Abstract
Objective:
Calcinosis is a debilitating complication of systemic sclerosis (SSc) with no effective treatments. We sought to identify clinical correlations and to characterize complications and disability associated with calcinosis in a multi-center, international cohort of SSc patients.
Methods:
We established a cohort of 568 consecutive SSc patients who fulfill 2013 revised ACR/EULAR criteria at 10 centers within North America, Australia, and Mexico. Calcinosis was defined as subcutaneous calcium deposition by imaging and/or physical examination, or a clear history of extruded calcium. All patients completed the Scleroderma Health Assessment Questionnaire Disability Index and Cochin Hand Functional Scale.
Results:
215 (38%) patients had calcinosis. In multivariable analysis, disease duration (OR=1.24, p=0.029), digital ischemia (OR=1.8, p=0.002) and Acro-osteolysis (OR=2.97, p=0.008) were significantly associated with calcinosis. In the subset of patients with bone densitometry (n=68), patients with calcinosis had significantly lower median T-scores than patients without (−2.2 vs. −1.7, p=0.004). The most common location of calcinosis lesions was the hands (70%), particularly the thumbs (19%) with decreasing frequency moving to the fifth fingers (8%). The most common complications were tenderness (29% of patients) and spontaneous extrusion of calcinosis through the skin (20%), while infection was rare (2%). Disability and hand function were worse in patients with calcinosis, particularly if locations in addition to the fingers/thumbs were involved.
Conclusions:
We confirmed a strong association between calcinosis and digital ischemia. Calcinosis in SSc patients most commonly affects the hands and is associated with a high burden of disability and hand dysfunction.
Keywords: Scleroderma, Calcinosis, Digital ischemia, Acro-osteolysis, Osteoporosis, Disability
Introduction
Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues (1). It is a frequent and potentially debilitating manifestation of systemic sclerosis (SSc) that often develops late in disease (1, 2).
Several studies have found an association between calcinosis and vascular manifestations of SSc including digital ulcers (DU) (3, 4) digital pitting scars(5), acro-osteolysis (AO),(6) and late nailfold videocapillaroscopy pattern (4) suggesting a role for ischemia in the pathogenesis of calcinosis. In addition, repetitive trauma has been implicated in the pathogenesis of calcinosis, and a prior single-center study found that the thumbs were most commonly affected, supporting this hypothesis(7). These studies were limited as they were small, single-center, retrospective studies.
We previously performed a retrospective analysis involving 5218 patients with SSc from 9 centers within the US, Australia, Canada, United Kingdom, Italy, and Mexico. 25% of patients in this cohort had calcinosis. In multivariable analysis, the strongest associations with calcinosis were DU (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), while telangiectasias, female gender, anti-centromere antibody positivity, cardiac disease and gastrointestinal disease were also significantly associated with calcinosis.(8)
Given that calcinosis is a common, debilitating complication of SSc with no effective therapies, we developed a prospective database of SSc patients to confirm these clinical associations. We hypothesized that calcinosis is a result of microvascular injury and ischemic damage, and is therefore correlated with other disease manifestations involving microvascular damage such as DU. We also sought to better understand the association between calcinosis and bone metabolism and bone loss.(9) Finally, we sought to quantify the complications and disability associated with calcinosis.
Methods
Study design
We developed a prospective multi-center cohort of SSc patients to evaluate patients with calcinosis, as well as those without calcinosis. Patients with SSc were enrolled consecutively at their routine clinic visits, over the course of one year. We designed this study protocol in accordance with the general ethical principles outlined in the Declaration of Helsinki. Each participating center obtained regulatory approval from their respective institution prior to enrollment of any patients.
Study Population
We included all patients diagnosed with SSc who fulfilled 2013 revised ACR/EULAR SSc criteria (10) at 10 centers (Stanford University, Northwestern University, Hospital for Special Surgery, University of Michigan, Harvard University, Rutgers Robert Wood Johnson Medical School, and Georgetown University in the US; Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico; Royal Adelaide Hospital in Australia; and Canadian Scleroderma Research Group (CSRG) registry in Canada). Patients with a diagnosis of mixed connective tissue disease and other overlap connective tissue diseases were excluded.
