Background
In children with JIIM, such as Juvenile Dermatomyositis (JDM) and Overlap Syndrome, dystrophic calcifications are a common and debilitating complication. The reported calcifications in JDM range from 71% [
1] to 8% [
2] with 40% most frequently cited [
3]. These calcifications usually occur in children with chronic inflammation and hypoxia associated with JIIM, which includes JDM, Polymyositis and Overlap Syndromes as well as in patients with other rheumatic diseases such as Scleroderma [
4] and Systemic Lupus Erythematosus [
5,
6].
Plain radiography is effective for the detection of calcinosis and the categorization of morphological patterns of calcification [
7]. Although radiography is recommended for the initial imaging of calcinosis, it fails to evaluate objectively the volume of calcifications. Case reports have employed different types of whole body scans (scintigraphy using Technetium methylene diphosphonate (Tc-99 m MDP) and Tc-99 m pyrophosphate and Strontium nitrate) in an attempt to identify the location of the calcifications and to provide a quantifiable assessment of their extent, as well as to develop a method to monitor the child’s therapeutic response [
8]. Scintigraphic evaluation using Tc-99 m MDP can effectively delineate sites of dystrophic calcifications in JDM and it is more sensitive in detecting visceral calcifications than plain radiographs [
9]. However, scintigraphy has failed to provide a quantitative estimation of the volume of the calcification. In contrast, micro CT and synchrotron x-ray diffraction studies of calcified deposit samples from four children with the diagnosis of JDM characterized the microstructure of calcinosis, and demonstrated excellent sensitivity with respect to quantitation of amount and spatial distribution of minerals in these calcifications samples [
10]. These studies suggested that CT could be used to measure the calcifications occurring in the soft tissues of children with JIIM, as this method had been effective in the experimental mouse model [
11].
The purpose of this pilot study was to determine the feasibility of the use of low dose, limited slice CT as an objective measure of in-situ calcification volume, over time, in patients with JIIM.
Discussion
The present study represents the first pilot study to evaluate objectively the volume of calcifications in patients with JIIM over time. The mechanisms controlling the pathophysiology of calcifications remain poorly understood. Studies of the composition of these calcifications have shown that hydroxyapatite is the main mineral component, as well as calcium carbonate [
23,
24]. Other bone matrix proteins such as osteonectin, osteopontin and bone sialoprotein have been documented [
24], in addition to members of the integrin family [
25]. Reported risk factors for the development of calcinosis include delayed diagnosis and treatment along with inadequate levels and duration of immunosuppressive therapy, [
26] suggesting that prolonged inflammation contributes to tissue injury which promotes the calcium deposition. A common feature among all the children in this study was the persistent and chronic course of an active inflammatory process, which may be a major factor in the development/progression of calcifications in children with myositis [
20]. Thirty percent of the JIIM group had a substitution of A at the TNFα-308 promoter region, which is similar to the 27–30% frequency in the general population, while 50% of the patients with JDM (4/8) were positive for the A substitution [
20].
This study was not designed to test the efficacy of specific agents to elicit change in the volume of the calcifications, but to document that the single slice CT gives sufficient information to evaluate and compare outcomes. Our analysis of 20 CT scans of patients with JIIM and calcifications during a 2 year period while they were given immunosuppressive therapy showed a tendency for the specific calcification to decrease in volume in that time frame. In this group, 6/10 had positive MSAs, of whom 3/8 JDM were positive for one of the more frequently occurring MSAs, anti-MJ, reported to be associated with calcification [
27].
We are not aware of any previous study that has used an objective method to measure the volume of calcifications embedded in the soft tissue of children with JIIM. For patients with systemic sclerosis, multidector computed tomography with multiplanar format has been employed successfully [
28]. Experimentally, microcomputed tomography was employed to measure the volume of calcification in Abcc6 deficient mice [
29] and to monitor the rate of resolution of induced calcification in mice with defective macrophage function [
11].
Effective radiation dose in CT is dependent on three primary factors: the amount of radiation necessary to achieve the desired contrast between tissues, the extent of the body that is included in the field-of-view and the types of organs exposed to the radiation. The exceptionally low radiation dose needed to acquire the images in this study is a result of the favorable constitution, size, and location of JIIM calcifications. First, by their very nature –the deposits contain calcium (and are therefore comparatively radiopaque)– the calcifications are a strong contrast when compared to surrounding soft tissue (similar to bone). For this reason, very little radiation dose is needed to achieve excellent subject contrast and subsequent volume delineation; this was reflected in the reported CTDI value, which was low. Second, the physical size of the calcifications was easily captured in a 12 mm z-axis length, therefore limiting the radiation exposure to a very small anatomical region, which is reflected in the low DLP of this study. Finally, the JIIM calcifications in this study were located primarily in the extremities, which are relatively radio-insensitive. The radiosensitivity of cells increases with the reproductive rate and decreases with the level of differentiation, therefore the nerve and muscle tissue in the extremities is the least radiosensitive tissue in the body. The radiosensitivity of the exposed tissue is included in the calculation of effective dose in this report. Due to the low radiosensitivity of extremities to radiation, it would be optimal if future clinical studies were to select calcifications located in a limb as one inclusion criteria for evaluation of therapeutic efficacy using CT [
30].
There are a few limitations to this pilot study: first, relatively few patients with calcifications were available at our Center for imaging. Another limitation is the lack of information to provide validation of this method (intra and inter rater reliability, validity, responsiveness). However, in a somewhat similar study, assessment of intrasubject change in lung tissue content over three CT scans was 2.75% +/−2.29% (mean and SD) [
31]. In the present report, although their CT scans did not document a significant improvement in the volume of the calcifications in the 7 months between the first and second scan, the data do suggest that a longer interval between scans might be more helpful.
Acknowledgements
This study could not have been performed without the support of the CureJM Foundation, for which the authors are very thankful. Expert administative assistance was suppllied by Ms Brittitany Hudanick, and was much appreciated. Finally, the authors valued the reviewer’s expert comments, which served to improve the manuscript.
M. Ibarra, MD, Associate Professor, Division of Rheumatology, Children’s Mercy Hospital, Kansas City, Missouri, USA.
C. K. Rigsby, MD, Department of Medical Imaging, Ann & Robert H. Lurie Children’s Hospital of Chicago, Professor of Radiology and Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
G.A. Morgan, MA, Database Manager, Stanley Manne Children’s Research Institute, Cure JM Center of Excellence in Juvenile Myositis (JM) Research and Care, Ann & Robert H. Lurie Children’s Hospital of Chicago, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
C.L. Sammet, Ph.D., Research Assistant Professor, Department of Radiology, Northwestern University, Medical Physicist, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA.
I.N. Targoff, MD, Professor, Department of Internal Medicine, The University of Oklahoma College of Medicine, Oklahoma City, Oklahoma; Veterans Affairs Medical Center (INT), University of Oklahoma Health Sciences Center, and Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
C.C. Huang, PhD, Associate Professor, Joseph J. Zilber School of Public Health, University of Wisconsin, Milwaukee, Wisconsin, USA.
D. Xu, MD, Research Assistant Professor, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois., Stanley Manne Children’s Research Institute, Cure JM Center of Excellence in Juvenile Myositis (JM) Research and Care.