A 27-year-old woman with a long-standing history of juvenile dermatomyositis developed cutaneous and subcutaneous nodules (Figure 1-6). A biopsy was performed.
What is the best diagnosis?
A. Gout
B. Pseudogout
C. Idiopathic calcinosis
D. Calcinosis cutis in the setting of dermatomyositis
Answer on page 2
{{pagebreak}}
Answer: D
Diagnosis: Calcinosis cutis in the setting of dermatomyositis
The biopsy shows highly characteristic findings as revealed by striking expansile nodular foci of calcium within the dermis.1 The calcium is discernible on routine light microscopic assessment as amorphous to granular bluish material within the dermis (Figure 1). The clue that this dermal calcification is occurring in the setting of dermatomyositis are the background changes of chronic microvascular injury. The latter is manifested by vascular ectasia and significant vascular basement membrane zone reduplication (Figure 2). The presumed basis of the vascular injury is related to antecedent episodes of immune-based vascular injury targeting the endothelium.2-4 The effector mechanism of endothelial cell injury is C5b-9 and in this biopsy extensive deposits of C5b-9 were noted in vessels and outlining the calcific foci, possibly representing calcified vessels (Figure 3). A particularly intriguing feature in this case was the intimate association of the calcific microspheres with blood vessels demonstrating advanced chronic microvascular alterations (Figure 4). There were altered vessels showing mineral deposits. In some of micronodular foci of calcification, there were ghost-like remnants of endothelium suggesting that the calcification was likely occurring in damaged vessels that acquired an osteogenic phenotype (Figure 5).
In our experience, lesions of calcinosis cutis related to dermatomyositis typically have no evidence of active microvascular injury in contradistinction to the discernible microvascular injury seen in skin biopsies procured from an active inflammatory skin rash seen in patients with dermatomyositis best exemplified by a Gottron papule.2,3 Likely dystrophic calcification in compromised tissue subjected to protracted and sustained vascular injury is its basis. From an immunohistochemical perspective, it is our experience that an upregulated type I interferon microenvironment as revealed by the extent of endothelial and inflammatory cell staining for MxA—the classic surrogate marker for the enhanced type I interferon microenvironment—is a cardinal hallmark of calcinosis cutis in the setting of dermatomyositis. This reflects the critical role of enhanced type I interferon activity in the pathogenesis of dermatomyositis especially as it applies to the microvascular changes.5 Additionally, there was striking upregulation of MxA staining in the calcified foci which may not be surprising since these calcified foci may represent damaged blood vessels (Figure 6).
Clinical Presentation
Calcinosis cutis is a frequent complication that is encountered in patients with juvenile dermatomyositis. It has been reported to occur in 50% of cases.6 This type of dermal and deeper-seated soft tissue calcification can be associated with significant patient morbidity. One study examined 650 patients with juvenile dermatomyositis procured from 55 centers throughout North America. The patients had longer duration of disease and often these patients had associated joint contractures. There was also a greater likelihood that patients received rituximab (Rituxan) and intravenous immunoglobulin, the latter reflective of the severity of the disease and therefore refractory to more conventional therapies. It should not be construed that these therapies in any way contribute to the development of the calcification. Overall severe disease, a longer duration of being symptomatic, treatment failure to more conventional therapies, and joint contractures are the main associations.6
A similar clinical parallel was not observed in adult patients who developed dermatomyositis. In adult patients with dermatomyositis who develop calcinosis cutis there is, however, a potential association with a specific antibody profile. These patients are most likely to have antibodies to aminoacyl-transfer RNA synthetase. Other concurrent features in these patients included poikiloderma and articular involvement.7
Our patient typifies the type of patient with juvenile dermatomyositis who develops calcinosis cutis. This patient had the onset of dermatomyositis at a very early age and did not receive any effective therapy for several years, hence emphasizing that long lapses in either no therapy or suboptimal therapy defines the prototypic risk factor for the development of calcinosis cutis in the setting of dermatomyositis. In this particular patient, the lesions of calcinosis cutis were large and debilitating, extending into the deeper soft tissue.
Further Considerations
As the diagnosis of calcinosis cutis in the setting of dermatomyositis is an obvious one from a clinical perspective, it is rarely biopsied. We had the opportunity to review cases of calcinosis cutis in the setting of dermatomyositis. The patients were younger suggesting that the cases were primarily in the context of juvenile dermatomyositis. In none of the cases were there striking active changes of dermatomyositis. Dermatomyositis is the prototypic anti-endothelial cell antibody syndrome whereby acute lesions will show significant endothelial cell necrosis with endothelial cell detachment and luminal thrombosis with the effector mechanism of vascular injury being C5b-9. In addition, there is evidence of an enhanced type I interferon microenvironment as revealed by the extent of staining with the surrogate type I interferon marker MxA.2-4 In the setting of calcinosis cutis, there are always chronic microvascular changes attributable to antecedent vascular injury characterized primarily by ectatic vessels exhibiting basement membrane zone reduplication along with areas of vascular drop out and anoxia driven fibroplasia. In addition, there will be persistent C5b-9 and MxA staining in blood vessels even though active vascular injury is not seen.
The question arises as to what the pathophysiology is of this distinctive and not uncommon complication encountered in juvenile dermatomyositis more so than its occurrence in the adult setting. It is clearly one of dystrophic calcification as opposed to metastatic or iatrogenic calcification. If its basis is simply antecedent injury, then any traumatic process involving the skin would lead to calcification, which is clearly not the case. Perhaps the underlying pathophysiology might be gleaned by considering the established pathogenetic basis of calcinosis in the setting of normophosphatemic familial calcinosis cutis. In particular, it has been recognized that normophosphatemic tumoral calcinosis exhibits a significant degree of overlap with dystrophic calcification, which is the type of calcification encountered in calcinosis cutis of dermatomyositis. Its pathogenetic basis is one of a mutation in a sterile alpha motif containing domain 9 (SAMD9) located on chromosome 7 q21.2, which leads to an overzealous function of the SAMD9 protein.8,9
The SMAD9 protein is thought to be a key regulatory of pro-inflammatory signals and it may represent a downstream protein that is upregulated by both tumor necrosis factor-alpha and the type I interferons. In addition, this protein shows the greatest degree of upregulation in endothelium. Not surprisingly vasculitic lesions presage calcinosis cutis in patients with normophosphatemic familial calcinosis cutis, perhaps reflecting the local inflammatory milieu needed to induce an upregulation of SAMD9 in endothelium. The exact mechanism by which SAMD9 leads to extraosseous calcification, however, remains elusive. Juvenile dermatomyositis is associated with severe endothelial cell injury and the type of interferon signature is markedly upregulated in the setting of dermatomyositis.10 Hence the microenvironment within the microvasculature is conducive to an overzealous production of SAMD9 protein, therefore recapitulating the pathophysiologic events that occur in normophosphatemic calcinosis cutis. The calcification is likely vasocentric given the high level of SAMD9 expression in endothelium and the further enhanced expression in vessels showing enhanced type I interferon expression. How the significant levels of SAMD9 in the microvasculature leads to calcification is unclear, but it is the general consensus that it is a critical protein determinant for an extraosseous osteogenic phenotype.
