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.
Keywords: Systemic sclerosis, Calcinosis, Digital ulcers, 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 [5–7], 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.
Methods
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 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 [11]. We defined organ system involvement as described previously [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 population
We 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 [13].
Statistical analysis
To 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 steroid 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).
Results
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 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).
Table 1.
Demographic characteristics and clinical features in SSc patients with and without calcinosis
| Sample size n (%) | Without calcinosis n (%) | With calcinosis n (%) | p Value | |
|---|---|---|---|---|
| Total | 5218 (100) | 3928/5218 (75.3) | 1290/5218 (24.7) | – |
| Age at last visit (mean years ± SD) | 4929 (94.5) | 56.8 ± 13.4 | 59.4 ± 12.8 | < 0.0001 |
| Female | 5218 (100) | 3279/3928 (83.5) | 1149/1290 (89.1) | < 0.0001 |
| Race | 5022 (96.2) | 0.7584 | ||
| Caucasian | 3220/3787 (85) | 1047/1235 (84.8) | ||
| Asian | 108/3787 (2.9) | 30/1235 (2.4) | ||
| African-American | 33/3787 (0.9) | 12/1235 (1) | ||
| Hispanic | 232/3787 (6.1) | 86/1235 (7) | ||
| Other or unknown | 194/3787 (5.1) | 60/1235 (4.9) | ||
| Smoking | 5057 (96.9) | 0.4136 | ||
| Never | 2023/3811 (53.1) | 678/1246 (54.4) | ||
| Ever | 1788/3811 (46.9) | 568/1246 (45.6) | ||
| SSc Subtype | 5211 (99.9) | 0.6200 | ||
| Diffuse | 1511/3922 (38.5) | 495/1289 (38.4) | ||
| Limited | 2411/3922 (61.5) | 794/1289 (61.6) | ||
| mRSS at first visit (mean ± SD) | 4978 (95.4) | 10.0 ± 10.5 | 10.7 ± 9.8 | 0.0635 |
| mRSS ≥ 11 at first visit | 4978 (95.4) | 1275/3745 (34.1) | 454/1233 (36.8) | 0.0758 |
| Maximum mRSS (mean ± SD) | 3838 (73.6) | 12.3 ± 11.9 | 13.6 ± 11.4 | 0.0071 |
| Disease duration from RP symptom (mean years ± SD) | 4915 (94.2) | 10.4 ± 11.7 | 17.1 ± 13.8 | < 0.0001 |
| Disease duration from first non-RP symptom (mean years ± SD) | 5052 (96.8) | 8.3 ± 9.2 | 12.9 ± 10.4 | < 0.0001 |
| BMI | 3473 (66.6) | 26.0 ± 6.6 | 25.4 ± 24.9 | 0.006 |
| Obese | 3473 (66.6) | 557/2561 (21.8) | 163/912 (17.9) | 0.0131 |
| Steroid use ever | 3509 (67.2) | 1292/2565 (50.4) | 392/938 (41.8) | < 0.0001 |
| Chronic renal disease | 3736 (71.6) | 88/2963 (3.0) | 20/773 (3.8) | 0.2665 |
| Raynaud phenomenon | 5199 (99.6) | 3773/3912 (96.5) | 1271/1287 (98.8) | < 0.0001 |
| Digital ulcers | 4992 (95.7) | 1293/3764 (34.4) | 804/1228 (65.5) | < 0.0001 |
