within the United States (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

Patient characteristics and calcinosis

Of 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. Overall, 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

Discussion

Calcinosis 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

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;

References (29)

  • N. Boulman et al.

    Calcinosis in rheumatic diseases

    Semin Arthritis Rheum

    (2005)
  • S. Koutaissoff et al.

    Hand radiological damage in systemic sclerosis: comparison with a control group and clinical and functional correlations

    Semin Arthritis Rheum

    (2011)
  • I. Katayama et al.

    Clinical manifestations in anticardiolipin antibody-positive patients with progressive systemic sclerosis

    J Am Acad Dermatol

    (1990)
  • A. Gutierrez et al.

    Calcinosis cutis in autoimmune connective tissue diseases

    Dermatol Ther

    (2012)
  • A. Valenzuela et al.

    Calcinosis: pathophysiology and management

    Curr Opin Rheumatol

    (2015)
  • S.J. Balin et al.

    Calcinosis cutis occurring in association with autoimmune connective tissue disease: the Mayo Clinic experience with 78 patients, 1996–2009

    Arch Dermatol

    (2012)
  • J. Avouac et al.

    Predictive factors of hand radiographic lesions in systemic sclerosis: a prospective study

    Ann Rheum Dis

    (2011)
  • L. Morardet et al.

    Late nailfold videocapillaroscopy pattern associated with hand calcinosis and acro-osteolysis in systemic sclerosis

    Arthritis Care Res

    (2016)
  • E.M. Johnstone et al.

    Acro-osteolysis in systemic sclerosis is associated with digital ischaemia and severe calcinosis

    Rheumatology (Oxford)

    (2012)
  • V.D. Steen et al.

    Clinical and laboratory associations of anticentromere antibody in patients with progressive systemic sclerosis

    Arthritis Rheum

    (1984)
  • J. D’Aoust et al.

    Clinical and serologic correlates of anti-PM/Scl antibodies in systemic sclerosis: a multicenter study of 763 patients

    Arthritis Rheumatol (Hoboken, NJ)

    (2014)
  • E.C. LeRoy et al.

    Criteria for the classification of early systemic sclerosis

    J Rheumatol

    (2001)
  • R.T. Domsic et al.

    Skin thickness progression rate: a predictor of mortality and early internal organ involvement in diffuse scleroderma

    Ann Rheum Dis

    (2011)
  • F. van den Hoogen et al.

    2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League Against Rheumatism Collaborative Initiative

    Arthritis Rheum

    (2013)
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