Dr Magro is the director of dermatopathology at Weill Cornell Medicine in New York, NY. For more information, please visit www.weillcornelldermpath.com.
Dr Saab is a pathology fellow at Memorial Sloan Kettering Cancer Center in New York, NY.
Dr Dantzig is a board-certified dermatologist with a practice in New York, NY.
Disclosures: The authors report no relevant financial relationships.
References
1. Le C, Bedocs PM. Calcinosis Cutis. Treasure Island, FL: StatPearls Publishing; 2018. https://www.ncbi.nlm.nih.gov/books/NBK448127/. Updated October 27, 2018. Accessed January 28, 2019.
2. Magro CM, Dyrsen M, Kerns MJ. Cutaneous lesions of dermatomyositis with supervening fibrosis. J Cutan Pathol. 2008;35(1):31-39. doi:10.1111/j.1600-0560.2007.00770.x
3. Magro CM, Ross P, Marsh CB, et al. The role of anti-endothelial cell antibody-mediated microvascular injury in the evolution of pulmonary fibrosis in the setting of collagen vascular disease. Am J Clin Pathol. 2007;127(2):237-247. doi:10.1309/CNQDMHLH2WGKL32T
4. Crowson AN, Magro CM. The role of microvascular injury in the pathogenesis of cutaneous lesions of dermatomyositis. Hum Pathol. 1996;27(1):15-19.
5. Magro CM, Segal JP, Crowson AN, Chadwick P. The phenotypic profile of dermatomyositis and lupus erythematosus: A comparative analysis. J Cutan Pathol. 2010;37(6):659-671. doi:10.1111/j.1600-0560.2009.01443
6. Orandi AB, Dharnidharka VR, Al-Hammadi N, Baszis KW; CARRA Legacy Registry Investigators. Clinical phenotypes and biologic treatment use in juvenile dermatomyositis-associated calcinosis. Pediatr Rheumatol Online J. 2018;16(1):84. doi:10.1186/s12969-018-0299-9
7. Best M, Jachiet M, Molinari N, et al. Distinctive cutaneous and systemic features associated with specific antimyositis antibodies in adults with dermatomyositis: A prospective multicentric study of 117 patients. J Eur Acad Dermatol Venereol. 2018;32(7):1164-1172. doi:10.1111/jdv.14759
8. Hershkovitz D, Gross Y, Nahum S, et al. Functional characterization of SAMD9, a protein deficient in normophosphatemic familial tumoral calcinosis.
J Invest Dermatol. 2011;131(3):662-669. doi:10.1038/jid.2010.387
9. Chefetz I, Ben Amitai D, Browning S, et al. Normophosphatemic familial tumoral calcinosis is caused by deleterious mutations in SAMD9, encoding a TNF-alpha responsive protein. J Invest Dermatol. 2008;128(6):1423-1429. doi: 10.1038/sj.jid.5701203
10. Papadopoulou C, McCann LJ. The vasculopathy of juvenile dermatomyositis. Front Pediatr. 2018;6:284. doi:10.3389/fped.2018.00284
A 27-year-old woman with a long-standing history of juvenile dermatomyositis developed cutaneous and subcutaneous nodules (Figure 1-6). A biopsy was performed.
What is the best diagnosis?
A. Gout
B. Pseudogout
C. Idiopathic calcinosis
D. Calcinosis cutis in the setting of dermatomyositis
Answer on page 2
Answer: D
Diagnosis: Calcinosis cutis in the setting of dermatomyositis
The biopsy shows highly characteristic findings as revealed by striking expansile nodular foci of calcium within the dermis.1 The calcium is discernible on routine light microscopic assessment as amorphous to granular bluish material within the dermis (Figure 1). The clue that this dermal calcification is occurring in the setting of dermatomyositis are the background changes of chronic microvascular injury. The latter is manifested by vascular ectasia and significant vascular basement membrane zone reduplication (Figure 2). The presumed basis of the vascular injury is related to antecedent episodes of immune-based vascular injury targeting the endothelium.2-4 The effector mechanism of endothelial cell injury is C5b-9 and in this biopsy extensive deposits of C5b-9 were noted in vessels and outlining the calcific foci, possibly representing calcified vessels (Figure 3). A particularly intriguing feature in this case was the intimate association of the calcific microspheres with blood vessels demonstrating advanced chronic microvascular alterations (Figure 4). There were altered vessels showing mineral deposits. In some of micronodular foci of calcification, there were ghost-like remnants of endothelium suggesting that the calcification was likely occurring in damaged vessels that acquired an osteogenic phenotype (Figure 5).
In our experience, lesions of calcinosis cutis related to dermatomyositis typically have no evidence of active microvascular injury in contradistinction to the discernible microvascular injury seen in skin biopsies procured from an active inflammatory skin rash seen in patients with dermatomyositis best exemplified by a Gottron papule.2,3 Likely dystrophic calcification in compromised tissue subjected to protracted and sustained vascular injury is its basis. From an immunohistochemical perspective, it is our experience that an upregulated type I interferon microenvironment as revealed by the extent of endothelial and inflammatory cell staining for MxA—the classic surrogate marker for the enhanced type I interferon microenvironment—is a cardinal hallmark of calcinosis cutis in the setting of dermatomyositis. This reflects the critical role of enhanced type I interferon activity in the pathogenesis of dermatomyositis especially as it applies to the microvascular changes.5 Additionally, there was striking upregulation of MxA staining in the calcified foci which may not be surprising since these calcified foci may represent damaged blood vessels (Figure 6).
