Subcutaneous calcinosis: Is it different between systemic sclerosis and dermatomyositis?

Abstract

Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues. It is a manifestation of several autoimmune connective tissue diseases, most frequently with systemic sclerosis and juvenile dermatomyositis, followed by adult dermatomyositis. Autoimmune connective tissue disease–associated calcinosis is of the dystrophic subtype, which occurs at sites of damaged tissue in the setting of normal serum calcium and phosphate levels. In juvenile dermatomyositis, calcinosis is considered a marker of ongoing disease activity and possibly inadequate treatment, while in adult dermatomyositis, it is a hallmark of skin damage due to chronic rather than active disease. Calcinosis is associated with long disease duration in systemic sclerosis and dermatomyositis, anti-polymyositis/sclerosis autoantibodies in systemic sclerosis and NXP-2 and melanoma differentiation-associated gene 5 in dermatomyositis. Calcinosis in systemic sclerosis occurs most frequently in the hands, particularly the fingers, whereas in dermatomyositis, it affects mainly the trunk and extremities. The primary mineral component of calcinosis is hydroxyapatite in systemic sclerosis and carbonate apatite in dermatomyositis. Calcinosis in dermatomyositis and systemic sclerosis share some pathogenic mechanisms, but vascular hypoxia seems to play a more important role in systemic sclerosis, whereas the release of calcium from mitochondria in muscle cells damaged by myopathy may be a primary mechanism contributing to dermatomyositis-related calcinosis. Multiple treatment strategies for dermatomyositis and systemic sclerosis-related calcinosis have been used with variable results. Early aggressive treatment of underlying myositis in patients with dermatomyositis may improve long-term outcomes of calcinosis. A better understanding of the pathogenesis of calcinosis is needed to improve treatment options.

Introduction

Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues. It is a manifestation of several autoimmune connective tissue diseases (ACTDs). Systemic sclerosis (SSc), juvenile dermatomyositis (JDM), and adult dermatomyositis (DM) are the most common ACTD associated with calcinosis. ¹ ACTD-associated calcinosis is of the dystrophic subtype, which by definition occurs at sites of damaged tissue in the setting of normal serum calcium and phosphate levels. ² Calcinosis is often associated with pain, functional impairment, and significant impact on quality of life. In this review, we summarize the most current knowledge regarding characteristics, pathogenesis, and treatment options for calcinosis with a focus on similarities and differences between SSc and JDM/DM-related calcinosis.

Epidemiology

Calcinosis cutis is more frequent in SSc and juvenile DM than adult DM. Around 1 in 4 patients with SSc develop calcinosis over the course of their disease; ³ however, the prevalence varies depending on the studied patient population, ranging from 18% in African American ⁴ to 37% in Mexican ⁵ and 49% in Malaysian cohorts. ⁶ Calcinosis occurs to a similar degree in all SSc cutaneous subtypes, with no preponderance in limited cutaneous SSc, as previously thought. In fact, in Mexican, Canadian, and Malaysian cohorts, calcinosis was associated with diffuse cutaneous SSc^5–7 while other studies have not found associations between calcinosis and cutaneous subset,^4,8 suggesting that these may be influenced by ethnic background or geographic region. Differences between ethnic groups may explain variable prevalence of calcinosis in JDM/DM as well. Calcinosis presents in up to 40% of patients with JDM;^9,10 however, a frequency of 71% was described in a retrospective study of 21 JDM children in a tertiary hospital in South Africa. ¹¹ Similarly, calcinosis in DM has been described in up to 20% of patients, ¹² but in a cohort of 627 adult DM patients from China, only 35 (5.6%) were found to have calcinosis. ¹³

Long disease duration has consistently been identified as a risk factor for calcinosis in patients with SSc.^3,8 This has also been demonstrated in DM ¹⁴ and JDM^9,15 where calcinosis is associated with a more severe and prolonged disease course.

Several clinical features have been linked to the development of calcinosis (Table 1). In SSc, multiple studies have found that calcinosis is associated with microvascular disease manifestations, such as digital ulcers (DUs),^{3,4,7,8,16–18} late nailfold capillary pattern,^19,20 and acro-osteolysis,^8,21 as well as with macrovascular disease, specifically ulnar artery occlusion, even in the absence of DU.^19,22 Interestingly, in DM, fingertip ulcers ¹⁴ and skin ulcers ¹³ have also been related to the development of calcinosis. In SSc, calcinosis has also been associated with dysregulated bone metabolism, including vitamin D deficiency and secondary hyperparathyroidism, ²³ osteoporosis,^3,24 and increased vertebral fracture. ²⁵ In DM patients, younger age at diagnosis and dysphagia have been shown to be independently associated with calcinosis, ¹³ while in JDM, calcinosis is associated with delayed diagnosis and initiation of therapy, chronic/severe disease, and cardiac involvement.^9,15

Table 1.

