[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.211.82.105. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Download PDF
Figure.
Examples of Calcinosis in Adults With Dermatomyositis
Examples of Calcinosis in Adults With Dermatomyositis

A, Multiple, grouped white papules on the elbow with associated scarring and scale crust. B, Large, multiloculated hard tumors of calcium with characteristic skin retraction extending along the axilla.

Table 1.  
Distribution of Calcinosis in the 14 Study Patients
Distribution of Calcinosis in the 14 Study Patients
Table 2.  
Characteristics, Symptoms, and Clinical Features of the Study Patientsa
Characteristics, Symptoms, and Clinical Features of the Study Patientsa
Table 3.  
Autoantibodies and Calcinosis (Univariate Analysis)
Autoantibodies and Calcinosis (Univariate Analysis)
Table 4.  
Predictors of Calcinosis in Patients With Dermatomyositis Using Multivariate Analysis
Predictors of Calcinosis in Patients With Dermatomyositis Using Multivariate Analysis
1.
Fiorentino  D, Chung  L, Zwerner  J, Rosen  A, Casciola-Rosen  L.  The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): a retrospective study. J Am Acad Dermatol. 2011;65(1):25-34.
PubMedArticle
2.
Clemente  G, Piotto  DG, Barbosa  C,  et al.  High frequency of calcinosis in juvenile dermatomyositis: a risk factor study. Rev Bras Reumatol. 2012;52(4):549-553.
PubMedArticle
3.
Mathiesen  P, Hegaard  H, Herlin  T, Zak  M, Pedersen  FK, Nielsen  S.  Long-term outcome in patients with juvenile dermatomyositis: a cross-sectional follow-up study. Scand J Rheumatol. 2012;41(1):50-58.
PubMedArticle
4.
Gutierrez  A  Jr, Wetter  DA.  Calcinosis cutis in autoimmune connective tissue diseases. Dermatol Ther. 2012;25(2):195-206.
PubMedArticle
5.
Walsh  JS, Fairley  JA.  Calcifying disorders of the skin. J Am Acad Dermatol. 1995;33(5, pt 1):693-710.
PubMedArticle
6.
Cook  CD, Rosen  FS, Banker  BQ.  Dermatomyositis and focal scleroderma. Pediatr Clin North Am. 1963;10:979-1016.
PubMed
7.
Boulman  N, Slobodin  G, Rozenbaum  M, Rosner  I.  Calcinosis in rheumatic diseases. Semin Arthritis Rheum. 2005;34(6):805-812.
PubMedArticle
8.
Blane  CE, White  SJ, Braunstein  EM, Bowyer  SL, Sullivan  DB.  Patterns of calcification in childhood dermatomyositis. AJR Am J Roentgenol. 1984;142(2):397-400.
PubMedArticle
9.
Reiter  N, El-Shabrawi  L, Leinweber  B, Berghold  A, Aberer  E. Calcinosis cutis, part II: treatment options .J Am Acad Dermatol.2011;65(1):15-24.
PubMed
10.
Chander  S, Gordon  P.  Soft tissue and subcutaneous calcification in connective tissue diseases. Curr Opin Rheumatol. 2012;24(2):158-164.
PubMedArticle
11.
Avouac  J, Guerini  H, Wipff  J,  et al.  Radiological hand involvement in systemic sclerosis. Ann Rheum Dis. 2006;65(8):1088-1092.
PubMedArticle
12.
Avouac  J, Mogavero  G, Guerini  H,  et al.  Predictive factors of hand radiographic lesions in systemic sclerosis: a prospective study. Ann Rheum Dis. 2011;70(4):630-633.
PubMedArticle
13.
Kang  EH, Nakashima  R, Mimori  T,  et al.  Myositis autoantibodies in Korean patients with inflammatory myositis: anti-140-kDa polypeptide antibody is primarily associated with rapidly progressive interstitial lung disease independent of clinically amyopathic dermatomyositis. BMC Musculoskelet Disord. 2010;11:223. doi:10.1186/1471-2474-11-223.
PubMedArticle
14.
Rider  LG, Shah  M, Mamyrova  G,  et al; Childhood Myositis Heterogeneity Collaborative Study Group.  The myositis autoantibody phenotypes of the juvenile idiopathic inflammatory myopathies. Medicine (Baltimore). 2013;92(4):223-243.
PubMedArticle
15.
Gunawardena  H, Betteridge  ZE, McHugh  NJ.  Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression. Rheumatology (Oxford). 2009;48(6):607-612.
PubMedArticle
16.
Fiorentino  DF, Chung  LS, Christopher-Stine  L,  et al.  Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1γ. Arthritis Rheum. 2013;65(11):2954-2962.