Clinical Presentation
Calcinosis cutis is a frequent complication that is encountered in patients with juvenile dermatomyositis. It has been reported to occur in 50% of cases.6 This type of dermal and deeper-seated soft tissue calcification can be associated with significant patient morbidity. One study examined 650 patients with juvenile dermatomyositis procured from 55 centers throughout North America. The patients had longer duration of disease and often these patients had associated joint contractures. There was also a greater likelihood that patients received rituximab (Rituxan) and intravenous immunoglobulin, the latter reflective of the severity of the disease and therefore refractory to more conventional therapies. It should not be construed that these therapies in any way contribute to the development of the calcification. Overall severe disease, a longer duration of being symptomatic, treatment failure to more conventional therapies, and joint contractures are the main associations.6
A similar clinical parallel was not observed in adult patients who developed dermatomyositis. In adult patients with dermatomyositis who develop calcinosis cutis there is, however, a potential association with a specific antibody profile. These patients are most likely to have antibodies to aminoacyl-transfer RNA synthetase. Other concurrent features in these patients included poikiloderma and articular involvement.7
Our patient typifies the type of patient with juvenile dermatomyositis who develops calcinosis cutis. This patient had the onset of dermatomyositis at a very early age and did not receive any effective therapy for several years, hence emphasizing that long lapses in either no therapy or suboptimal therapy defines the prototypic risk factor for the development of calcinosis cutis in the setting of dermatomyositis. In this particular patient, the lesions of calcinosis cutis were large and debilitating, extending into the deeper soft tissue.
Further Considerations
As the diagnosis of calcinosis cutis in the setting of dermatomyositis is an obvious one from a clinical perspective, it is rarely biopsied. We had the opportunity to review cases of calcinosis cutis in the setting of dermatomyositis. The patients were younger suggesting that the cases were primarily in the context of juvenile dermatomyositis. In none of the cases were there striking active changes of dermatomyositis. Dermatomyositis is the prototypic anti-endothelial cell antibody syndrome whereby acute lesions will show significant endothelial cell necrosis with endothelial cell detachment and luminal thrombosis with the effector mechanism of vascular injury being C5b-9. In addition, there is evidence of an enhanced type I interferon microenvironment as revealed by the extent of staining with the surrogate type I interferon marker MxA.2-4 In the setting of calcinosis cutis, there are always chronic microvascular changes attributable to antecedent vascular injury characterized primarily by ectatic vessels exhibiting basement membrane zone reduplication along with areas of vascular drop out and anoxia driven fibroplasia. In addition, there will be persistent C5b-9 and MxA staining in blood vessels even though active vascular injury is not seen.
The question arises as to what the pathophysiology is of this distinctive and not uncommon complication encountered in juvenile dermatomyositis more so than its occurrence in the adult setting. It is clearly one of dystrophic calcification as opposed to metastatic or iatrogenic calcification. If its basis is simply antecedent injury, then any traumatic process involving the skin would lead to calcification, which is clearly not the case. Perhaps the underlying pathophysiology might be gleaned by considering the established pathogenetic basis of calcinosis in the setting of normophosphatemic familial calcinosis cutis. In particular, it has been recognized that normophosphatemic tumoral calcinosis exhibits a significant degree of overlap with dystrophic calcification, which is the type of calcification encountered in calcinosis cutis of dermatomyositis. Its pathogenetic basis is one of a mutation in a sterile alpha motif containing domain 9 (SAMD9) located on chromosome 7 q21.2, which leads to an overzealous function of the SAMD9 protein.8,9
The SMAD9 protein is thought to be a key regulatory of pro-inflammatory signals and it may represent a downstream protein that is upregulated by both tumor necrosis factor-alpha and the type I interferons. In addition, this protein shows the greatest degree of upregulation in endothelium. Not surprisingly vasculitic lesions presage calcinosis cutis in patients with normophosphatemic familial calcinosis cutis, perhaps reflecting the local inflammatory milieu needed to induce an upregulation of SAMD9 in endothelium. The exact mechanism by which SAMD9 leads to extraosseous calcification, however, remains elusive. Juvenile dermatomyositis is associated with severe endothelial cell injury and the type of interferon signature is markedly upregulated in the setting of dermatomyositis.10 Hence the microenvironment within the microvasculature is conducive to an overzealous production of SAMD9 protein, therefore recapitulating the pathophysiologic events that occur in normophosphatemic calcinosis cutis. The calcification is likely vasocentric given the high level of SAMD9 expression in endothelium and the further enhanced expression in vessels showing enhanced type I interferon expression. How the significant levels of SAMD9 in the microvasculature leads to calcification is unclear, but it is the general consensus that it is a critical protein determinant for an extraosseous osteogenic phenotype.
Dr Magro is the director of dermatopathology at Weill Cornell Medicine in New York, NY. For more information, please visit www.weillcornelldermpath.com.
Dr Saab is a pathology fellow at Memorial Sloan Kettering Cancer Center in New York, NY.
Dr Dantzig is a board-certified dermatologist with a practice in New York, NY.
Disclosures: The authors report no relevant financial relationships.
References
1. Le C, Bedocs PM. Calcinosis Cutis. Treasure Island, FL: StatPearls Publishing; 2018. https://www.ncbi.nlm.nih.gov/books/NBK448127/. Updated October 27, 2018. Accessed January 28, 2019.
2. Magro CM, Dyrsen M, Kerns MJ. Cutaneous lesions of dermatomyositis with supervening fibrosis. J Cutan Pathol. 2008;35(1):31-39. doi:10.1111/j.1600-0560.2007.00770.x
3. Magro CM, Ross P, Marsh CB, et al. The role of anti-endothelial cell antibody-mediated microvascular injury in the evolution of pulmonary fibrosis in the setting of collagen vascular disease. Am J Clin Pathol. 2007;127(2):237-247. doi:10.1309/CNQDMHLH2WGKL32T
4. Crowson AN, Magro CM. The role of microvascular injury in the pathogenesis of cutaneous lesions of dermatomyositis. Hum Pathol. 1996;27(1):15-19.