Study Measures and Covariates
We collected the following information: demographic information, symptoms and physical examination findings, internal organ involvement, auto-antibodies including scleroderma-specific and anti-phospholipid antibodies, date of first non-Raynaud’s phenomenon (RP) symptom, and date of first RP symptom. We defined calcinosis as either radiological or physical examination evidence of subcutaneous calcium deposition that is clinically apparent as part of routine clinical care, or a clear history of extruded calcium. We collected the clinical characteristics and specific locations of all calcinotic lesions in a standardized fashion by providing a detailed case report form to all investigators (available in supplemental material). We defined DU as the presence of denuded areas with a defined border, loss of epithelialization and loss of epidermis and dermis on the volar aspect distal to proximal interphalangeal joints (PIPs). We defined AO as bony resorption of the terminal digital tufts as determined by radiography. As a surrogate of digital ischemia, we used a combination of DU, loss of digital pulp, and/or digital pitting scars. We defined osteopenia as a T-score by bone densitometry (DXA) that is 1 to 2.5 SD below the young-adult mean, and osteoporosis as a T-score of 2.5 SD or more below the young-adult mean or the use of medications to specifically treat osteoporosis including bisphosphonates (alendronate, risedronate, zoledronic acid, ibandronate), selective estrogen receptor modulators (raloxifen, bazedoxifene), teriparatide (Forteo), denosumab (Prolia), calcitonin, and strontium ranelate, but excluding calcium/vitamin D. Given the limited amount of funding available, DXA as well as laboratory values including serum calcium, phosphate, Vitamin D, uric acid and parathyroid hormone were not routinely performed at most centers, but were ordered only if deemed consistent with standard of care by the site investigator. Internal organ involvement was defined as previously described.(11, 12) Infection was defined as requiring topical or oral antibiotics as per physician discretion, and tenderness was defined as tender to palpation as per physician assessment. We also collected patient questionnaires, including the Scleroderma Health Assessment Questionnaire (SHAQ),(13) and Cochin Hand Functional Scale (CHFS) (14) in all patients, and patient/physician global assessment of calcinosis (“Overall, considering how much pain, discomfort, limitations in your/the patient’s daily life, and other changes in your/the patient’s body and life, how severe would you rate your/the patient’s calcinosis today?) using a visual analog scale (VAS, 1–10) in patients with calcinosis only. Study data were collected and managed using REDCap electronic data capture tools hosted at Stanford University.(15)
Statistical Analysis
We performed crude bivariate analysis to characterize patients with and without calcinosis with respect to demographic characteristics, clinical features, and autoantibodies using student’s t-test for continuous variables and chi-square or Fisher’s exact test for categorical variables. We used logistic regression to assess the association between calcinosis and digital ischemia or osteoporosis, adjusting for other significant variables and potential confounders (such as disease duration). We selected variables a priori based on clinical relevance per our prior retrospective study(8), and also used stepwise elimination to determine the final regression model, retaining those factors with a p-value < 0.05 in univariate analysis. Variables with >10% of missing values were excluded. To further assess whether calcinosis was responsible for functional impairment, we performed multivariable regressions on patient reported outcomes, after adjusting for other significant predictors of disability in univariate analysis (Raynaud phenomenon, DU, myositis, arthritis, PAH any GI involvement, pulmonary fibrosis, AO, disease duration from first RP, disease cutaneous subtype, gender and age) and retaining those factors with a p-value <0.05. To adjust for missing values in regression models, multiple imputation was performed after checking for multicollinearity. Discriminant function was applied to impute categorical variables and regression was used to impute continuous variables. Forty imputed datasets were generated; pooled results were retained by multivariable analyses for the imputed datasets. All statistical analyses were performed using SAS statistical software, version 9.4 (SAS Institute Inc, Cary, NC).
Results
We enrolled 568 patients into the central database. Our cohort was 87% female, 70% Caucasian, 39% had diffuse cutaneous SSc (dcSSc), and 45% had never smoked. Mean age at enrollment was 58 ± 13 years, mean disease duration from first RP was 15 ± 12 years, mean disease duration from first non-RP symptom was 11 ± 9 years, and mean modified Rodnan Skin Score (mRSS) was 8±9. 215 (38%) patients in this cohort had calcinosis.