Clinical features associated with calcinosis in systemic sclerosis, dermatomyositis, and juvenile dermatomyositis.

	Systemic sclerosis	Adult dermatomyositis	Juvenile dermatomyositis
Demographics	Longer disease duration a	Longer disease duration b Younger age at diagnosis	Longer disease duration b Delayed diagnosis and initiation of therapy
Clinical features	Digital ulceration Acro-osteolysis Late nailfold capillary pattern Ulnar artery occlusion Vitamin D deficiency Secondary hyperparathyroidism Osteoporosis Vertebral fracture	Fingertip ulcers Skin ulcers Dysphagia	Cardiac involvement More severe and prolonged disease course
Autoantibodies	Anti-PM/Scl	Anti-PM/Scl NXP2/MJ MDA-5	NXP2/MJ

MDA-5: melanoma differentiation-associated gene 5.

^aFrom first non-Raynaud symptom to enrollment.

^bFrom DM diagnosis to last clinic visit.

Autoantibodies often serve as markers of distinct clinical phenotypes in DM and SSc and as such several have been associated with calcinosis. Anti-PM/Scl (anti-PM-100 and anti-PM-75) autoantibodies are frequently reported in patients with overlap syndromes of myositis and SSc. A consistent association has been found between calcinosis and anti-PM/Scl autoantibody in SSc^3,26–29 and DM patients. ³⁰ The association between calcinosis and scleroderma-specific autoantibodies has not been consistent. Traditionally, calcinosis in SSc has been linked to positive anti-centromere antibody (ACA);^8,31–33 however, anti-nucleolar and anti-topoisomerase (Scl-70) antibodies were more prevalent in Mexican patients with calcinosis, ⁵ and ACA but also RNA-polymerase-III antibody were predictors of calcinosis in a cohort of 1305 SSc patients from the Canadian Scleroderma Research Group (CSRG) registry. ⁷ Other studies have not found associations between SSc-related calcinosis and a specific autoantibody profile.^4,8 In contrast, the myositis-specific autoantibody (MSA) anti-NXP2/MJ has been strongly associated with calcinosis in several studies in both DM^13,14,34 and JDM patients;^35,36 however, this association has not been universal, with some studies finding no relationship. ¹² In adult DM patients, anti-TIF1-γ (p155/140) autoantibodies are thought to be protective against calcinosis. ¹⁴ A single-center study of 134 adult patients with DM found that despite having more severe skin disease, anti-TIF1-γ-positive patients had a lower prevalence of calcinosis compared to anti-TIF1-γ-negative patients (2% vs 18%, respectively). ³⁷ In contrast, in the largest study looking at this in JDM patients, calcinosis was common (30%) in anti-TIF-1γ-positive patients and this autoantibody was not found to be protective. ³⁵ Anti-melanoma differentiation-associated gene 5 (MDA-5) autoantibodies were associated with calcinosis in 126 adult DM patients from a tertiary academic medical center, although the finding was not significant after adjusting for DU on multivariable analysis. ¹⁴ In 285 JDM patients from the United Kingdom, no association between anti-MDA-5 autoantibodies and calcinosis was found. ³⁶

Clinical presentation

SSc-related calcinosis usually presents as chalky-white to yellow papules, plaques, or nodules of the dermis, panniculus, or deeper subcutaneous structures (Figure 1). More rarely, calcinosis may present as large, calcified masses (pseudotumoral calcinosis) (Figure 2). In DM, calcinosis can present as localized superficial nodules or papules (superficial calcareal or superficial nodular) (Figure 3); deeper tumoral deposits (tumoral calcinosis or deep calcareal) (Figure 4); or intramuscular and fascial calcification (universalis) (Figure 5), rarely leading to a generalized form with a widespread distribution (exoskeleton) (Figure 6). ¹²

Figure 1.

Calcinosis of the fingers in a 59-year-old female with SSc.

Figure 2.

Frontal chest radiograph in a 57-year-old female with SSc demonstrates extensive pseudotumoral calcinosis around the left shoulder and upper chest wall bilaterally. Reticular opacities at the left lung base are compatible with interstitial lung disease.