5. Magro CM, Segal JP, Crowson AN, Chadwick P. The phenotypic profile of dermatomyositis and lupus erythematosus: A comparative analysis. J Cutan Pathol. 2010;37(6):659-671. doi:10.1111/j.1600-0560.2009.01443
6. Orandi AB, Dharnidharka VR, Al-Hammadi N, Baszis KW; CARRA Legacy Registry Investigators. Clinical phenotypes and biologic treatment use in juvenile dermatomyositis-associated calcinosis. Pediatr Rheumatol Online J. 2018;16(1):84. doi:10.1186/s12969-018-0299-9
7. Best M, Jachiet M, Molinari N, et al. Distinctive cutaneous and systemic features associated with specific antimyositis antibodies in adults with dermatomyositis: A prospective multicentric study of 117 patients. J Eur Acad Dermatol Venereol. 2018;32(7):1164-1172. doi:10.1111/jdv.14759
8. Hershkovitz D, Gross Y, Nahum S, et al. Functional characterization of SAMD9, a protein deficient in normophosphatemic familial tumoral calcinosis.
J Invest Dermatol. 2011;131(3):662-669. doi:10.1038/jid.2010.387
9. Chefetz I, Ben Amitai D, Browning S, et al. Normophosphatemic familial tumoral calcinosis is caused by deleterious mutations in SAMD9, encoding a TNF-alpha responsive protein. J Invest Dermatol. 2008;128(6):1423-1429. doi: 10.1038/sj.jid.5701203
10. Papadopoulou C, McCann LJ. The vasculopathy of juvenile dermatomyositis. Front Pediatr. 2018;6:284. doi:10.3389/fped.2018.00284
A 27-year-old woman with a long-standing history of juvenile dermatomyositis developed cutaneous and subcutaneous nodules (Figure 1-6). A biopsy was performed.
What is the best diagnosis?
A. Gout
B. Pseudogout
C. Idiopathic calcinosis
D. Calcinosis cutis in the setting of dermatomyositis
Answer on page 2
A 27-year-old woman with a long-standing history of juvenile dermatomyositis developed cutaneous and subcutaneous nodules (Figure 1-6). A biopsy was performed.
What is the best diagnosis?
A. Gout
B. Pseudogout
C. Idiopathic calcinosis
D. Calcinosis cutis in the setting of dermatomyositis
Answer on page 2
{{pagebreak}}
Answer: D
Diagnosis: Calcinosis cutis in the setting of dermatomyositis
The biopsy shows highly characteristic findings as revealed by striking expansile nodular foci of calcium within the dermis.1 The calcium is discernible on routine light microscopic assessment as amorphous to granular bluish material within the dermis (Figure 1). The clue that this dermal calcification is occurring in the setting of dermatomyositis are the background changes of chronic microvascular injury. The latter is manifested by vascular ectasia and significant vascular basement membrane zone reduplication (Figure 2). The presumed basis of the vascular injury is related to antecedent episodes of immune-based vascular injury targeting the endothelium.2-4 The effector mechanism of endothelial cell injury is C5b-9 and in this biopsy extensive deposits of C5b-9 were noted in vessels and outlining the calcific foci, possibly representing calcified vessels (Figure 3). A particularly intriguing feature in this case was the intimate association of the calcific microspheres with blood vessels demonstrating advanced chronic microvascular alterations (Figure 4). There were altered vessels showing mineral deposits. In some of micronodular foci of calcification, there were ghost-like remnants of endothelium suggesting that the calcification was likely occurring in damaged vessels that acquired an osteogenic phenotype (Figure 5).
In our experience, lesions of calcinosis cutis related to dermatomyositis typically have no evidence of active microvascular injury in contradistinction to the discernible microvascular injury seen in skin biopsies procured from an active inflammatory skin rash seen in patients with dermatomyositis best exemplified by a Gottron papule.2,3 Likely dystrophic calcification in compromised tissue subjected to protracted and sustained vascular injury is its basis. From an immunohistochemical perspective, it is our experience that an upregulated type I interferon microenvironment as revealed by the extent of endothelial and inflammatory cell staining for MxA—the classic surrogate marker for the enhanced type I interferon microenvironment—is a cardinal hallmark of calcinosis cutis in the setting of dermatomyositis. This reflects the critical role of enhanced type I interferon activity in the pathogenesis of dermatomyositis especially as it applies to the microvascular changes.5 Additionally, there was striking upregulation of MxA staining in the calcified foci which may not be surprising since these calcified foci may represent damaged blood vessels (Figure 6).
Clinical Presentation
Calcinosis cutis is a frequent complication that is encountered in patients with juvenile dermatomyositis. It has been reported to occur in 50% of cases.6 This type of dermal and deeper-seated soft tissue calcification can be associated with significant patient morbidity. One study examined 650 patients with juvenile dermatomyositis procured from 55 centers throughout North America. The patients had longer duration of disease and often these patients had associated joint contractures. There was also a greater likelihood that patients received rituximab (Rituxan) and intravenous immunoglobulin, the latter reflective of the severity of the disease and therefore refractory to more conventional therapies. It should not be construed that these therapies in any way contribute to the development of the calcification. Overall severe disease, a longer duration of being symptomatic, treatment failure to more conventional therapies, and joint contractures are the main associations.6
A similar clinical parallel was not observed in adult patients who developed dermatomyositis. In adult patients with dermatomyositis who develop calcinosis cutis there is, however, a potential association with a specific antibody profile. These patients are most likely to have antibodies to aminoacyl-transfer RNA synthetase. Other concurrent features in these patients included poikiloderma and articular involvement.7
Our patient typifies the type of patient with juvenile dermatomyositis who develops calcinosis cutis. This patient had the onset of dermatomyositis at a very early age and did not receive any effective therapy for several years, hence emphasizing that long lapses in either no therapy or suboptimal therapy defines the prototypic risk factor for the development of calcinosis cutis in the setting of dermatomyositis. In this particular patient, the lesions of calcinosis cutis were large and debilitating, extending into the deeper soft tissue.
Further Considerations
As the diagnosis of calcinosis cutis in the setting of dermatomyositis is an obvious one from a clinical perspective, it is rarely biopsied. We had the opportunity to review cases of calcinosis cutis in the setting of dermatomyositis. The patients were younger suggesting that the cases were primarily in the context of juvenile dermatomyositis. In none of the cases were there striking active changes of dermatomyositis. Dermatomyositis is the prototypic anti-endothelial cell antibody syndrome whereby acute lesions will show significant endothelial cell necrosis with endothelial cell detachment and luminal thrombosis with the effector mechanism of vascular injury being C5b-9. In addition, there is evidence of an enhanced type I interferon microenvironment as revealed by the extent of staining with the surrogate type I interferon marker MxA.2-4 In the setting of calcinosis cutis, there are always chronic microvascular changes attributable to antecedent vascular injury characterized primarily by ectatic vessels exhibiting basement membrane zone reduplication along with areas of vascular drop out and anoxia driven fibroplasia. In addition, there will be persistent C5b-9 and MxA staining in blood vessels even though active vascular injury is not seen.