Characteristics of calcinosis
We collected information from 215 patients with calcinosis, corresponding to 1472 lesions. Mean disease duration from first RP to calcinosis diagnosis was 17.1±11.4 years, and mean disease duration from first non-RP symptom to calcinosis diagnosis was 12.6±9.3 years. 58 patients had calcinosis that was not clinically apparent and only visible on radiographs. 93% of patients had lesions in more than one location. The most common location of calcinosis was the hands (70% of calcinosis lesions), particularly the fingers/thumbs (67%) with only 3% affecting the palms, followed by the arms and/or forearms (7%) and the elbows (6%). Within the hands, calcinosis most commonly affected the thumbs (19%) with decreasing frequency moving to the fifth fingers (8%) (Figure 1). 73 (34%) patients experienced some complication from calcinosis, the most common being tenderness (29% of patients) and spontaneous extrusion of calcinosis through the skin (20%). Ulceration of calcinosis lesions occurred in 7% of patients, and calcinosis infection was rare (2%). Patients with calcinosis in the fingers/thumbs did not have more complications (ulcerations, infection, tenderness, erythema or extrusion through the skin) than patients with calcinosis elsewhere (data not shown).
Figure 1.
Location of 1472 Calcinosis Lesions
Clinical associations of calcinosis
In univariate analysis, patients with calcinosis had longer mean disease duration from RP or first non-RP, and were more likely to have digital ulcers, digital pitting scars, loss of digital pulp, acro-osteolysis, telangiectasias, and cardiac disease (Table 1). Patients with calcinosis did not differ from patients without calcinosis with respect to the presence of ulcers in locations other than the fingers and/or thumbs, cutaneous subtype or the presence of SSc-specific antibodies. Patients with calcinosis had similar serum calcium, phosphate, Vitamin D, uric acid and parathyroid hormone levels to patients without calcinosis, however few centers were able to provide this information. Patients with calcinosis were more likely to ever have taken calcium/vitamin D supplements (68.3% vs. 53.2%, p=0.014), and bisphosphonates (14.6% vs. 6.4%, p=0.025) than patients without calcinosis. 68 patients had DXA results; patients with calcinosis had significantly lower median T-scores than patients without calcinosis (−2.2 versus −1.7, p=0.004). In multivariable analysis, disease duration (OR=1.24, CI 1.02–1.51, p=0.029), digital ischemia (OR=1.80, CI 1.25– 2.59, p=0.002) and acro-osteolysis (OR=2.97, CI 1.34 – 6.61, p=0.008) remained significantly associated with calcinosis (Table 2). A sensitivity analysis done excluding the 58 patients that had calcinosis only visible on radiographs showed similar results to those presented for the total population of patients with calcinosis (data not shown).
Table 1.
Characteristics of patients without and with calcinosis
| Without calcinosis n (%) | With calcinosis n (%) | p-value | Sample size* n | |
|---|---|---|---|---|
| Total | 353 (62) | 215 (38) | 568 | |
| Disease duration from first non-RP (mean years ± SD) | 9.8 (9.2) | 12.6 (9.3) | <0.001 | 537 |
| Disease duration from first RP (mean years ± SD) | 14.0 (12.1) | 17.1 (11.4) | <0.001 | 493 |
| Cutaneous subtype | 0.095 | 550 | ||
| Diffuse | 144 (42.5) | 80 (37.9) | ||
| Limited | 195 (57.5) | 131 (62.1) | ||
| Raynaud’s phenomenon | 288 (94.1) | 190 (96.9) | 0.148 | 502 |
| Digital ulcers | 117 (34.7) | 98 (46.5) | 0.003 | 548 |
| Others ulcers** | 23 (13.1) | 13 (12.5) | 0.754 | 280 |
| Digital pitting scars | 94 (30.9) | 89 (45.4) | 0.001 | 500 |
| Loss of digital pulp | 55 (18.0) | 52 (26.8) | 0.006 | 499 |
| Abnormal nailfold capillary exam | 215 (72.9) | 130 (70.7) | 0.810 | 479 |
| Acro-osteolysis | 10 (5.7) | 25 (24.3) | 0.002 | 279 |
| Telangiectasias | 229 (74.6) | 169 (85.8) | 0.007 | 504 |
| Osteopenia or Osteoporosis | 43 (24.4) | 35 (33.7) | 0.748 | 280 |
| Cardiac disease | 4 (2.3) | 9 (8.7) | 0.036 | 280 |
| Autoantibodies | ||||
| Positive Scl-70 | 70 (25.8) | 34 (19.7) | 0.112 | 444 |
| Positive Anticentromere | 93 (34.3) | 66 (38.2) | 0.416 | 444 |
| Positive PM-Scl | 37 (14.8) | 26 (16.7) | 0.388 | 406 |
| Positive Anti-RNA polymerase III | 32 (11.9) | 20 (11.6) | 0.851 | 443 |
| Positive U1 RNP | 14 (5.6) | 8 (5.1) | 0.723 | 406 |
| Positive ANA | 226 (90.4) | 145 (93) | 0.307 | 406 |
| Medications | ||||
| Calcium channel blockers use ever | 170 (56.7) | 110 (55.8) | 0.926 | 497 |
| Steroid use ever | 102 (30.9) | 61 (29.2) | 0.672 | 539 |
| Biphosphonates | 11 (6.4) | 15 (14.6) | 0.025 | 275 |
| Calcium/Vitamin D supplements | 91 (53.2) | 71 (68.3) | 0.014 | 275 |
Sample size includes patients with answers of “yes”, “no” and “not assessed” for each variable
Other ulcers i.e. over PIPs or over other extensor surfaces as elbows
SD=Standard Deviation, DXA=Bone Densitometry, RP=Raynaud phenomenon, DU=Digital Ulcers
Table 2.