PubMedArticle
17.
Ichimura  Y, Matsushita  T, Hamaguchi  Y,  et al.  Anti-NXP2 autoantibodies in adult patients with idiopathic inflammatory myopathies: possible association with malignancy. Ann Rheum Dis. 2012;71(5):710-713.
PubMedArticle
18.
Sallum  AM, Pivato  FC, Doria-Filho  U,  et al.  Risk factors associated with calcinosis of juvenile dermatomyositis. J Pediatr (Rio J). 2008;84(1):68-74.
PubMedArticle
19.
Sanner  H, Gran  JT, Sjaastad  I, Flatø  B.  Cumulative organ damage and prognostic factors in juvenile dermatomyositis: a cross-sectional study median 16.8 years after symptom onset. Rheumatology (Oxford). 2009;48(12):1541-1547.
PubMedArticle
20.
Gunawardena  H, Wedderburn  LR, Chinoy  H,  et al; Juvenile Dermatomyositis Research Group, UK and Ireland.  Autoantibodies to a 140-kd protein in juvenile dermatomyositis are associated with calcinosis. Arthritis Rheum. 2009;60(6):1807-1814.
PubMedArticle
21.
Ceribelli  A, Fredi  M, Taraborelli  M,  et al.  Anti-MJ/NXP-2 autoantibody specificity in a cohort of adult Italian patients with polymyositis/dermatomyositis. Arthritis Res Ther. 2012;14(2):R97. doi:10.1186/ar3822.
PubMedArticle
22.
Casciola-Rosen  L, Mammen  AL.  Myositis autoantibodies. Curr Opin Rheumatol. 2012;24(6):602-608.
PubMedArticle
23.
Bohan  A, Peter  JB.  Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292(7):344-347.
PubMedArticle
24.
Sontheimer  RD.  Dermatomyositis: an overview of recent progress with emphasis on dermatologic aspects. Dermatol Clin. 2002;20(3):387-408.
PubMedArticle
25.
Rider  LG, Werth  VP, Huber  AM,  et al.  Measures of adult and juvenile dermatomyositis, polymyositis, and inclusion body myositis: Physician and Patient/Parent Global Activity, Manual Muscle Testing (MMT), Health Assessment Questionnaire (HAQ)/Childhood Health Assessment Questionnaire (C-HAQ), Childhood Myositis Assessment Scale (CMAS), Myositis Disease Activity Assessment Tool (MDAAT), Disease Activity Score (DAS), Short Form 36 (SF-36), Child Health Questionnaire (CHQ), physician global damage, Myositis Damage Index (MDI), Quantitative Muscle Testing (QMT), Myositis Functional Index-2 (FI-2), Myositis Activities Profile (MAP), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Cutaneous Assessment Tool (CAT), Dermatomyositis Skin Severity Index (DSSI), Skindex, and Dermatology Life Quality Index (DLQI). Arthritis Care Res (Hoboken). 2011;63(suppl 11):S118-S157.
PubMedArticle
26.
Casciola-Rosen  L, Andrade  F, Ulanet  D, Wong  WB, Rosen  A.  Cleavage by granzyme B is strongly predictive of autoantigen status: implications for initiation of autoimmunity. J Exp Med. 1999;190(6):815-826.
PubMedArticle
27.
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(4):455-462.
PubMedArticle
28.
Marvi  U, Chung  L, Fiorentino  DF.  Clinical presentation and evaluation of dermatomyositis. Indian J Dermatol. 2012;57(5):375-381.
PubMedArticle
29.
Rider  LG, Feldman  BM, Perez  MD,  et al; Juvenile Dermatomyositis Disease Activity Collaborative Study Group.  Development of validated disease activity and damage indices for the juvenile idiopathic inflammatory myopathies, I: physician, parent, and patient global assessments. Arthritis Rheum. 1997;40(11):1976-1983.
PubMedArticle
30.
Vitiello  M, Abuchar  A, Santana  N, Dehesa  L, Kerdel  FA.  An update on the treatment of the cutaneous manifestations of systemic sclerosis: the dermatologist’s point of view. J Clin Aesthet Dermatol. 2012;5(7):33-43.
PubMed
31.
Zaba  LC, Fiorentino  DF.  Skin disease in dermatomyositis. Curr Opin Rheumatol. 2012;24(6):597-601.
PubMedArticle
32.
Fiorentino  DF, Chung  LS, Zaba  L, Lingala  B, Rosen  A, Casciola-Rosen  L.  Immune responses to NXP-2 and TIF-g are associated with distinct clinical phenotypes and prognosis for skin disease in dermatomyositis patients .Arthritis Rheum.2012;64(S10):S828.
Original Investigation
July 2014