| Digital pitting scars | 5182 (99.3) | 1477/3898 (37.9) | 835/1284 (65) | < 0.0001 |
| Loss of digital pulp | 3452 (66.1) | 735/2365 (31.1) | 619/1087 (57) | < 0.0001 |
| Nailfold capillary changesa | 3826 (73.3) | 1365/3051 (44.7) | 534/775 (68.9) | < 0.0001 |
| Puffy fingers | 4922 (94.3) | 2531/3726 (67.9) | 770/1196 (64.4) | 0.0232 |
| Sclerodactyly | 5204 (99.7) | 3420/3917 (87.3) | 1181/1287 (91.8) | < 0.0001 |
| Acro-osteolysis | 1156 (22.1) | 82/871 (9.4) | 76/285 (26.7) | < 0.0001 |
| Telangiectasias | 4888 (93.7) | 2392/3701 (64.6) | 1048/1187 (88.3) | < 0.0001 |
| Tendon friction rub | 4869 (93.3) | 627/3676 (17.1) | 219/1193 (18.4) | 0.3030 |
| Osteoporosis | 2127 (40.8) | 51/1816 (2.8) | 71/311 (22.8) | < 0.0001 |
| SRC | 5176 (99.2) | 188/3891 (4.8) | 60/1285 (4.7) | 0.8132 |
| Cardiac disease | 4907 (94) | 463/3709 (12.5) | 217/1198 (18.1) | < 0.0001 |
| Pericardial involvement | 1986 (38) | 73/1292 (5.7) | 72/694 (10.4) | < 0.0001 |
| Myocardial involvement | 1986 (38) | 48/1292 (3.7) | 60/694 (8.7) | < 0.0001 |
| Conduction abnormalities | 2076 (40) | 188/1486 (12.7) | 79/590 (13.4) | 0.6503 |
| PAH | 4990 (95.8) | 517/3757 (13.8) | 202/1233 (16.4) | 0.0229 |
| Pulmonary fibrosis | 3860 (74) | 1081/3070 (35.2) | 283/790 (35.8) | 0.7486 |
| GI disease | 5179 (99.3) | 2477/3920 (63.2) | 938/1259 (74.5) | < 0.0001 |
| GERD symptoms | 3343 | 1663/2299 (73.3) | 837/1044 (80.2) | < 0.0001 |
| Esophageal dysmotility | 3316 | 753/2277 (33.1) | 397/1039 (38.2) | 0.0039 |
| Esophageal stricture | 3423 | 148/2360 (6.3) | 165/1063 (15.5) | < 0.0001 |
| Use of antibiotics for SIBO | 3440 | 111/2372 (4.7) | 112/1068 (10.5) | < 0.0001 |
| Malabsorption | 2098 | 89/1518 (5.9) | 58/580 (10) | 0.0009 |
| GAVE | 1997 | 69/1320 (5.2) | 45/677 (6.7) | 0.1955 |
| Muscle diseaseb | 4580 (87.8) | 410/3325 (12.3) | 111/1255 (8.8) | 0.0009 |
| Arthritisc | 4606 (88.3) | 936/3504 (26.7) | 329/1102 (29.9) | 0.0415 |
| Use of vasodilators everd | 5218 (100) | 2079/3928 (52.93) | 825/1290 (63.95) | < 0.0001 |
| Use of biphosphonates ever | 2395 (45.9) | 69/1987 (3.47) | 48/408 (11.76) | < 0.0001 |
Abbreviations: 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.
Nailfold capillary changes included pericapillary hemorrhages, dilated loops, and drop-outs.
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.
Arthritis was defined as radiologic evidence of erosive arthritis or clinical synovitis, defined by tender and swollen joints.
Vasodilators included calcium channel blockers, endothelin-1 receptor antogonists, phosphodiesterase inhibitors, and prostanoids.
Autoantibodies and calcinosis
Anti-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).
Table 2.