Predictors of calcinosis in univariate and multivariable analysis
| Univariate analysis | Multivariable analysis | |||
|---|---|---|---|---|
| OR | p-value | OR | p-value | |
| Age | 1.01 (0.9 – 1.02) | 0.173 | ||
| Female gender | 1.60 (0.91 – 2.81) | 0.101 | 1.83 (1.002 – 3.33) | 0.049 |
| Ever smoking | 1.32 (0.92 – 1.90) | 0.127 | ||
| BMI | 0.97 (0.93 – 1.01) | 0.179 | ||
| Disease duration from first non-RP (10 unit increase) | 1.03 (1.01 – 1.05) | 0.001 | 1.24 (1.02 – 1.51) | 0.029 |
| Disease duration from first RP (10 unit increase) | 1.02 (1.01 – 1.04) | 0.005 | ||
| Limited cutaneous subtype | 1.16 (0.81 – 1.65) | 0.425 | ||
| Maximum modified skin Rodnan score | 1.00 (0.98 – 1.02) | 0.986 | ||
| Raynaud’s phenomenon | 1.98 (0.77 – 5.08) | 0.156 | ||
| Digital ischemia* | 1.95 (1.37 – 2.78) | 0.0002 | 1.80 (1.25 – 2.59) | 0.002 |
| Others ulcers** | 1.21 (0.50 – 2.94) | 0.678 | ||
| Abnormal nailfold capillary exam | 0.94 (0.58 – 1.53) | 0.810 | ||
| Acro-osteolysis | 3.55 (1.58 – 7.97) | 0.0022 | 2.97 (1.34 – 6.61) | 0.008 |
| Telangiectasias | 1.92 (1.19 – 3.11) | 0.007 | ||
| Osteopenia or Osteoporosis | 1.11 (0.58 – 2.13) | 0.748 | 1.03 (0.61 – 1.73) | 0.920 |
| Cardiac disease | 3.93 (1.18 – 13.10) | 0.026 | 3.13 (0.88 – 11.18) | 0.079 |
| Autoantibodies | ||||
| Positive Scl-70 | 0.69 (0.43 – 1.09) | 0.1133 | ||
| Positive Anticentromere | 1.18 (0.79 – 1.77) | 0.4158 | ||
| Positive PM-Scl | 1.29 (0.72 – 2.31) | 0.3887 | ||
| Positive Anti-RNA polymerase III | 0.94 (0.51 – 1.73) | 0.8505 | ||
| Positive U1 RNP | 0.85 (0.35 – 2.09) | 0.7231 | ||
| Positive ANA | 2.09 (0.67 – 6.52) | 0.2064 | ||
| Medications | ||||
| Biphosphonates use ever | 2.49 (1.10 – 5.67) | 0.029 | ||
| Calcium channel blockers use ever | 0.97 (0.67 – 1.39) | 0.855 | ||
| Steroid use ever | 0.92 (0.63 – 1.35) | 0.671 | ||
| Calcium/Vitamin D supplements use ever | 1.89 (1.14 – 3.15) | 0.014 | ||
Digital ischemia=digital ulcers, loss of digital pulp, and/or digital pitting scars.