Identification of Clinical Features and Autoantibodies Associated With Calcinosis in Dermatomyositis

Author Affiliations
  • 1Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California
  • 2Department of Dermatology, Stanford University School of Medicine, Stanford, California
  • 3Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
JAMA Dermatol. 2014;150(7):724-729. doi:10.1001/jamadermatol.2013.10416
Abstract

Importance  Prior studies have estimated that up to 20% of adults with dermatomyositis (DM) have calcinosis, which can lead to significant morbidity. Identification of risk factors may provide a better understanding of the pathogenesis and ultimately therapy for this difficult clinical problem. Risk factors for calcinosis in adults with DM have not been extensively studied.

Objectives  To determine the prevalence of calcinosis and to identify associated clinical features in a cohort of extensively phenotyped adults with DM.

Design, Setting, and Participants  A cross-sectional study of 126 patients diagnosed as having DM from January 1, 2006, through January 1, 2013, was performed. Patients were adults (≥18 years of age) attending the Stanford University Medical Center clinic.

Main Outcomes and Measures  Calcinosis, defined as the presence of calcium deposition in the skin and subcutaneous tissues on physical examination.

Results  Fourteen patients (11.1%) had calcinosis, with the extremities most commonly involved. Patients with vs those without calcinosis had a longer disease duration (median, 6.9 years; range, 2.4–18.1; vs median, 3.9 years; range, 0.2-19.2 years; P = .003) and more fingertip ulcers (50.0% vs 9.3%, P < .001). An association between calcinosis and both interstitial lung disease and anti–MDA-5 autoantibodies was identified, but this association did not persist in multivariate models that adjusted for fingertip ulcers. Fingertip ulcers and disease duration were strongly associated with calcinosis in all multivariate models, independent of the underlying autoantibody present. Autoantibodies to NXP-2 were associated with calcinosis (odds ratio, 15.52; 95% CI, 2.01-119.90), whereas anti–transcriptional intermediary factor 1-γ antibodies were protective (odds ratio, 0.2; 95% CI, 0.01-0.99) in multivariate analyses that adjusted for fingertip ulcers and other covariates.

Conclusions and Relevance  Calcinosis was a relatively uncommon clinical feature in our cohort of adults with DM. Our data suggest that calcinosis is positively associated with longer disease duration, fingertip ulcers, and NXP-2 autoantibodies and negatively associated with transcriptional intermediary factor 1-γ antibodies. A common vascular mechanism may underlie the development of both calcinosis and fingertip ulcers in patients with DM.

Dermatomyositis (DM) is a systemic autoimmune disease characterized by chronic inflammation of skin and muscles.1 Calcinosis, which is the deposition of calcium in the skin and subcutaneous tissues, develops in 20% to 70% of patients with juvenile dermatomyositis (JDM)2,3 and up to 20% of adults with DM.46 It is often painful and may cause recurrent episodes of local inflammation or infection, leading to considerable distress and disability.7 Calcinosis may present as small superficial papules or nodules, deeper nodules or tumors in the dermis or subcutaneous tissue, or diffuse deposits along the myofascial planes, which, if generalized, can form an extensive exoskeleton.7,8

Case reports and small case series have described the benefits of using various medical therapies to treat calcinosis in patients with DM, including warfarin sodium, bisphosphonates, minocycline, diltiazem, probenecid, aluminum hydroxide, sodium thiosulfate, colchicine, and intravenous immunoglobulin.4 Unfortunately, no medical therapy is reliably efficacious, and surgical management is often the best option.4,9