Autoantibodies in SSc patients with and without calcinosis
| Sample size n (%) | Without calcinosis n (%) | With calcinosis n (%) | p Value | |
|---|---|---|---|---|
| Positive ANA | 4689 (89.9) | 3316/3494 (94.9) | 1123/1195 (94) | 0.2164 |
| Positive Scl-70 | 4578 (87.7) | 698/3409 (20.5) | 166/1169 (14.2) | < 0.0001 |
| Positive ACA | 3370 (64.6) | 717/2651 (27.1) | 277/719 (38.5) | < 0.0001 |
| Positive anti-PM/Scl | 1825 (35) | 87/1365 (6.4) | 49/460 (10.7) | 0.0025 |
| Positive RNA-polymerase-III | 2414 (46.3) | 481/1772 (27.1) | 143/642 (22.3) | 0.0157 |
| Positive U1-RNP | 4286 (82.1) | 238/3174 (7.5) | 47/1112 (4.2) | 0.0002 |
| Positive Lupus anticoagulant | 1637 (31.4) | 44/1118 (3.9) | 28/519 (5.4) | 0.1803 |
| Positive anti-beta-2-glycoprotein | 588 (11.3) | 105/401 (26.2) | 46/187 (24.6) | 0.6819 |
| Positive anticardiolipin | 949 (18.2) | 200/653 (30.6) | 125/296 (42.2) | 0.0005 |
Abbreviations: ANA = antinuclear, ACA = anticentromere, RNP = ribonucleoprotein.
Factors associated with calcinosis in univariate and multivariate analysis
In 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 < 0.0001). 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).
Table 3.
Univariate and multivariate analyses
| Univariate analysis
|
Multivariate analysis**
|
|||||
|---|---|---|---|---|---|---|
| OR | 95% CI | p Value | OR | 95% CI | p Value | |
| Age at last visit | 1.02 | 1.01–1.02 | < 0.0001* | |||
| Disease duration | 1.05 | 1.04–1.05 | < 0.0001* | – | – | – |
| Female | 1.6 | 1.3–2 | < 0.0001* | 3.1 | 1.5–6.2 | 0.0016 |
| Obese | 0.8 | 0.6–0.9 | 0.0133 | |||
| Steroids use ever | 0.7 | 0.6–0.8 | < 0.0001* | |||
| mRSS > 11 | 1.1 | 0.98–1.3 | 0.0759 | – | – | – |
| Puffy fingers | 0.8 | 0.7–0.9 | 0.0232 | |||
| Sclerodactyly | 1.6 | 1.3–2.0 | < 0.0001* | |||
| Raynaud phenomenon | 2.9 | 1.7–4.9 | < 0.0001* | |||
| Digital ulcers | 3.6 | 3.2–4.2 | < 0.0001* | 3.9 | 2.7–5.5 | < 0.0001 |
| Digital pitting scars | 3.0 | 2.7–3.5 | < 0.0001* | |||
| Loss of digital pulp | 2.9 | 2.5–3.4 | < 0.0001* | |||
| Nailfold capillary changes | 2.7 | 2.3–3.2 | < 0.0001* | |||
| Acro-osteolysis | 3.5 | 2.5–4.9 | < 0.0001* | |||
| Telangiectasias | 4.1 | 3.4–4.9 | < 0.0001* | 3.6 | 2.2–5.8 | < 0.0001 |
| Osteoporosis | 10.2 | 6.9–15 | < 0.0001* | 4.2 | 2.3–7.9 | < 0.0001 |
| Cardiac disease | 1.6 | 1.3–1.9 | < 0.0001* | 1.8 | 1.1–2.9 | 0.0181 |
| PAH | 1.2 | 1.0–1.5 | 0.0231 | |||
| GI disease | 1.7 | 1.5–2 | < 0.0001* | 1.7 | 1.1–2.6 | 0.0128 |
| Muscle disease | 0.7 | 0.6–0.9 | 0.001* | – | – | – |
| Arthritis | 1.2 | 1.0–1.4 | 0.0416 | |||
| Scl-70 | 0.6 | 0.5–0.8 | < 0.0001* | |||
| Anticentromere | 1.7 | 1.4–2 | < 0.0001* | 2.2 | 1.5–3.2 | < 0.0001 |
| Anti-PM/Scl | 1.8 | 1.2–2.5 | 0.0028 | |||
| RNA-polymerase-III | 0.8 | 0.6–0.9 | 0.0159 | |||
| U1-RNP | 0.5 | 0.4–0.8 | 0.0002* | |||
| Anticardiolipin | 1.7 | 1.2–2.2 | 0.0005* | |||
| Vasodilators use | 1.6 | 1.4–1.8 | < 0.0001* | |||
Abbreviations: mRSS = modified Rodnan skin score, PAH = pulmonary artery hypertension, GI = gastrointestinal, ACA = anticentromere, RNP = ribonucleoprotein.