Figure 3.

Calcinosis circumscripta or nodules or plaque, as demonstrated by elbow lesions in a patient with DM.

Source: Reprinted with permission from Valenzuela et al. ¹⁴

Figure 4.

Tumoral calcinosis, or larger nodular deposits extending to muscle, depicted on CT chest as an enlarged calcified mass within the chest wall musculature in a patient with DM.

Source: Reprinted with permission from Chung and Chung. ³⁸

Figure 5.

Collections along myofascial planes of tendons or muscles, such as the lower leg in a patient with DM.

Source: Reprinted with permission from Chung and Chung. ³⁸

Figure 6.

An exoskeleton with calcium deposition over surface area, shown on radiographs as extensive calcifications of lobular morphology projecting over the majority of the pelvis in a patient with DM.

Source: Reprinted with permission from Chung and Chung. ³⁸

Calcinosis in SSc occurs most frequently in the hands,^5,8,39 particularly the fingers, and within the fingers, most commonly in the thumbs or index of the dominant hand.^40,41 Other less common locations include the arms/forearms, knee/proximal lower extremities, feet, and hips.^8,42 These latter sites are thought to be areas affected by trauma or pressure. Likewise, in patients with DM, the distribution of calcinosis favors sites of repeated trauma and/or pressure sites ⁴³ such as the extremities and trunk; ⁴⁴ in addition, areas previously involved by the disease, such as muscle or at sites of ulceration can be affected by calcinosis in DM patients. ³⁸ Similarly, in JDM the sites most frequently affected are the elbows, knees, trunk, hands, feet, buttocks, and head, although it may occur virtually anywhere on the body.^9,45 Of note, secondary calcification is a frequent finding in both JDM and adult DM panniculitis, a rare clinical manifestation, especially in late-stage lesions. ⁴⁶ In a review of 24 DM patients, including 5 children, with clinical and histologic confirmation of panniculitis, calcification was found in 6 patients (25%) at the site of biopsy. ⁴⁷ Panniculitis has been considered by some authors to be a preceding manifestation of the calcific process in DM.^48,49

Calcinosis is a late complication of the disease in patients with SSc, presenting usually more than 10 years after the first non-Raynaud’s symptom.^3,8 In DM, calcinosis typically occurs around 8 years after the diagnosis, much later than in JDM, which presents around 3 years after the onset of the disease.^34,44 In JDM, calcinosis is considered a marker of ongoing disease activity and possibly inadequate treatment, while in adult DM, it is a hallmark of skin damage due to chronic rather than active disease.

Pain/tenderness, impaired physical function, and decreased quality of life are frequent complications from both SSc and JDM/DM-related calcinosis.^8,10,43,50 In addition, ulceration at the site of lesions, spontaneous extrusion of calcinosis through the skin, and infection can occur.^8,43 Infection usually occurs in the overlying skin and soft tissue around calcified lesions and manifests as spreading redness and/or thick green/yellow discharge from the lesions. When cultured, the most frequent organism identified has been Staphylococcus aureus.^50–52 In DM, the deep, myofascial form may significantly limit joint motion. ⁴³

Pathogenesis

The composition of DM and SSc-related calcinosis seems to be different. Calcinosis in SSc resembles the composition of bone, with hydroxyapatite (HA) as the primary mineral component. ⁵³ The analysis of spontaneously draining calcinosis material from 10 SSc patients using X-ray diffraction, a tool for identifying precipitated crystallized phases, confirmed that HA—in variable proportions—was the only inorganic material. ⁵⁴ In contrast, a study of calcified deposits surgically removed from 8 patients with inflammatory myopathy using scanning electron microscopy/silicon drift detector energy-dispersive X-ray spectrometry and other advanced techniques revealed that the mineral present consisted of carbonate apatite and was closest to enamel, while clearly differing from bone. ⁵⁵

The detailed pathophysiology of calcinosis in dystrophic calcinosis remains poorly understood; however, several interacting mechanisms have been proposed, including vascular hypoxia, chronic inflammation, recurrent trauma or damage, and dysregulation in bone matrix proteins.