Little is known about the pathogenesis of calcinosis in DM. One possible mechanism is the release of calcium from mitochondria in muscle cells damaged by myopathy.6 Macrophages, proinflammatory cytokines, and the impairment of calcium-regulating proteins have also been implicated.10 Furthermore, in patients with systemic sclerosis, digital ischemic ulcers are associated with calcinosis, suggesting a role of vascular ischemia and injury.1012

Between 60% and 70% of patients with DM are reported to have circulating, myositis-specific autoantibodies that are associated with particular clinical features.13,14 Several novel autoantibody targets in DM have been recently identified. MDA-5, CADM-140, and IFIH1 are targeted in patients with mild or no muscle disease, rapidly progressive interstitial lung disease (ILD), cutaneous ulcers, and palmar papules that have vasculopathy on histopathologic analysis.1 Antibodies against p155/140, TRIM33, and transcriptional intermediary factor 1-γ (TIF1-γ) are associated with cancer in adults (60%-80%) and low rates of ILD but more widespread and severe skin disease in JDM; NXP-2/MJ antibodies were initially described in patients with JDM who were at higher risk for calcinosis.15 Recent data suggest that antibodies against NXP-2 are also associated with cancer in adults with DM.16,17

Previous studies18,19 of patients with JDM have identified particular clinical features associated with calcinosis, including longer disease duration, sustained disease activity, and internal organ involvement. Although antibodies to NXP-2 have been associated with calcinosis in JDM,20 there are conflicting data with regard to this association in adults with DM.17,21,22 We sought to identify the clinical features associated with calcinosis in our cohort of extensively phenotyped adults with DM.

Methods
Study Design

This is a cross-sectional study of 126 patients with DM. The study was approved by the institutional review board at Stanford University. We retrospectively collected demographic information, symptoms, physical examination findings, and internal organ involvement. All patients provided written informed consent.

Study Population

We included all adults (≥18 years of age) diagnosed as having DM and followed up in the rheumatology and dermatology clinics at Stanford University Medical Center from January 1, 2006, through January 1, 2013. We excluded patients with a diagnosis of mixed connective tissue disease whose features were not primarily consistent with DM, patients with other overlap connective tissue disease, and patients with JDM. Patients were diagnosed as having DM according to the Bohan and Peter23 criteria for DM and the modified Sontheimer24 criteria for clinically amyopathic DM.

Study End Points

The objective of our study was to determine the prevalence of calcinosis in our cohort of patients with DM and to identify associated clinical features. Calcinosis was defined as the presence of calcium deposition in the skin and subcutaneous tissues on physical examination regardless of its extent or severity.25 Radiographic confirmation was not required.

Detection of Autoantibodies

Plasma was screened for DM-specific and associated autoantibodies as previously described.1,16,26 Briefly, antibodies against NXP-2 and MDA-5 were detected by immunoprecipitations using [35S]-methionine–labeled in vitro transcription and translation proteins. TIF1-γ antibodies were determined by an immunoprecipitation and blot assay, whereas Mi-2 and SAE1/2 antibodies were detected by immunoprecipitation using [35S]-methionine–labeled proteins generated by in vitro transcription and translation from the appropriate complementary DNAs. Jo-1 and Ro-52 antibodies were assayed by enzyme-linked immunosorbent assay.

Statistical Analysis

Descriptive statistics and frequency distributions of all variables of interest were reported as proportion for categorical variables and as mean (SD) or median (range) for continuous variables. We performed univariate analysis to characterize patients with and without calcinosis with respect to demographic characteristics, clinical features, antibodies, disease duration, and measures of highest disease activity, using χ2 test for categorical variables or the t test for continuous variables if a normal distribution was observed and nonparametric methods for continuous variables without a normal distribution. Logistic regression models were developed to obtain odds ratios (ORs) that related calcinosis to various variables. We selected statistically significant univariate variables to establish predictors for multivariate analysis. The logistic regression model β-coefficient was evaluated with and without potential confounders and adjusted for them if inclusion in the model changed it by greater than 10%.

Statistical significance was defined as P ≤ .05. All statistical analysis was performed using SAS statistical software, version 9.3 (SAS Institute Inc).