Adjusted p < 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.
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 significant independent predictor for radiographic progression of calcinosis (HR = 3.16, 95% CI: 1.22–9.43) [5]. Koutaissoff et al. [6] reported that SSc patients with terminal tuft calcinosis on hand radiographs were more likely to have digital ulcerations (28% vs. 11%, p = 0.03), digital pitting scars (64% vs. 38%, p = 0.03), and a history of digital gangrene (75% vs. 45%, p = 0.008). A retrospective study of 101 SSc patients concluded that those with moderate or severe acro-osteolysis (assessed by hand radiographs) were more likely to have severe calcinosis (33% vs. 13%), although this did not reach statistical significance after adjustment for potential confounders [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) [14]. Similarly, in a cross-sectional study of 126 patients with DM, our group found that patients with calcinosis were significantly more likely to have fingertip ulcers than patients without calcinosis (50.0% vs. 9.3%, p < 0.001) [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 need to be further evaluated, but preliminary observations in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) registry have found improvement in calcinosis lesions with subcutaneous treprostinil in SSc patients being treated for PAH [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 [17]. Although poorly understood, proposed mechanisms have included inflammation [18], osteoblast-like behavior of vascular cells [19], involvement of pathways including osteoprotegerin, an inhibitor of bone resorption and calcification, and RANKL, a key factor of osteoclast maturation [20], and circulating cells with osteogenic/calcifying potential [18]. Although there are no data supporting the association of osteoporosis and extravascular calcifications, it is plausible that there might be shared mechanisms. Multiple mouse models with deletions of bone-related genes display vascular and ectopic calcification, including targeted deletions of osteoprotegerin and fetuin-A, another inhibitor of calcification, in knockout mice [19]. A systematic review [21 ] identified calcinosis as a candidate risk factor for low bone mineral density (BMD) in SSc patients; however, the data were conflicting with two small studies (37 and 25 SSc patients, respectively) reporting lower total bone mineral content in patients with calcinosis (p < 0.05) [22,23], while another (43 SSc females) noted no effect of calcinosis on BMD [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 [25]. Two case reports showed successful use of bisphosphonates for the treatment of calcinosis in SSc patients suggesting that impaired bone metabolism may play a role in the pathogenesis of calcinosis [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. [21 ] who concluded that the use of steroids did not have a significant effect on BMD in SSc patients. Of note, areas of calcinosis overlying the field of the lumbar spine, or the proximal femur might artifactually increase BMD, but these are not common locations for calcinosis [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]. Subjects with acro-osteolysis were more likely to have calcinosis than subjects without acro-osteolysis, 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 video-capillaroscopy features in SSc [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 [9]. The positive association between calcinosis and anti-PM/Scl antibody was also described by D’ Aoust et al. [10] 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. 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 [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 [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.
Supplementary Material
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.
Investigators of the 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.