Several clinical studies suggest that vascular ischemia may contribute to SSc-related calcinosis development.^{4,7,8,16,21,56} In addition, Davies et al. demonstrated increased expression of the hypoxia-associated glucose transporter molecule (GLUT-1) ⁵⁷ and markers of oxidative stress, the advanced glycation/lipoperoxidation end products (AGEs) and their receptor (RAGE), in the dermis of SSc patients with calcinosis. ⁵⁸ Similarly, in DM patients, digital ischemic ulcers have also been associated with calcinosis. ¹⁴ Furthermore, calcifications removed from 4 JDM patients demonstrated the presence of mineral matrix proteins in vascular endothelial cells near mineralized deposits, suggesting an interplay between immune regulation, angiogenesis, and calcification. ⁵⁹

Patients with JDM exhibit elevated serum levels of interleukin (IL)-1, and the presence of IL-6, IL-1β, and tumor necrosis factor (TNF)-alpha in the “milk of calcium” (calcium-laden fluid collections), supporting the role of inflammation in the development of calcinosis. ⁶⁰ More recently, it has been suggested that inflammation, particularly the procalcific inflammatory mediator IL-6, in association with senescence promoted by persistent DNA damage by oxidative stress, may also be involved in driving dystrophic calcification in SSc. ⁶¹

The association between calcinosis and long disease duration in SSc and DM suggests that cumulative disease damage may play a role in the development of calcinosis. The fact that the index finger and thumb are the two digits most affected by SSc-related calcinosis raises the potential role for repetitive trauma in the pathogenesis of SSc-related calcinosis.^40,41 Similarly, it has been suggested that the release of calcium from mitochondria in muscle cells damaged by myopathy could be a possible mechanism in DM-related calcinosis. ⁶² Duvvuri et al. ⁶³ demonstrated the presence of calcified mitochondria and their remnants in degenerated muscle fibers and blood of JDM patients with calcinosis. A subsequent study from the same group showed that both hypoxia and inflammation promoted mitochondrial calcification in muscle cells, which in turn caused further inflammation as measured by increased secretion of IL-6 in cellular supernatants and interferon-induced gene expression. ⁶⁴

There is some evidence supporting the role of a systemic imbalance of mineralization inhibitors and promotors in patients with calcinosis. A study of 33 subjects (19 control and 14 SSc, 5 of whom had SSc-calcinosis) demonstrated the lowest mean levels of inorganic pyrophosphate (PPi), a key regulator of ectopic mineralization acting by inhibiting HA crystal growth, in the SSc-calcinosis group. ⁶⁵ Fetuin-A, another known inhibitor of systemic calcification, was found to be significantly lower in serum of patients with calcinosis as compared to those without calcinosis in a study of 23 SSc patients (15 with calcinosis). ⁶⁶ In a study of 212 JDM patients, fetuin-A levels did not differ significantly between JDM patients with calcinosis compared to those without calcinosis. ⁶⁷ However, fetuin-A levels in all children were much lower compared to prior studies in adults, which could explain why calcinosis is more frequent in JDM than DM. Finally, circulating osteoprotegerin (OPG), a promoter of mineralization, was found to be significantly higher in patients with active DU and calcinosis in a study of 60 SSc patients, 8 of whom had calcinosis. ⁶⁸ Another promoter of calcification, osteonectin, has been found to be increased in endothelial cells and fibroblasts of SSc patients, particularly in those with calcinosis compared with those without calcinosis. ⁶⁹ Osteonectin was also present within both central and peripheral mineral deposits of calcifications from JDM patients, as well as vascular endothelial cells. ⁵⁹ Finally, poly(ADP-ribose) polymerase (PARP) enzymes, another proposed promoter of HA nucleation of mineralized deposits, are overexpressed in response to DNA damage. Although not evaluated in ACTD-related calcinosis, studies have demonstrated that overexpression of PARP-1 in rat aortas increased vascular calcification and osteogenic differentiation of vascular smooth muscle cells. ⁷⁰

Although DM and SSc-related calcinosis likely share some pathogenic mechanisms (Table 2), further research is required to advance our understanding of the pathogenesis of this complication in these two diseases.

Table 2.

Differences in calcinosis in systemic sclerosis, adult dermatomyositis, and juvenile dermatomyositis.