The question arises as to what the pathophysiology is of this distinctive and not uncommon complication encountered in juvenile dermatomyositis more so than its occurrence in the adult setting. It is clearly one of dystrophic calcification as opposed to metastatic or iatrogenic calcification. If its basis is simply antecedent injury, then any traumatic process involving the skin would lead to calcification, which is clearly not the case. Perhaps the underlying pathophysiology might be gleaned by considering the established pathogenetic basis of calcinosis in the setting of normophosphatemic familial calcinosis cutis. In particular, it has been recognized that normophosphatemic tumoral calcinosis exhibits a significant degree of overlap with dystrophic calcification, which is the type of calcification encountered in calcinosis cutis of dermatomyositis. Its pathogenetic basis is one of a mutation in a sterile alpha motif containing domain 9 (SAMD9) located on chromosome 7 q21.2, which leads to an overzealous function of the SAMD9 protein.8,9
The SMAD9 protein is thought to be a key regulatory of pro-inflammatory signals and it may represent a downstream protein that is upregulated by both tumor necrosis factor-alpha and the type I interferons. In addition, this protein shows the greatest degree of upregulation in endothelium. Not surprisingly vasculitic lesions presage calcinosis cutis in patients with normophosphatemic familial calcinosis cutis, perhaps reflecting the local inflammatory milieu needed to induce an upregulation of SAMD9 in endothelium. The exact mechanism by which SAMD9 leads to extraosseous calcification, however, remains elusive. Juvenile dermatomyositis is associated with severe endothelial cell injury and the type of interferon signature is markedly upregulated in the setting of dermatomyositis.10 Hence the microenvironment within the microvasculature is conducive to an overzealous production of SAMD9 protein, therefore recapitulating the pathophysiologic events that occur in normophosphatemic calcinosis cutis. The calcification is likely vasocentric given the high level of SAMD9 expression in endothelium and the further enhanced expression in vessels showing enhanced type I interferon expression. How the significant levels of SAMD9 in the microvasculature leads to calcification is unclear, but it is the general consensus that it is a critical protein determinant for an extraosseous osteogenic phenotype.
Dr Magro is the director of dermatopathology at Weill Cornell Medicine in New York, NY. For more information, please visit www.weillcornelldermpath.com.
Dr Saab is a pathology fellow at Memorial Sloan Kettering Cancer Center in New York, NY.
Dr Dantzig is a board-certified dermatologist with a practice in New York, NY.
Disclosures: The authors report no relevant financial relationships.
References
1. Le C, Bedocs PM. Calcinosis Cutis. Treasure Island, FL: StatPearls Publishing; 2018. https://www.ncbi.nlm.nih.gov/books/NBK448127/. Updated October 27, 2018. Accessed January 28, 2019.
2. Magro CM, Dyrsen M, Kerns MJ. Cutaneous lesions of dermatomyositis with supervening fibrosis. J Cutan Pathol. 2008;35(1):31-39. doi:10.1111/j.1600-0560.2007.00770.x
3. Magro CM, Ross P, Marsh CB, et al. The role of anti-endothelial cell antibody-mediated microvascular injury in the evolution of pulmonary fibrosis in the setting of collagen vascular disease. Am J Clin Pathol. 2007;127(2):237-247. doi:10.1309/CNQDMHLH2WGKL32T
4. Crowson AN, Magro CM. The role of microvascular injury in the pathogenesis of cutaneous lesions of dermatomyositis. Hum Pathol. 1996;27(1):15-19.
5. Magro CM, Segal JP, Crowson AN, Chadwick P. The phenotypic profile of dermatomyositis and lupus erythematosus: A comparative analysis. J Cutan Pathol. 2010;37(6):659-671. doi:10.1111/j.1600-0560.2009.01443
6. Orandi AB, Dharnidharka VR, Al-Hammadi N, Baszis KW; CARRA Legacy Registry Investigators. Clinical phenotypes and biologic treatment use in juvenile dermatomyositis-associated calcinosis. Pediatr Rheumatol Online J. 2018;16(1):84. doi:10.1186/s12969-018-0299-9
7. Best M, Jachiet M, Molinari N, et al. Distinctive cutaneous and systemic features associated with specific antimyositis antibodies in adults with dermatomyositis: A prospective multicentric study of 117 patients. J Eur Acad Dermatol Venereol. 2018;32(7):1164-1172. doi:10.1111/jdv.14759
8. Hershkovitz D, Gross Y, Nahum S, et al. Functional characterization of SAMD9, a protein deficient in normophosphatemic familial tumoral calcinosis.
J Invest Dermatol. 2011;131(3):662-669. doi:10.1038/jid.2010.387
9. Chefetz I, Ben Amitai D, Browning S, et al. Normophosphatemic familial tumoral calcinosis is caused by deleterious mutations in SAMD9, encoding a TNF-alpha responsive protein. J Invest Dermatol. 2008;128(6):1423-1429. doi: 10.1038/sj.jid.5701203
10. Papadopoulou C, McCann LJ. The vasculopathy of juvenile dermatomyositis. Front Pediatr. 2018;6:284. doi:10.3389/fped.2018.00284
A 27-year-old woman with a long-standing history of juvenile dermatomyositis developed cutaneous and subcutaneous nodules (Figure 1-6). A biopsy was performed.
What is the best diagnosis?
A. Gout
B. Pseudogout
C. Idiopathic calcinosis
D. Calcinosis cutis in the setting of dermatomyositis
Answer on page 2
Answer: D
Diagnosis: Calcinosis cutis in the setting of dermatomyositis
The biopsy shows highly characteristic findings as revealed by striking expansile nodular foci of calcium within the dermis.1 The calcium is discernible on routine light microscopic assessment as amorphous to granular bluish material within the dermis (Figure 1). The clue that this dermal calcification is occurring in the setting of dermatomyositis are the background changes of chronic microvascular injury. The latter is manifested by vascular ectasia and significant vascular basement membrane zone reduplication (Figure 2). The presumed basis of the vascular injury is related to antecedent episodes of immune-based vascular injury targeting the endothelium.2-4 The effector mechanism of endothelial cell injury is C5b-9 and in this biopsy extensive deposits of C5b-9 were noted in vessels and outlining the calcific foci, possibly representing calcified vessels (Figure 3). A particularly intriguing feature in this case was the intimate association of the calcific microspheres with blood vessels demonstrating advanced chronic microvascular alterations (Figure 4). There were altered vessels showing mineral deposits. In some of micronodular foci of calcification, there were ghost-like remnants of endothelium suggesting that the calcification was likely occurring in damaged vessels that acquired an osteogenic phenotype (Figure 5).