Abbreviations
- SSc
systemic sclerosis
- DM
dermatomyositis
- ACA
anticentromere antibody
- OR
Odds ratios
- RP
Raynaud phenomenon
- ANA
antinuclear antibodies
- BMI
body mass index
- BMD
bone mineral density
Appendix A. Supplementary material
Supplementary data are available in the online version of this article at http://dx.doi.org/10.1016/j.semarthrit.2016.05.008
References
- 1.Gutierrez A, Jr, Wetter DA. Calcinosis cutis in autoimmune connective tissue diseases. Dermatol Ther. 2012;25:195–206. doi: 10.1111/j.1529-8019.2012.01492.x. [DOI] [PubMed] [Google Scholar]
- 2.Valenzuela A, Chung L. Calcinosis: pathophysiology and management. Curr Opin Rheumatol. 2015;27:542–8. doi: 10.1097/BOR.0000000000000220. [DOI] [PubMed] [Google Scholar]
- 3.Boulman N, Slobodin G, Rozenbaum M, Rosner I. Calcinosis in rheumatic diseases. Semin Arthritis Rheum. 2005;34:805–12. doi: 10.1016/j.semarthrit.2005.01.016. [DOI] [PubMed] [Google Scholar]
- 4.Balin SJ, Wetter DA, Andersen LK, Davis MD. Calcinosis cutis occurring in association with autoimmune connective tissue disease: the Mayo Clinic experience with 78 patients, 1996–2009. Arch Dermatol. 2012;148:455–62. doi: 10.1001/archdermatol.2011.2052. [DOI] [PubMed] [Google Scholar]
- 5.Avouac J, Mogavero G, Guerini H, Drape JL, Mathieu A, Kahan A, et al. Predictive factors of hand radiographic lesions in systemic sclerosis: a prospective study. Ann Rheum Dis. 2011;70:630–3. doi: 10.1136/ard.2010.134304. [DOI] [PubMed] [Google Scholar]
- 6.Koutaissoff S, Vanthuyne M, Smith V, De Langhe E, Depresseux G, Westhovens R, et al. Hand radiological damage in systemic sclerosis: comparison with a control group and clinical and functional correlations. Semin Arthritis Rheum. 2011;40:455–60. doi: 10.1016/j.semarthrit.2010.06.008. [DOI] [PubMed] [Google Scholar]
- 7.Morardet L, Avouac J, Sammour M, Baron M, Kahan A, Feydy A, et al. Late nailfold videocapillaroscopy pattern associated with hand calcinosis and acro-osteolysis in systemic sclerosis. Arthritis Care Res. 2016;68:366–73. doi: 10.1002/acr.22672. [DOI] [PubMed] [Google Scholar]
- 8.Johnstone EM, Hutchinson CE, Vail A, Chevance A, Herrick AL. Acro-osteolysis in systemic sclerosis is associated with digital ischaemia and severe calcinosis. Rheumatology (Oxford) 2012;51:2234–8. doi: 10.1093/rheumatology/kes214. [DOI] [PubMed] [Google Scholar]
- 9.Steen VD, Ziegler GL, Rodnan GP, Medsger TA., Jr Clinical and laboratory associations of anticentromere antibody in patients with progressive systemic sclerosis. Arthritis Rheum. 1984;27:125–31. doi: 10.1002/art.1780270202. [DOI] [PubMed] [Google Scholar]
- 10.D’Aoust J, Hudson M, Tatibouet S, Wick J, Mahler M, Baron M, 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;66:1608–15. doi: 10.1002/art.38428. [DOI] [PubMed] [Google Scholar]
- 11.LeRoy EC, Medsger TA., Jr Criteria for the classification of early systemic sclerosis. J Rheumatol. 2001;28:1573–6. [PubMed] [Google Scholar]
- 12.Domsic RT, Rodriguez-Reyna T, Lucas M, Fertig N, Medsger TA., Jr Skin thickness progression rate: a predictor of mortality and early internal organ involvement in diffuse scleroderma. Ann Rheum Dis. 2011;70:104–9. doi: 10.1136/ard.2009.127621. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League Against Rheumatism Collaborative Initiative. Arthritis Rheum. 2013;65(11):2737–47. doi: 10.1002/art.38098. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Morardet L, Avouac J, Sammour M, Baron M, Kahan A, Feydy A, et al. Late nailfold videocapillaroscopy patterns associated with hand calcinosis and acro-osteolysis in systemic sclerosis. Arthritis Care Res. 2016;68(3):366–73. doi: 10.1002/acr.22672. [DOI] [PubMed] [Google Scholar]