	Systemic sclerosis	Adult dermatomyositis	Juvenile dermatomyositis
Prevalence	25%	20%	40%
Distribution	Hands (>fingers)	Extremities and trunk	Elbows, knees, trunk, hands, feet, buttocks, and head
Composition	Hydroxyapatite	Carbonate apatite	Carbonate apatite
Pathogenic Mechanisms Vascular hypoxia	Association with microvascular disease manifestations Increased dermis GLUT-1 and markers of oxidative stress	Association with digital ulcers	Presence of mineral matrix proteins in vascular endothelial cells near mineralized deposits
Inflammation	Elevated circulating levels of IL-6 in serum and skin		Evidence of inflammatory cytokines in the “milk of calcium”
Cumulative damage/repetitive trauma	Association with long disease duration and thumbs/index fingers location	Association with long disease duration Release of calcium from damaged muscle cell mitochondria	Presence of calcified mitochondria and their remnants in degenerated muscle fibers and blood
Bone metabolism protein dysregulation	Low serum levels of inhibitors of systemic calcification (PPi, fetuin-A, ?PARP enzymes) High levels of promoter of calcification (OPG, osteonectin)		Presence of osteonectin was also present within mineral deposits and vascular endothelial cells

GLUT-1: glucose transporter molecule; IL-6: interleukin-6; PPi: inorganic pyrophosphate; PARP: poly(ADP-ribose) polymerase; OPG: osteoprotegerin.

Diagnosis

Although calcinosis is often clearly visible or palpable on physical exam, imaging can help confirm the diagnosis of subclinical deposits. Plain radiography is the recommended initial imaging for calcinosis, ⁷¹ given its low cost and comparable information to three-dimensional modalities. ⁷² The Scleroderma Clinical Trials Consortium (SCTC) developed and validated a radiographic scoring system for hand SSc-related calcinosis, which takes into account the area covered, density, number, and anatomic location of calcinosis lesions and provides an estimate of calcinosis burden. ⁷³ Calcinosis can also be identified by ultrasound, various forms of computerized tomography (CT) imaging including dual-energy computed tomography (DECT)—a modern technique used for assessing monosodium urate deposits in soft tissue from patients with gout—magnetic resonance imaging (MRI)^74,75 and ¹⁸F-NaF positron emission tomography PET/CT. ⁷⁶ However, further studies are needed to determine whether ultrasound (US), CT, MRI, or PET might be more useful in the assessment and measurement of calcinosis burden than plain radiography.

Treatment

Treatment of calcinosis remains an unmet need in patients with SSc and DM (Figure 7). If there is suspicion for infection of calcinotic lesions, antibiotics covering Staphylococci, such as cephalexin, dicloxacillin, or clindamycin, should be prescribed. In JDM patients, there is anecdotal experience with prophylactic oral flucloxacillin for 1 year to prevent this complication.

Figure 7.

Algorithm for the diagnosis and treatment of calcinosis in dermatomyositis and systemic sclerosis.

Evidence on medical therapies mainly comes from small retrospective studies, case series, and case reports, since no large, prospective randomized controlled trials have been conducted. This is in part due to the lack of validated outcome measures to study these agents, but the development of such outcome measures is currently an area of active research. Importantly, it has been demonstrated that early aggressive treatment of underlying myositis in patients with DM may improve long-term outcomes of calcinosis, whereas delayed or inadequate treatment has been associated with poorer prognosis.^45,77 Multiple treatment strategies specifically for calcinosis have been used with variable results (Table 3). A recent systematic review of 30 studies (288 patients) identified 11 therapeutic classes, surgery, and physical therapies as potential treatment options for calcinosis in DM and SSc patients. ¹ This review highlighted the potential benefit of diltiazem and bisphosphonates in both groups of patients and identified biologic agents such as rituximab and anti-tumor necrosis factor (TNF) drugs, as well as intralesional sodium thiosulfate as promising therapies.

Table 3.

Pharmacological treatments of calcinosis in systemic sclerosis and juvenile and adult dermatomyositis.