In our experience, lesions of calcinosis cutis related to dermatomyositis typically have no evidence of active microvascular injury in contradistinction to the discernible microvascular injury seen in skin biopsies procured from an active inflammatory skin rash seen in patients with dermatomyositis best exemplified by a Gottron papule.2,3 Likely dystrophic calcification in compromised tissue subjected to protracted and sustained vascular injury is its basis. From an immunohistochemical perspective, it is our experience that an upregulated type I interferon microenvironment as revealed by the extent of endothelial and inflammatory cell staining for MxA—the classic surrogate marker for the enhanced type I interferon microenvironment—is a cardinal hallmark of calcinosis cutis in the setting of dermatomyositis. This reflects the critical role of enhanced type I interferon activity in the pathogenesis of dermatomyositis especially as it applies to the microvascular changes.5 Additionally, there was striking upregulation of MxA staining in the calcified foci which may not be surprising since these calcified foci may represent damaged blood vessels (Figure 6).
Clinical Presentation
Calcinosis cutis is a frequent complication that is encountered in patients with juvenile dermatomyositis. It has been reported to occur in 50% of cases.6 This type of dermal and deeper-seated soft tissue calcification can be associated with significant patient morbidity. One study examined 650 patients with juvenile dermatomyositis procured from 55 centers throughout North America. The patients had longer duration of disease and often these patients had associated joint contractures. There was also a greater likelihood that patients received rituximab (Rituxan) and intravenous immunoglobulin, the latter reflective of the severity of the disease and therefore refractory to more conventional therapies. It should not be construed that these therapies in any way contribute to the development of the calcification. Overall severe disease, a longer duration of being symptomatic, treatment failure to more conventional therapies, and joint contractures are the main associations.6
A similar clinical parallel was not observed in adult patients who developed dermatomyositis. In adult patients with dermatomyositis who develop calcinosis cutis there is, however, a potential association with a specific antibody profile. These patients are most likely to have antibodies to aminoacyl-transfer RNA synthetase. Other concurrent features in these patients included poikiloderma and articular involvement.7
Our patient typifies the type of patient with juvenile dermatomyositis who develops calcinosis cutis. This patient had the onset of dermatomyositis at a very early age and did not receive any effective therapy for several years, hence emphasizing that long lapses in either no therapy or suboptimal therapy defines the prototypic risk factor for the development of calcinosis cutis in the setting of dermatomyositis. In this particular patient, the lesions of calcinosis cutis were large and debilitating, extending into the deeper soft tissue.
Further Considerations
As the diagnosis of calcinosis cutis in the setting of dermatomyositis is an obvious one from a clinical perspective, it is rarely biopsied. We had the opportunity to review cases of calcinosis cutis in the setting of dermatomyositis. The patients were younger suggesting that the cases were primarily in the context of juvenile dermatomyositis. In none of the cases were there striking active changes of dermatomyositis. Dermatomyositis is the prototypic anti-endothelial cell antibody syndrome whereby acute lesions will show significant endothelial cell necrosis with endothelial cell detachment and luminal thrombosis with the effector mechanism of vascular injury being C5b-9. In addition, there is evidence of an enhanced type I interferon microenvironment as revealed by the extent of staining with the surrogate type I interferon marker MxA.2-4 In the setting of calcinosis cutis, there are always chronic microvascular changes attributable to antecedent vascular injury characterized primarily by ectatic vessels exhibiting basement membrane zone reduplication along with areas of vascular drop out and anoxia driven fibroplasia. In addition, there will be persistent C5b-9 and MxA staining in blood vessels even though active vascular injury is not seen.
The question arises as to what the pathophysiology is of this distinctive and not uncommon complication encountered in juvenile dermatomyositis more so than its occurrence in the adult setting. It is clearly one of dystrophic calcification as opposed to metastatic or iatrogenic calcification. If its basis is simply antecedent injury, then any traumatic process involving the skin would lead to calcification, which is clearly not the case. Perhaps the underlying pathophysiology might be gleaned by considering the established pathogenetic basis of calcinosis in the setting of normophosphatemic familial calcinosis cutis. In particular, it has been recognized that normophosphatemic tumoral calcinosis exhibits a significant degree of overlap with dystrophic calcification, which is the type of calcification encountered in calcinosis cutis of dermatomyositis. Its pathogenetic basis is one of a mutation in a sterile alpha motif containing domain 9 (SAMD9) located on chromosome 7 q21.2, which leads to an overzealous function of the SAMD9 protein.8,9
The SMAD9 protein is thought to be a key regulatory of pro-inflammatory signals and it may represent a downstream protein that is upregulated by both tumor necrosis factor-alpha and the type I interferons. In addition, this protein shows the greatest degree of upregulation in endothelium. Not surprisingly vasculitic lesions presage calcinosis cutis in patients with normophosphatemic familial calcinosis cutis, perhaps reflecting the local inflammatory milieu needed to induce an upregulation of SAMD9 in endothelium. The exact mechanism by which SAMD9 leads to extraosseous calcification, however, remains elusive. Juvenile dermatomyositis is associated with severe endothelial cell injury and the type of interferon signature is markedly upregulated in the setting of dermatomyositis.10 Hence the microenvironment within the microvasculature is conducive to an overzealous production of SAMD9 protein, therefore recapitulating the pathophysiologic events that occur in normophosphatemic calcinosis cutis. The calcification is likely vasocentric given the high level of SAMD9 expression in endothelium and the further enhanced expression in vessels showing enhanced type I interferon expression. How the significant levels of SAMD9 in the microvasculature leads to calcification is unclear, but it is the general consensus that it is a critical protein determinant for an extraosseous osteogenic phenotype.
Dr Magro is the director of dermatopathology at Weill Cornell Medicine in New York, NY. For more information, please visit www.weillcornelldermpath.com.