Results
Patient Characteristics

Of 126 adults with DM, 93 were women (73.8%), and the racial distribution was 66.4% white, 11.2% Asian, 12.8% Hispanic, 4.0% African American, and 5.6% unknown. Mean age at diagnosis was 50.0 (14.8) years, 22.2% had clinically amyopathic DM, and 83.6% had DM-specific antibodies. Fourteen patients (11.1%) developed calcinosis. Sites affected by calcinosis are listed in Table 1. Calcinosis was most common on the extremities (Figure, A) and axilla but not on the hands. In some patients, the calcinosis was deposited in large subcutaneous tumors (Figure, B).

Table 2 lists the demographic and clinical features of patients with and without calcinosis. Patients with calcinosis had longer median disease duration from DM diagnosis to last clinic visit (6.9 [2.4-18.1] vs 3.9 [0.2-19.2] years; P = .003) than patients without calcinosis. There was a trend for whites to be less likely to develop calcinosis relative to other races. More patients in the calcinosis group had interstitial lung disease (53.9% vs 15.2%, P < .001) and fingertip ulcers (50.0% vs 9.3%, P < .001) but not other types of mucocutaneous ulceration (Table 2).

Autoantibodies and Calcinosis

Autoantibodies against MDA-5 and Ro-52 were more frequently found in patients with vs those without calcinosis (35.7% vs 9.8%, P = .006, and 42.9% vs 17.9%, P = .02, respectively). Anti–NXP-2 antibodies were also more frequently found in patients with vs those without calcinosis (28.6% vs 10.7%, P = .06). In contrast, anti–TIF1-γ antibodies were less frequently found in patients with vs those without calcinosis (14.3% vs 45.5%, P = .02) (Table 3). Of the 6 patients with calcinosis with anti–Ro-52, 2 had autoantibodies against MDA-5 and 1 had autoantibodies against TIF1-γ.

Factors Associated With Calcinosis in Multivariate Analysis

Because these autoantibodies define groups of patients with certain clinical features, we thought it likely that many of these clinical and laboratory features might not be independently associated with calcinosis because of confounding. For example, anti–MDA-5 antibodies are associated with both ILD and fingertip ulcers.1 Because these antibodies are often mutually exclusive,14 these analyses require separate models to analyze the effect of each antibody. Thus, we examined separate multivariate models for each antibody (NXP-2, MDA-5, and TIF1-γ), while including all other significant predictors identified in Table 2. In all 3 models, fingertip ulcers and increasing duration of disease were risk factors for the presence of calcinosis (Table 4). In addition, antibodies to NXP-2 were significantly associated with calcinosis (OR, 15.52; 95% CI, 2.0-119.9; P = .009), whereas antibodies to TIF1-γ were protective of calcinosis (OR, 0.2; 95% CI, 0.01-0.99; P = .04). Interstitial lung disease was not significantly associated with calcinosis in multivariate analyses.

Interestingly, the strong association between calcinosis and anti–MDA-5 antibodies did not persist when disease duration, fingertip ulcers, and ILD were included in the model. We hypothesized that this might be due to the strong association between anti–MDA-5 antibodies and fingertip ulcers. This theory was supported by evaluation of another multivariate model that excluded fingertip ulcers, which then demonstrated that anti–MDA-5 antibodies were highly predictive of calcinosis (OR, 6.9; 95% CI, 1.8-27.0; P = .005) (data not shown).

Discussion

Calcinosis is a significant clinical problem for patients with autoimmune disease, especially systemic sclerosis and DM. Traditionally, it is believed that calcinosis occurs more often in the JDM population, although data are scarce on the prevalence in adults with DM. We found a prevalence of calcinosis of 11.1% in this large cohort of adults with DM. Our data suggest that calcinosis is more frequent in patients with longer disease duration, which is consistent with prior studies27 and with the view that this complication results from damage caused by longstanding disease activity.28 Prior studies have used time to initiation of therapy or number of prescribed immunosuppressants as indirect measures of time of active disease. Measures of disease activity have been developed and partially validated as measures of response to therapy,29 although it is unclear whether disease activity as defined by these measures is associated with calcinosis.