Other ulcers i.e. over PIPs or over other extensor surfaces as elbows
OR=Odds Ratio, RP=Raynaud phenomenon, BMI=Body Mass Index
Patient reported outcomes
The mean Health Assessment Questionnaire disability index (HAQ-DI) component of the SHAQ was significantly higher in patients with calcinosis than in patients without calcinosis (0.9±0.8 vs. 0.6±0.7, p=0.002) (Table 3). The visual analog scale (VAS) domains for pain, gastrointestinal disease and DU were also higher in patients with calcinosis (4.0±3.0 vs. 2.8±2.8, p=0.001; 2.8±3.0 vs. 2.1±2.7, p=0.032; and 2.5±3.4 vs. 1.2±2.3, p<0.0001, respectively). Patients with calcinosis had higher CHFS scores than patients without calcinosis (13.8±16.4 vs. 9±12.7, p=0.001). Patients with lesions exclusively in the fingers/thumbs had lower VAS pain (3.1±2.6 vs. 5.2±3.0, p=0.004), CHFS scores (11.2±14.2 vs. 17.8±18.3, p=0.018), and physician and patient global assessment for overall calcinosis VAS (1.7±1.6 vs. 4.2±2.9, p<0.0001, and 3.2±3.0 vs. 4.4±3.2, p=0.018, respectively) than patients with lesions involving both the fingers/thumbs and locations elsewhere in the body.
Table 3.
Patient reported outcomes in patients without and with calcinosis
| Without calcinosis (mean ± SD) | With calcinosis (mean ± SD) | p-value | Sample size | |
|---|---|---|---|---|
| Total n (%) | 353 (62) | 215 (38) | 568 | |
| SHAQ Disability Index (HAQ-DI) | 0.6 (0.7) | 0.9 (0.8) | 0.002 | 407 |
| SHAQ VAS pain | 2.8 (2.8) | 4.0 (3.0) | 0.001 | 404 |
| SHAQ VAS GI | 2.1 (2.7) | 2.8 (3.0) | 0.032 | 397 |
| SHAQ VAS Breathing | 1.7 (2.4) | 2.1 (2.6) | 0.147 | 402 |
| SHAQ VAS RP | 2.5 (2.8) | 2.9 (2.9) | 0.114 | 404 |
| SHAQ VAS DU | 1.2 (2.3) | 2.5 (3.4) | <0.0001 | 400 |
| SHAQ VAS Overall Disease | 3.3 (2.8) | 3.8 (3.0) | 0.134 | 404 |
| Cochin Hand Functional Scale | 9.0 (12.7) | 13.8 (16.4) | 0.001 | 551 |
SD=Standard Deviation, SHAQ=Scleroderma Health Assessment Questionnaire, VAS=Visual Analogue Scale, GI=Gastrointestinal, RP=Raynaud phenomenon, DU=Digital Ulcers
In multivariable analysis, calcinosis was a strong predictor of HAQ-DI (OR 1.57, CI 1.12 – 2.20, p=0.009) and VAS pain (1.46, CI 1.08 – 1.97, p=0.015), while digital ulcers were not. There was also a trend towards an association between calcinosis and hand disability as assessed by CHFS, however this did not reach statistical significance (1.47, CI 0.94 – 2.30, p=0.096) (Table 4).
Table 4.
Predictors of patient reported outcomes in multivariable analyses
| RR (CI) | p-value | |
|---|---|---|
| HAQ-DI | ||
| Calcinosis | 1.57 (1.12 – 2.20) | 0.009 |
| Digital ulcers | 1.22 (0.87 – 1.70) | 0.255 |
| Arthritis | 1.56 (1.12 – 2.18) | 0.009 |
| Any GI involvement | 1.31 (0.78 – 2.21) | 0.307 |
| Pulmonary fibrosis | 1.06 (0.75 – 1.51) | 0.748 |
| Acro-osteolysis | 0.99 (0.58 – 1.67) | 0.967 |
| Diffuse disease subtype | 1.76 (1.26 – 2.47) | 0.001 |
| Female | 1.52 (0.93 – 2.48) | 0.095 |
| Cochin Hand Functional Scale | ||
| Calcinosis | 1.47 (0.94 – 2.30) | 0.096 |
| Digital ulcers | 1.70 (1.07 – 2.72) | 0.025 |
| Arthritis | 1.56 (0.99 – 2.47) | 0.054 |
| Any GI involvement | 0.94 (0.46 – 1.92) | 0.863 |
| Pulmonary fibrosis | 0.82 (0.50 – 1.32) | 0.411 |
| Acro-osteolysis | 0.88 (0.42 – 1.86) | 0.738 |
| Diffuse disease subtype | 1.88 (1.19 – 2.96) | 0.007 |
| VAS Pain | ||
| Calcinosis | 1.46 (1.08 – 1.97) | 0.015 |
| Digital ulcers | 1.21 (0.91 – 1.62) | 0.187 |
| Arthritis | 1.47 (1.09 – 1.98) | 0.012 |
| Acro-osteolysis | 1.27 (0.81 – 2.01) | 0.298 |
RR=Relative risk, HAQ-DI=Health Assessment Questionnaire disability index, GI=Gastrointestinal, VAS=visual analog scale.