Treatment	Proposed mechanism of action	Drug dosage	Disease	Number of responses/numbers of patients treated	References
Diltiazem	Reduce intracellular calcium influx	240–480 mg/day for 1–12 years	SSc	4/4	Palmieri et al. 78
		120 mg/day for 2 years	SSc	1/1	Dolan et al. 79
		240 mg/day for 5 years	SSc	1/1	Farah et al. 80
		180 mg/day for 1–15 years	SSc	3/12	Vayssairat et al. 31
		30 mg/day for 1 year	JDM	1/1	Ichiki et al. 81
		5 mg/kg/day for 21 months	JDM	1/1	Oliveri et al. 82
		6 mg/kg/day for 1 year	JDM	2/6	Bertorini et al. 83
		360 mg daily for 2.5 years	DM	1/1	Vinen et al. 62
		<480 mg/day for unknown duration	SSc, JDM, DM	9/17	Balin et al. 43
Bisphosphonates	Inhibits macrophage proinflammatory cytokine production and reduces bone resorption	Risedronate for 6 months	SSc	1/1	Fujii et al. 85
		Pamidronate 1 mg/kg/day every 3 months for 9 months or IV alendronate 70 mg/week for 2 years	DM	2/8	Jiang et al. 13
		Alendronate for 22 months	JDM	4/6	Saini et al. 15
		Pamidronate 1 mg/kg/day IV every 3 months Risedronate 1.25 mg/day Alendronate 70 mg/week for 84 months	JDM	4/6	Tayfur et al. 87
		Pamidronate 1 mg/kg/day IV every 3 months for 42 months	JDM	3/3	Marco Puche et al. 88
Sodium thiosulfate Topical	May dissolve calcium deposits and promote local vasodilation and wound healing	25% sodium metabisulfite BID	SSc DM	1/1 2/2	Barrio-Diaz et al. 82
		25% STS compounded in zinc oxide ointment for mean duration of 3.9 months	SSc JDM	11/15 0/1	Ma et al. 90
		10% STS for at least 4 weeks	SSc	6/6	von Hodenberg 91
		STS for 3–7 months	SSc	0/4	Pelrine et al. 92
		10% STS daily for 9 months	JDM	1/1	Pagnini et al. 93
		10% STS daily for 8 weeks	JDM	1/1	Topham et al. 94
Intralesional Intravenous		STS 1–3 g/week × 1 year	SSc	2/2	Goosens et al. 95
	STS 12.5 mg–150 mg × 1–4 times		SSc	5/5	Baumgartner-Nielsen, et al. 96
	25 g two times weekly for 6 months		DM MCTD with SSc features	0/2 0/1	Song et al. 97
	20 g/day, 5 days/month, at least 6 cycles		DM JDM SSc	0/1 0/1 0/1	Mageau et al. 98
Infliximab	Monoclonal antibody anti-TNF-α	3 mg/kg IV at 0, 2 and 6 weeks, and every 8 weeks × 7 months	SSc	1/1	Tosonidou et al. 100
		3 mg/kg at 0, 2, and 6 weeks followed by every 8 weeks) for 8 to 30 months.	JDM	4/5	Riley et al. 101
		Not reported	DM	0/1	Siddiqui et al. 102
Rituximab	Humanized chimeric anti-CD20 monoclonal antibody	1 or more cycles (1 g × 2 weeks)	SSc	4/8	Narvaez et al. 103
		500 mg on day 0 and day 14, and then twice every 3 months	SSc	3/3	Moazedi-Fuerst et al. 104
		375 mg/m2 IV weekly × 4	SSc	1/1	De Paula et al. 105
		4 weekly infusions (375 mg/m2) with repeated dose in 6 months	SSc	1/1	Daoussis et al. 106
		2 infusions at 2-week intervals, 1 g each and 1 g 6 months later	SSc	0/1	Poormoghim et al. 107
		1 g IV × 2 at 2-week interval and then every 6 months	SSc	0/1	Hurabielle et al. 108
		375 mg/m2 weekly for 4 doses	JDM	4/4	Alhemairi et al. 109
		500 mg/m2 for 2 doses or 375 mg/m2 for 4 doses	JDM	0/6	Bader-Meunier et al. 110
		1 g for 2 doses or 375 mg/m2 week 1–4	SSc/PM overlap	0/2	Dubos et al. 111
Abatacept	Anti-inflammatory effects by down-regulating T cell activation	10 mg/kg/dose at 0, 2, and 4 weeks and then every 4 weeks × 3 months IV	JDM	1/1	Sukumaran et al. 113
Tofacitinib	JAK-1 inhibitor that targets multiple proinflammatory cytokines	5 mg twice daily for 28 weeks	DM	2/2	Wendel et al. 114
		11 mg daily for 3 months	DM	3/3	Shneyderman et al. 115
		5 -10 mg twice daily	JDM	1/2	Sabbagh et al. 116
Intravenous immunoglobulin	Anti-inflammatory properties, possibly related to suppression of activated macrophages	1–3 grams/day in a 1- to 3-day protocol once a month	JDM DM	2/2 3/6	Galimberti et al. 120
		2 grams/day in a 4-day protocol once a month × 5 cycles	SSc	1/1	Schanz et al. 121
Minocycline	Anti-inflammatory and calcium-binding properties. Suppress PARP-1 and inhibit mineralization of human vascular smooth muscle cells in vitro	50–100 mg/day for 3.5 years	SSc	8/9	Robertson et al. 123
		50–200 mg/day for 6–12 weeks	SSc	34/78	Fonseca et al. 124
		50–100 mg/d for unknown duration	SSc, JDM, DM	1/3	Balin et al. 43

SSc: systemic sclerosis; JDM: juvenile dermatomyositis; DM: dermatomyositis; IV: intravenous; BID: twice a day; STS: sodium thiosulfate; TNF-α: tumor necrosis factor alpha; PARP-1: poly(ADP-ribose) polymerase-1.