A novel finding in our study was that calcinosis in adults with DM was strongly associated with fingertip ulcers. Interestingly, ulcers on other areas of skin (including the oral mucosa) were not associated with calcinosis. The cause of digital ulceration in DM is currently unclear, although vascular inflammation and/or injury likely plays an important role because biopsy specimens of fingertip lesions in patients with DM demonstrate a vasculopathy.1 Thus, vascular injury may be involved in the pathogenesis of both digital ulcers and calcinosis, which has been previously suggested in patients with systemic sclerosis.11,12 Another explanation for this association is that, because ulcerations frequently develop in areas with calcinosis in patients with systemic sclerosis,30 the same could happen in patients with DM, although in our patients, calcifications did not occur in sites of ulceration (data not shown). It is unclear why other sites of ulceration were not significantly associated with calcinosis, although all forms of ulcers tended to be associated with calcinosis, and low numbers may have precluded statistical significance.

We also evaluated whether any of the DM-specific or associated autoantibodies were risk factors for calcinosis. In our cohort, the autoantibody NXP-2 was strongly associated with calcinosis in multivariate analysis (OR, 15.52; 95% CI, 2.01-119.90; P = .009), consistent with prior studies in JDM and one study in adults with DM,31 and yielded a nonstatistically significant trend (P = .06) with calcinosis in the univariate analysis. Certainly, it is possible that adjusting for confounders might have strengthened the statistical association because we needed to correct for confounders to unveil the association between NXP-2 and calcinosis. In our opinion, the results of the multivariate analysis are the most robust way of looking at this association. MDA-5 antibodies were not associated with calcinosis in multivariate analyses, although they were more common in patients with calcinosis, likely because of their strong association with fingertip ulcers. Patients with the circulating autoantibody MDA-5 have a characteristic cutaneous phenotype that consists of skin ulceration and/or tender palmar papules that show vasculopathy on skin biopsy specimens.1 They also have an increased risk of oral pain and/or ulceration, hand swelling, arthritis and arthralgia, diffuse hair loss, and ILD, associated with little or absence of myositis. Our data support the consideration of calcinosis as part of this phenotype. Interestingly, antibodies to TIF1-γ were observed with a high frequency in our overall cohort (42.1%) and were inversely associated with calcinosis (OR, 0.20; 95% CI, 0.01-0.99; P = .04). Along with other studies, we have found that DM patients with TIF1-γ antibodies tend to have a more treatment-resistant and chronic course of skin disease,14,32 which traditionally is thought to be a risk factor for the development of calcinosis, at least in the JDM population. Consequently, our finding that this group of patients tends to have less calcinosis is somewhat surprising and suggests that our understanding of pathogenic risk factors for calcinosis is incomplete.

The current study is the first, to our knowledge, to examine specific risk factors for calcinosis in a large, well-phenotyped cohort of adults with DM. However, because this patient population is a sample from a tertiary care clinic, our results may not be generalizable. Because our study has the potential for significant confounding, we used multivariate methods to adjust for the well-defined risk factors; however, it is possible that other relevant risk factors may have been missed. Finally, the small sample size of patients who developed the outcome limited the potential to build models with more predictors; therefore, these results should be validated in other existing cohorts and future prospective studies.

Conclusions

Calcinosis is a relatively uncommon clinical feature in patients with DM and is associated with autoantibodies to NXP-2, whereas anti–TIF1-γ appears to be protective. Calcinosis is associated with longer disease duration and fingertip ulcers. A common underlying vascular mechanism between calcinosis in DM and digital ulcers is suggested by our data. A medication known to prevent or ameliorate vascular dysfunction in other connective tissue disorders (such as phosphodiesterase 5 inhibitors, endothelin receptor antagonists, or prostacyclins) might be effective for the prevention or treatment of calcinosis in patients with DM.

Back to top
Article Information

Accepted for Publication: December 12, 2013.

Corresponding Author: David Fiorentino, MD, PhD, Department of Dermatology, Stanford University School of Medicine, 450 Broadway, Pavilion C, Room 234, Stanford, CA 94063 (Fiorentino@stanford.edu).

Published Online: May 28, 2014. doi:10.1001/jamadermatol.2013.10416.

Author Contributions: Dr Valenzuela had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Valenzuela.

Critical revision of the manuscript for important intellectual content: Chung, Casciola-Rosen, Fiorentino.