- 15.Valenzuela A, Chung L, Casciola-Rosen L, Fiorentino D. Identification of clinical features and autoantibodies associated with calcinosis in dermatomyositis. JAMA Dermatol. 2014;150:724–9. doi: 10.1001/jamadermatol.2013.10416. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Valenzuela A, Chung L. Management of calcinosis associated with systemic sclerosis. Curr Treat Options Rheumatol. 2016;2:85–96. [Google Scholar]
- 17.Lampropoulos CE, Papaioannou I, D’Cruz DP. Osteoporosis-a risk factor for cardiovascular disease? Nature reviews Rheumatology. 2012;8:587–98. doi: 10.1038/nrrheum.2012.120. [DOI] [PubMed] [Google Scholar]
- 18.Fadini GP, Rattazzi M, Matsumoto T, Asahara T, Khosla S. Emerging role of circulating calcifying cells in the bone-vascular axis. Circulation. 2012;125:2772–81. doi: 10.1161/CIRCULATIONAHA.112.090860. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Hofbauer LC, Brueck CC, Shanahan CM, Schoppet M, Dobnig H. Vascular calcification and osteoporosis–from clinical observation towards molecular understanding. Osteoporos Int. 2007;18:251–9. doi: 10.1007/s00198-006-0282-z. [DOI] [PubMed] [Google Scholar]
- 20.Wu M, Rementer C, Giachelli CM. Vascular calcification: an update on mechanisms and challenges in treatment. Calcif Tissue Int. 2013;93:365–73. doi: 10.1007/s00223-013-9712-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Omair MA, Pagnoux C, McDonald-Blumer H, Johnson SR. Low bone density in systemic sclerosis. A systematic review. J Rheumatol. 2013;40(11):1881–90. doi: 10.3899/jrheum.130032. [DOI] [PubMed] [Google Scholar]
- 22.Serup J, Hagdrup H, Tvedegaard E. Bone mineral content in systemic sclerosis measured by photonabsorptiometry. Acta Derm Venereol. 1983;63:235–7. [PubMed] [Google Scholar]
- 23.da Silva HC, Szejnfeld VL, Assis LS, Sato EI. Study of bone density in systemic scleroderma. Rev Assoc Med Bras. 1997;43:40–6. [PubMed] [Google Scholar]
- 24.Di Munno O, Mazzantini M, Massei P, Ferdeghini M, Pitaro N, Latorraca A, et al. Reduced bone mass and normal calcium metabolism in systemic sclerosis with and without calcinosis. Clin Rheumatol. 1995;14:407–12. doi: 10.1007/BF02207673. [DOI] [PubMed] [Google Scholar]
- 25.Dovio A, Data V, Carignola R, Calzolari G, Vitetta R, Ventura M, et al. Circulating osteoprotegerin and soluble RANK ligand in systemic sclerosis. J Rheumatol. 2008;35:2206–13. doi: 10.3899/jrheum.080192. [DOI] [PubMed] [Google Scholar]
- 26.Rabens SF, Bethune JE. Disodium etidronate therapy for dystrophic cutaneous calcification. Arch Dermatol. 1975;111:357–61. [PubMed] [Google Scholar]
- 27.Fujii N, Hamano T, Isaka Y, Ito T, Imai E. Risedronate: a possible treatment for extraosseous calcification. Clin Calcium. 2005;15(Suppl.1):75–8. [discussion 8–9] [PubMed] [Google Scholar]
- 28.Katayama I, Otoyama K, Kondo S, Nishioka K, Nishiyama S. Clinical manifestations in anticardiolipin antibody-positive patients with progressive systemic sclerosis. J Am Acad Dermatol. 1990;23:198–201. doi: 10.1016/0190-9622(90)70198-q. [DOI] [PubMed] [Google Scholar]
- 29.Chung L, Valenzuela A, Fiorentino D, Stevens K, Li S, Harris J, et al. Validation of a novel radiographic scoring system for calcinosis affecting the hands of patients with systemic sclerosis. Arthritis Care Res. 2015;67:425–30. doi: 10.1002/acr.22434. [DOI] [PubMed] [Google Scholar]
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