Calcium channel blockers

Calcium channel blockers (CCBs) reduce intracellular calcium influx, altering the formation and crystallization of the calcium nidus in affected tissues. Diltiazem is the most well-studied CCB for treating calcinosis. Early case reports showed encouraging results with 240–480 mg/day of diltiazem for calcinosis in SSc patients.^78,79,111 However, a larger retrospective study of 12 SSc patients did not show a benefit from diltiazem 180 mg/day for 1–15 years on radiographs. ³¹

Similarly, in patients with JDM, treatment with diltiazem completely suppressed the development of calcinosis in a 3-year-old patient. ⁸⁰ Another case report of an 8-year-old patient treated with diltiazem 5 mg/kg/day in association with oral pamidronate 4 mg/kg/day for corticosteroid-induced osteoporosis showed clinical and radiological regression of the calcinosis after 21 months. ⁸¹ Finally, in a study of 6 JDM patients who received diltiazem up to 6 mg/kg/day for 1 year on top of standard JDM immunosuppressive therapy, calcinosis resolved in one patient and improved in another as assessed by a semi-quantitative method. ⁸² A patient with adult DM also experienced a fall in mineral content of the regions affected by calcinosis on serial dual-energy X-ray absorptiometry (DXA) scans and functional improvement by health assessment questionnaires (HAQ) with diltiazem up to 360 mg daily for 2.5 years. ⁶²

A study of 78 patients with ACTD (including 14 with JDM, 16 adult DM and 24 SSc) showed that diltiazem was the most used medical therapy for calcinosis, and 9 of 17 patients had a partial response, defined as regression or recurrence of a lesion that had previously regressed or completely healed (complete response was defined as total resolution of an individual lesion and lack of recurrence in that area). ⁴⁴

Bisphosphonates

Bisphosphonates may be useful in reversing the calcification process by inhibiting macrophage proinflammatory cytokine production and reducing bone resorption. ⁸³ Few data are available for SSc patients. A case report describes resolution of calcinosis in a patient with SSc after 6 months of risedronate therapy for glucocorticoid-induced osteoporosis. ⁸⁴ A retrospective observational study of 627 adult DM patients, 35 of whom had calcinosis, showed partial response, defined as resolution of lesions with recurrence in that area, in 2 out of 8 patients treated with bisphosphonates (pamidronate and alendronate). ¹³ Bisphosphonates are the most likely treatment to be used by experienced physicians for calcinosis in JDM. ⁸⁵ There are reports of calcinosis improving or even disappearing after heterogeneous regimens of bisphosphonates in JDM patients, with partial response ranging from 50% to 100% and complete response from 0% to 33%.^15,86,87 Therefore, bisphosphonates might be a useful treatment option for calcinosis in patients with JDM; however, the lack of substantive data precludes recommending a specific regimen.^1,38

Sodium thiosulfate

Topical, intralesional and intravenous (IV) sodium thiosulfate (STS) have been studied as treatments for calcinosis as it may dissolve calcium deposits and promote local vasodilation and wound healing. Topical STS may be a safe and non-invasive treatment for patients with calcinosis. Four patients with calcinosis (including one with SSc and two with DM) showed significant decrease in size, erythema and pain with topical 25% sodium metabisulfite, a metabolite of STS. ⁸⁸ Similarly, a case series of 26 patients with ACTD (including 15 with SSc and 1 with JDM) treated with topical 25% STS compounded in zinc oxide ointment, reported that 19 (68%) experienced clinical improvement, defined as total resolution or regression of the lesion without recurrence, at a mean follow-up of 3.9 months. ⁸⁹ A recent case series reported that all 6 SSc patients with small calcinosis lesions (<2 mm) at the fingertips who were treated with 10% STS formulation for at least 4 weeks, experienced a substantial reduction in the number and/or diameter of lesions. ⁹⁰ However, in a small retrospective study that included four patients with SSc-related calcinosis, no significant change in calcinosis SCTC radiologic scores was seen at 6 months with topical STS, and one patient did not tolerate treatment due to erythema and inflammation of ulcerating calcinosis. ¹¹² Topical 10% STS also has shown significant improvement and lack of progression in calcinosis and ulcerations in JDM patients.^91,92