Discussion
Calcinosis remains a frequent clinical problem in patients with SSc. To date, there are no effective therapies to treat this complication, in part because little is known about the pathogenesis.(16) We sought to validate clinical associations with calcinosis from prior studies in a large international prospective cohort of SSc patients. Indeed, we confirmed that the presence of calcinosis was correlated with ischemic manifestations such as digital ulceration and acro-osteolysis. Although we were not able to validate the association between calcinosis and osteoporosis, we did find that patients with calcinosis had a lower T-score on DXA. In addition, to our knowledge, we are the first to report the impact of calcinosis on patients’ assessment of disability, function, and scleroderma-related symptoms.
The frequency of calcinosis in this cohort was 38%, which is higher than in our prior retrospective study. The CSRG, which contributed 48% of patients in this cohort, has routinely obtained hand radiographs on all SSc patients at their first clinical evaluation since 2016. Given the higher sensitivity of radiography to detect small calcinosis lesions compared with physical examination, our cohort likely included a relatively large proportion of patients with mild calcinosis affecting the hands. This is consistent with the relatively low VAS and HAQ-DI scores recorded in the patient and physician outcome measures.
The causative mechanisms leading to calcinosis in patients with SSc remain to be elucidated, although vascular injury has been implicated as a major factor. In this study, we confirmed the previously shown association between calcinosis and digital ischemia, manifested by the strong relationship between calcinosis and markers of vascular impairment, such as distal DU (but not ulcers at other more proximal sites), loss of digital pulp, and digital pitting scars. Although this does not prove causality, it complements other studies implicating vascular ischemia in the development of calcinosis. (8, 17)
Similarly, in our study, AO also had a strong association with calcinosis. AO has been suggested as a marker of digital vascular disease progression and also involves bone remodeling. A retrospective study of 101 SSc patients showed that patients with moderate/severe AO were more likely to have severe calcinosis (33% vs. 13%) on hand radiograph, but this was not statistically significant after adjustment for potential confounders.(6) A French study of 103 consecutive SSc patients who underwent dual time-point X-rays of the hands showed that the likelihood of AO was higher in patients with calcinosis (46% vs. 14%, p=0.001, 42% vs. 18%, p=0.009 at the time of the second x-ray).(3) More recently, a study showed that up-regulation of VEGF, a potent angiogenic factor induced by hypoxia, was associated with increased osteoclast activity in SSc patients with AO, 73% of whom had calcinosis (18). This hypoxia-induced osteoclast activity in SSc may also be involved in the development of calcinosis, implicating a potential role for bone remodeling and bone loss in calcinosis.
Numerous studies have found a high prevalence of osteoporosis in patients with SSc, some of them showing a similar risk of osteoporosis in patients with SSc and rheumatoid arthritis.(19) However, screening for osteoporosis in SSc is not done routinely. In the present study, the frequency of osteopenia/osteoporosis was high (24% in SSc patients without calcinosis, and 34% in patients with calcinosis), which provides rationale for future studies focusing on bone loss in patients with SSc, whether or not they have calcinosis. The presence of subcutaneous calcinosis has been postulated as a clinical risk factor for osteoporosis in SSc patients (8, 20, 21). Although we did not find a significantly higher prevalence of osteoporosis in SSc patients with calcinosis, in the subset of patients who had DXA, median T-scores of patients with calcinosis were significantly lower than those from patients without calcinosis. Unfortunately, not all participating centers collected this information, and we had missing data with regards to DXA. Patients with DXA data were older, had longer disease duration, were more likely to have AO, and had more lcSSc than patients with missing DXA data. Therefore, our results are only generalizable to this group of patients who are at higher risk for calcinosis. Also, although calcinosis affecting the hip or spine is relatively rare in SSc, the presence of calcinosis can falsely elevate the T-score and underestimate the presence of osteoporosis.(22) Finally, the connection between calcinosis and osteoporosis may only be detectable in those with more severe calcinosis. Interestingly, a recent retrospective study of 70 patients with SSc with clinical risks for osteoporosis found that calcinosis elsewhere in the body was associated with a 6-fold higher risk of vertebral fracture estimated by a low scanographic bone attenuation coefficient at first lumbar vertebra on CT scan (OR=6.3, CI 1.61–24.75). The authors suggested that the presence of calcinosis in SSc might be an indication for osteoporosis screening.(23) However, the association between calcinosis and osteoporosis should be explored further before making such a recommendation.