Statistical analysis: Valenzuela, Chung, Fiorentino.

Study supervision: Chung, Fiorentino.

Conflict of Interest Disclosures: None reported.

References
1.
Fiorentino  D, Chung  L, Zwerner  J, Rosen  A, Casciola-Rosen  L.  The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): a retrospective study. J Am Acad Dermatol. 2011;65(1):25-34.
PubMedArticle
2.
Clemente  G, Piotto  DG, Barbosa  C,  et al.  High frequency of calcinosis in juvenile dermatomyositis: a risk factor study. Rev Bras Reumatol. 2012;52(4):549-553.
PubMedArticle
3.
Mathiesen  P, Hegaard  H, Herlin  T, Zak  M, Pedersen  FK, Nielsen  S.  Long-term outcome in patients with juvenile dermatomyositis: a cross-sectional follow-up study. Scand J Rheumatol. 2012;41(1):50-58.
PubMedArticle
4.
Gutierrez  A  Jr, Wetter  DA.  Calcinosis cutis in autoimmune connective tissue diseases. Dermatol Ther. 2012;25(2):195-206.
PubMedArticle
5.
Walsh  JS, Fairley  JA.  Calcifying disorders of the skin. J Am Acad Dermatol. 1995;33(5, pt 1):693-710.
PubMedArticle
6.
Cook  CD, Rosen  FS, Banker  BQ.  Dermatomyositis and focal scleroderma. Pediatr Clin North Am. 1963;10:979-1016.
PubMed
7.
Boulman  N, Slobodin  G, Rozenbaum  M, Rosner  I.  Calcinosis in rheumatic diseases. Semin Arthritis Rheum. 2005;34(6):805-812.
PubMedArticle
8.
Blane  CE, White  SJ, Braunstein  EM, Bowyer  SL, Sullivan  DB.  Patterns of calcification in childhood dermatomyositis. AJR Am J Roentgenol. 1984;142(2):397-400.
PubMedArticle
9.
Reiter  N, El-Shabrawi  L, Leinweber  B, Berghold  A, Aberer  E. Calcinosis cutis, part II: treatment options .J Am Acad Dermatol.2011;65(1):15-24.
PubMed
10.
Chander  S, Gordon  P.  Soft tissue and subcutaneous calcification in connective tissue diseases. Curr Opin Rheumatol. 2012;24(2):158-164.
PubMedArticle
11.
Avouac  J, Guerini  H, Wipff  J,  et al.  Radiological hand involvement in systemic sclerosis. Ann Rheum Dis. 2006;65(8):1088-1092.
PubMedArticle
12.
Avouac  J, Mogavero  G, Guerini  H,  et al.  Predictive factors of hand radiographic lesions in systemic sclerosis: a prospective study. Ann Rheum Dis. 2011;70(4):630-633.
PubMedArticle
13.
Kang  EH, Nakashima  R, Mimori  T,  et al.  Myositis autoantibodies in Korean patients with inflammatory myositis: anti-140-kDa polypeptide antibody is primarily associated with rapidly progressive interstitial lung disease independent of clinically amyopathic dermatomyositis. BMC Musculoskelet Disord. 2010;11:223. doi:10.1186/1471-2474-11-223.
PubMedArticle
14.
Rider  LG, Shah  M, Mamyrova  G,  et al; Childhood Myositis Heterogeneity Collaborative Study Group.  The myositis autoantibody phenotypes of the juvenile idiopathic inflammatory myopathies. Medicine (Baltimore). 2013;92(4):223-243.
PubMedArticle
15.
Gunawardena  H, Betteridge  ZE, McHugh  NJ.  Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression. Rheumatology (Oxford). 2009;48(6):607-612.
PubMedArticle
16.
Fiorentino  DF, Chung  LS, Christopher-Stine  L,  et al.  Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1γ. Arthritis Rheum. 2013;65(11):2954-2962.
PubMedArticle
17.
Ichimura  Y, Matsushita  T, Hamaguchi  Y,  et al.  Anti-NXP2 autoantibodies in adult patients with idiopathic inflammatory myopathies: possible association with malignancy. Ann Rheum Dis. 2012;71(5):710-713.
PubMedArticle
18.
Sallum  AM, Pivato  FC, Doria-Filho  U,  et al.  Risk factors associated with calcinosis of juvenile dermatomyositis. J Pediatr (Rio J). 2008;84(1):68-74.