Dr Saab is a pathology fellow at Memorial Sloan Kettering Cancer Center in New York, NY.
Dr Dantzig is a board-certified dermatologist with a practice in New York, NY.
Disclosures: The authors report no relevant financial relationships.
References
1. Le C, Bedocs PM. Calcinosis Cutis. Treasure Island, FL: StatPearls Publishing; 2018. https://www.ncbi.nlm.nih.gov/books/NBK448127/. Updated October 27, 2018. Accessed January 28, 2019.
2. Magro CM, Dyrsen M, Kerns MJ. Cutaneous lesions of dermatomyositis with supervening fibrosis. J Cutan Pathol. 2008;35(1):31-39. doi:10.1111/j.1600-0560.2007.00770.x
3. Magro CM, Ross P, Marsh CB, et al. The role of anti-endothelial cell antibody-mediated microvascular injury in the evolution of pulmonary fibrosis in the setting of collagen vascular disease. Am J Clin Pathol. 2007;127(2):237-247. doi:10.1309/CNQDMHLH2WGKL32T
4. Crowson AN, Magro CM. The role of microvascular injury in the pathogenesis of cutaneous lesions of dermatomyositis. Hum Pathol. 1996;27(1):15-19.
5. Magro CM, Segal JP, Crowson AN, Chadwick P. The phenotypic profile of dermatomyositis and lupus erythematosus: A comparative analysis. J Cutan Pathol. 2010;37(6):659-671. doi:10.1111/j.1600-0560.2009.01443
6. Orandi AB, Dharnidharka VR, Al-Hammadi N, Baszis KW; CARRA Legacy Registry Investigators. Clinical phenotypes and biologic treatment use in juvenile dermatomyositis-associated calcinosis. Pediatr Rheumatol Online J. 2018;16(1):84. doi:10.1186/s12969-018-0299-9
7. Best M, Jachiet M, Molinari N, et al. Distinctive cutaneous and systemic features associated with specific antimyositis antibodies in adults with dermatomyositis: A prospective multicentric study of 117 patients. J Eur Acad Dermatol Venereol. 2018;32(7):1164-1172. doi:10.1111/jdv.14759
8. Hershkovitz D, Gross Y, Nahum S, et al. Functional characterization of SAMD9, a protein deficient in normophosphatemic familial tumoral calcinosis.
J Invest Dermatol. 2011;131(3):662-669. doi:10.1038/jid.2010.387
9. Chefetz I, Ben Amitai D, Browning S, et al. Normophosphatemic familial tumoral calcinosis is caused by deleterious mutations in SAMD9, encoding a TNF-alpha responsive protein. J Invest Dermatol. 2008;128(6):1423-1429. doi: 10.1038/sj.jid.5701203
10. Papadopoulou C, McCann LJ. The vasculopathy of juvenile dermatomyositis. Front Pediatr. 2018;6:284. doi:10.3389/fped.2018.00284
Answer: D
Diagnosis: Calcinosis cutis in the setting of dermatomyositis
The biopsy shows highly characteristic findings as revealed by striking expansile nodular foci of calcium within the dermis.1 The calcium is discernible on routine light microscopic assessment as amorphous to granular bluish material within the dermis (Figure 1). The clue that this dermal calcification is occurring in the setting of dermatomyositis are the background changes of chronic microvascular injury. The latter is manifested by vascular ectasia and significant vascular basement membrane zone reduplication (Figure 2). The presumed basis of the vascular injury is related to antecedent episodes of immune-based vascular injury targeting the endothelium.2-4 The effector mechanism of endothelial cell injury is C5b-9 and in this biopsy extensive deposits of C5b-9 were noted in vessels and outlining the calcific foci, possibly representing calcified vessels (Figure 3). A particularly intriguing feature in this case was the intimate association of the calcific microspheres with blood vessels demonstrating advanced chronic microvascular alterations (Figure 4). There were altered vessels showing mineral deposits. In some of micronodular foci of calcification, there were ghost-like remnants of endothelium suggesting that the calcification was likely occurring in damaged vessels that acquired an osteogenic phenotype (Figure 5).
In our experience, lesions of calcinosis cutis related to dermatomyositis typically have no evidence of active microvascular injury in contradistinction to the discernible microvascular injury seen in skin biopsies procured from an active inflammatory skin rash seen in patients with dermatomyositis best exemplified by a Gottron papule.2,3 Likely dystrophic calcification in compromised tissue subjected to protracted and sustained vascular injury is its basis. From an immunohistochemical perspective, it is our experience that an upregulated type I interferon microenvironment as revealed by the extent of endothelial and inflammatory cell staining for MxA—the classic surrogate marker for the enhanced type I interferon microenvironment—is a cardinal hallmark of calcinosis cutis in the setting of dermatomyositis. This reflects the critical role of enhanced type I interferon activity in the pathogenesis of dermatomyositis especially as it applies to the microvascular changes.5 Additionally, there was striking upregulation of MxA staining in the calcified foci which may not be surprising since these calcified foci may represent damaged blood vessels (Figure 6).
Clinical Presentation
Calcinosis cutis is a frequent complication that is encountered in patients with juvenile dermatomyositis. It has been reported to occur in 50% of cases.6 This type of dermal and deeper-seated soft tissue calcification can be associated with significant patient morbidity. One study examined 650 patients with juvenile dermatomyositis procured from 55 centers throughout North America. The patients had longer duration of disease and often these patients had associated joint contractures. There was also a greater likelihood that patients received rituximab (Rituxan) and intravenous immunoglobulin, the latter reflective of the severity of the disease and therefore refractory to more conventional therapies. It should not be construed that these therapies in any way contribute to the development of the calcification. Overall severe disease, a longer duration of being symptomatic, treatment failure to more conventional therapies, and joint contractures are the main associations.6
A similar clinical parallel was not observed in adult patients who developed dermatomyositis. In adult patients with dermatomyositis who develop calcinosis cutis there is, however, a potential association with a specific antibody profile. These patients are most likely to have antibodies to aminoacyl-transfer RNA synthetase. Other concurrent features in these patients included poikiloderma and articular involvement.7
Our patient typifies the type of patient with juvenile dermatomyositis who develops calcinosis cutis. This patient had the onset of dermatomyositis at a very early age and did not receive any effective therapy for several years, hence emphasizing that long lapses in either no therapy or suboptimal therapy defines the prototypic risk factor for the development of calcinosis cutis in the setting of dermatomyositis. In this particular patient, the lesions of calcinosis cutis were large and debilitating, extending into the deeper soft tissue.