In our study, neither cutaneous subtype nor the presence of SSc-specific autoantibodies were associated with calcinosis. Traditionally, calcinosis has been linked to limited cutaneous SSc (lcSSc) as part of the CREST syndrome, in association with positive anti-centromere antibody (ACA) (21, 24–26). However, in Mexican, Canadian, and Malaysian cohorts, calcinosis was associated with dcSSc (27–29). Similarly, anti-nucleolar and anti-topoisomerase (Scl-70) antibodies were more prevalent in Mexican patients with calcinosis(27), and in a cohort of 1305 SSc patients from the CSRG registry, ACA but also RNA-polymerase-III antibody were predictors of calcinosis (29). Concordant with our study, a multicenter study of 1009 African Americans with SSc, did not show associations between calcinosis and cutaneous subtype, or ACA (30). The reasons for these conflicting results are unclear but suggest that the association between calcinosis and cutaneous subtype and autoantibody profile may be influenced by ethnic background and geographic region.
With respect to characteristics of calcinosis, we confirmed that calcinosis preferentially affects the fingers and particularly the thumbs, which suggests that repetitive trauma, including daily life activities such as the use of smartphones and computer, can contribute to calcinosis development(7). These areas of recurrent trauma may be more susceptible due to the impaired compensatory angiogenesis that characterizes the proliferative obliterative vasculopathy seen in SSc (31, 32). We also found that tenderness was the most common complication of calcinosis, while infection was rare. Importantly, calcinosis clearly worsens patients’ disability, function, and symptoms, particularly when locations in addition to the fingers, including thumbs, are involved. Moreover, calcinosis is an independent predictor of dysfunction and pain as assessed by patient reported outcomes, contributing as much as arthritis to the disability index.
Our study has several limitations. First, physicians were asked to include as much information as possible in the database, but always within what it is done in their center’s standard of care. This introduced some missing data, particularly with respect to osteoporosis and DXA information, since several centers do not collect this routinely. Second, we did not include a quantitative assessment of the severity of calcinosis; however, hand radiographs were obtained in a subset of patients and we plan to evaluate calcinosis burden in the hands using our previously described radiographic scoring system.(33) Finally, the cross-sectional design of this study did not permit evaluation of the natural history and causality of calcinosis in these patients. We plan to analyze the change in radiographic calcinosis burden in a future study.
In conclusion, calcinosis is associated with digital ulcers and acro-osteolysis, suggesting that vascular hypoxia and abnormal bone metabolism may be involved in the pathogenesis of calcinosis. Despite poor blood flow to the fingers where the majority of calcinosis lesions develop in SSc patients, ulceration and infection are not common. Calcinosis clearly worsens patientś quality of life and thus should be a major focus for development of targeted therapies.
Supplementary Material
Acknowledgments
Funding statement: This work was supported by the Scleroderma Clinical Trials Consortium. Dr. Khanna is supported by NIH/NIAMS K24 AR AR063120. The authors have no financial support or other benefits from commercial sources to report, or any other financial interests, which could create a potential conflict of interest or the appearance of a conflict of interest with regard to the work described in this manuscript.
Abbreviations:
- SSc
Systemic sclerosis
- DU
Digital ulcers
- AO
Acro-osteolysis
- CSRG
Canadian Scleroderma Research Group
- RP
Raynaud’s phenomenon
- DXA
Bone densitometry
- SHAQ
Scleroderma Health Assessment Questionnaire
- HAQ-DI
Health Assessment Questionnaire disability index
- CHFS
Cochin Hand Functional Scale
- VAS
Visual analog scale
- dcSSc
Diffuse cutaneous systemic sclerosis
- OR
Odds Ratio
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