PubMedArticle
19.
Sanner  H, Gran  JT, Sjaastad  I, Flatø  B.  Cumulative organ damage and prognostic factors in juvenile dermatomyositis: a cross-sectional study median 16.8 years after symptom onset. Rheumatology (Oxford). 2009;48(12):1541-1547.
PubMedArticle
20.
Gunawardena  H, Wedderburn  LR, Chinoy  H,  et al; Juvenile Dermatomyositis Research Group, UK and Ireland.  Autoantibodies to a 140-kd protein in juvenile dermatomyositis are associated with calcinosis. Arthritis Rheum. 2009;60(6):1807-1814.
PubMedArticle
21.
Ceribelli  A, Fredi  M, Taraborelli  M,  et al.  Anti-MJ/NXP-2 autoantibody specificity in a cohort of adult Italian patients with polymyositis/dermatomyositis. Arthritis Res Ther. 2012;14(2):R97. doi:10.1186/ar3822.
PubMedArticle
22.
Casciola-Rosen  L, Mammen  AL.  Myositis autoantibodies. Curr Opin Rheumatol. 2012;24(6):602-608.
PubMedArticle
23.
Bohan  A, Peter  JB.  Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292(7):344-347.
PubMedArticle
24.
Sontheimer  RD.  Dermatomyositis: an overview of recent progress with emphasis on dermatologic aspects. Dermatol Clin. 2002;20(3):387-408.
PubMedArticle
25.
Rider  LG, Werth  VP, Huber  AM,  et al.  Measures of adult and juvenile dermatomyositis, polymyositis, and inclusion body myositis: Physician and Patient/Parent Global Activity, Manual Muscle Testing (MMT), Health Assessment Questionnaire (HAQ)/Childhood Health Assessment Questionnaire (C-HAQ), Childhood Myositis Assessment Scale (CMAS), Myositis Disease Activity Assessment Tool (MDAAT), Disease Activity Score (DAS), Short Form 36 (SF-36), Child Health Questionnaire (CHQ), physician global damage, Myositis Damage Index (MDI), Quantitative Muscle Testing (QMT), Myositis Functional Index-2 (FI-2), Myositis Activities Profile (MAP), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Cutaneous Assessment Tool (CAT), Dermatomyositis Skin Severity Index (DSSI), Skindex, and Dermatology Life Quality Index (DLQI). Arthritis Care Res (Hoboken). 2011;63(suppl 11):S118-S157.
PubMedArticle
26.
Casciola-Rosen  L, Andrade  F, Ulanet  D, Wong  WB, Rosen  A.  Cleavage by granzyme B is strongly predictive of autoantigen status: implications for initiation of autoimmunity. J Exp Med. 1999;190(6):815-826.
PubMedArticle
27.
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(4):455-462.
PubMedArticle
28.
Marvi  U, Chung  L, Fiorentino  DF.  Clinical presentation and evaluation of dermatomyositis. Indian J Dermatol. 2012;57(5):375-381.
PubMedArticle
29.
Rider  LG, Feldman  BM, Perez  MD,  et al; Juvenile Dermatomyositis Disease Activity Collaborative Study Group.  Development of validated disease activity and damage indices for the juvenile idiopathic inflammatory myopathies, I: physician, parent, and patient global assessments. Arthritis Rheum. 1997;40(11):1976-1983.
PubMedArticle
30.
Vitiello  M, Abuchar  A, Santana  N, Dehesa  L, Kerdel  FA.  An update on the treatment of the cutaneous manifestations of systemic sclerosis: the dermatologist’s point of view. J Clin Aesthet Dermatol. 2012;5(7):33-43.
PubMed
31.
Zaba  LC, Fiorentino  DF.  Skin disease in dermatomyositis. Curr Opin Rheumatol. 2012;24(6):597-601.
PubMedArticle
32.
Fiorentino  DF, Chung  LS, Zaba  L, Lingala  B, Rosen  A, Casciola-Rosen  L.  Immune responses to NXP-2 and TIF-g are associated with distinct clinical phenotypes and prognosis for skin disease in dermatomyositis patients .Arthritis Rheum.2012;64(S10):S828.
×