Further Considerations
As the diagnosis of calcinosis cutis in the setting of dermatomyositis is an obvious one from a clinical perspective, it is rarely biopsied. We had the opportunity to review cases of calcinosis cutis in the setting of dermatomyositis. The patients were younger suggesting that the cases were primarily in the context of juvenile dermatomyositis. In none of the cases were there striking active changes of dermatomyositis. Dermatomyositis is the prototypic anti-endothelial cell antibody syndrome whereby acute lesions will show significant endothelial cell necrosis with endothelial cell detachment and luminal thrombosis with the effector mechanism of vascular injury being C5b-9. In addition, there is evidence of an enhanced type I interferon microenvironment as revealed by the extent of staining with the surrogate type I interferon marker MxA.2-4 In the setting of calcinosis cutis, there are always chronic microvascular changes attributable to antecedent vascular injury characterized primarily by ectatic vessels exhibiting basement membrane zone reduplication along with areas of vascular drop out and anoxia driven fibroplasia. In addition, there will be persistent C5b-9 and MxA staining in blood vessels even though active vascular injury is not seen.
The question arises as to what the pathophysiology is of this distinctive and not uncommon complication encountered in juvenile dermatomyositis more so than its occurrence in the adult setting. It is clearly one of dystrophic calcification as opposed to metastatic or iatrogenic calcification. If its basis is simply antecedent injury, then any traumatic process involving the skin would lead to calcification, which is clearly not the case. Perhaps the underlying pathophysiology might be gleaned by considering the established pathogenetic basis of calcinosis in the setting of normophosphatemic familial calcinosis cutis. In particular, it has been recognized that normophosphatemic tumoral calcinosis exhibits a significant degree of overlap with dystrophic calcification, which is the type of calcification encountered in calcinosis cutis of dermatomyositis. Its pathogenetic basis is one of a mutation in a sterile alpha motif containing domain 9 (SAMD9) located on chromosome 7 q21.2, which leads to an overzealous function of the SAMD9 protein.8,9
The SMAD9 protein is thought to be a key regulatory of pro-inflammatory signals and it may represent a downstream protein that is upregulated by both tumor necrosis factor-alpha and the type I interferons. In addition, this protein shows the greatest degree of upregulation in endothelium. Not surprisingly vasculitic lesions presage calcinosis cutis in patients with normophosphatemic familial calcinosis cutis, perhaps reflecting the local inflammatory milieu needed to induce an upregulation of SAMD9 in endothelium. The exact mechanism by which SAMD9 leads to extraosseous calcification, however, remains elusive. Juvenile dermatomyositis is associated with severe endothelial cell injury and the type of interferon signature is markedly upregulated in the setting of dermatomyositis.10 Hence the microenvironment within the microvasculature is conducive to an overzealous production of SAMD9 protein, therefore recapitulating the pathophysiologic events that occur in normophosphatemic calcinosis cutis. The calcification is likely vasocentric given the high level of SAMD9 expression in endothelium and the further enhanced expression in vessels showing enhanced type I interferon expression. How the significant levels of SAMD9 in the microvasculature leads to calcification is unclear, but it is the general consensus that it is a critical protein determinant for an extraosseous osteogenic phenotype.
Dr Magro is the director of dermatopathology at Weill Cornell Medicine in New York, NY. For more information, please visit www.weillcornelldermpath.com.
Dr Saab is a pathology fellow at Memorial Sloan Kettering Cancer Center in New York, NY.
Dr Dantzig is a board-certified dermatologist with a practice in New York, NY.
Disclosures: The authors report no relevant financial relationships.
References
1. Le C, Bedocs PM. Calcinosis Cutis. Treasure Island, FL: StatPearls Publishing; 2018. https://www.ncbi.nlm.nih.gov/books/NBK448127/. Updated October 27, 2018. Accessed January 28, 2019.
2. Magro CM, Dyrsen M, Kerns MJ. Cutaneous lesions of dermatomyositis with supervening fibrosis. J Cutan Pathol. 2008;35(1):31-39. doi:10.1111/j.1600-0560.2007.00770.x
3. Magro CM, Ross P, Marsh CB, et al. The role of anti-endothelial cell antibody-mediated microvascular injury in the evolution of pulmonary fibrosis in the setting of collagen vascular disease. Am J Clin Pathol. 2007;127(2):237-247. doi:10.1309/CNQDMHLH2WGKL32T
4. Crowson AN, Magro CM. The role of microvascular injury in the pathogenesis of cutaneous lesions of dermatomyositis. Hum Pathol. 1996;27(1):15-19.
5. Magro CM, Segal JP, Crowson AN, Chadwick P. The phenotypic profile of dermatomyositis and lupus erythematosus: A comparative analysis. J Cutan Pathol. 2010;37(6):659-671. doi:10.1111/j.1600-0560.2009.01443
6. Orandi AB, Dharnidharka VR, Al-Hammadi N, Baszis KW; CARRA Legacy Registry Investigators. Clinical phenotypes and biologic treatment use in juvenile dermatomyositis-associated calcinosis. Pediatr Rheumatol Online J. 2018;16(1):84. doi:10.1186/s12969-018-0299-9
7. Best M, Jachiet M, Molinari N, et al. Distinctive cutaneous and systemic features associated with specific antimyositis antibodies in adults with dermatomyositis: A prospective multicentric study of 117 patients. J Eur Acad Dermatol Venereol. 2018;32(7):1164-1172. doi:10.1111/jdv.14759
8. Hershkovitz D, Gross Y, Nahum S, et al. Functional characterization of SAMD9, a protein deficient in normophosphatemic familial tumoral calcinosis.
J Invest Dermatol. 2011;131(3):662-669. doi:10.1038/jid.2010.387
9. Chefetz I, Ben Amitai D, Browning S, et al. Normophosphatemic familial tumoral calcinosis is caused by deleterious mutations in SAMD9, encoding a TNF-alpha responsive protein. J Invest Dermatol. 2008;128(6):1423-1429. doi: 10.1038/sj.jid.5701203
10. Papadopoulou C, McCann LJ. The vasculopathy of juvenile dermatomyositis. Front Pediatr. 2018;6:284. doi:10.3389/fped.2018.00284