More invasive forms of STS have also been used with varying success. Goossens et al. ⁹³ reported two cases of weekly intralesional injections of 1–3 g STS leading to pain relief, functional improvement, and 59% size reduction after 12 months. A larger series describes the treatment of 8 lesions in 6 patients (5 with SSc and 1 with nephrogenic systemic fibrosis) with injections of 12.5–150 mg STS 150 mg/mL for up to 4 weeks. By weeks 4 and 12, the lesions decreased in size by 67% and 90%, respectively, and all patients reported improved pain and disability. ⁹⁴ A report of three patients with recalcitrant ACTD-associated calcinosis treated with IV STS did not show any notable clinical improvement. ⁹⁵ However, another series of four patients (SSc, DM, JDM, and SLE) demonstrated improvement in calcinosis after six cycles of IV STS except in the patient with SSc. ⁹⁶ Finally, a retrospective analysis of 80 calcinosis lesions treated with either topical, intralesional, or IV STS showed that topical STS completely resolved all lesions <0.2 cm, 78% of 0.2–0.3 cm, but only 20% of 0.3–0.5 cm calcinosis lesions. Intralesional STS injections were successful for all calcifications <2 cm, but failed to resolve lesions >2 cm. IV STS failed to resolve the tumoral calcinosis lesions. ⁹⁷ In summary, intralesional and topical STS may have some therapeutic utility for the treatment of small calcinotic lesions. Further studies are necessary to determine the efficacy of the various formulations of STS in the treatment of ACTD-associated calcinosis.

Infliximab

Given the potential role of inflammation and TNF-alpha in calcinosis, there may be a role for anti-TNF agents in the treatment of calcinotic lesions. A patient with SSc-myositis overlap and refractory calcinosis treated with infliximab 3 mg/kg infused at 0, 2, and 6 weeks, and every 8 weeks thereafter, experienced reduction in size of calcifications and no new deposits at 41 months on serial CT imaging. ⁹⁸ In a case series of 5 JDM patients refractory to standard therapy, 4 reported having softer, painless, and less-extensive calcinosis and 1 patient reported mild worsening after receiving infliximab (3 mg/kg at 0, 2, and 6 weeks followed by every 8 weeks) for 8–30 months. ⁹⁹ In contrast, diffuse calcinosis progressed in a woman with DM despite infliximab. ¹⁰⁰

Rituximab

The chimeric anti-CD20 antibody rituximab (RTX) has been increasingly used in SSc and DM, particularly for patients with interstitial lung disease. A recent single-center observational study showed that 4 out of 8 patients (50%) with refractory SSc-related calcinosis treated with 1 or more cycles of RTX (1 g × 2 weeks) had no new episodes of local inflammation or skin ulceration; additionally, 2 patients (25%) had significant reduction in the size of the calcifications on X-ray, according to the SCTC radiographic scoring system after at least 12 months of RTX treatment. ¹⁰¹ A case series of 5 SSc patients treated with RTX 500 mg on day 0 and day 14, with repeated courses every 3 months showed that three patients had calcinosis cutis affecting the hands and the integument, which resolved in the first 6 months of RTX treatment, with no relapse after 1–2 years of follow-up. ¹⁰² Two additional case reports have shown benefits from RTX for calcinosis in patients with SSc;^103,113 however, there are also reports of no response ¹⁰⁴ and even worsening of the number and size of calcifications after RTX infusions. ¹⁰⁵

In a study of 4 JDM patients with severe calcinosis refractory to bisphosphonates, colchicines, and warfarin, RTX (375 mg/m² weekly × 4 doses) led to complete clearance of calcinosis in 1 patient and to partial response with no new lesions and decreased density of lesions in the other 3 when added to other conventional treatments. ¹⁰⁶ However, RTX did not improve calcinosis in a small series of 6 JDM patients ¹¹⁴ and in two patients with SSc/PM overlap. ¹¹⁵ Similarly, a post hoc analysis of 72 DM patients and 48 JDM patients with refractory disease from the rituximab in myositis (RIM) study, a randomized placebo-phase-controlled trial of RTX added to standard therapy, did not show differences in calcinosis at 44 weeks using the Myositis Damage Index (MDI), a validated myositis damage assessment tool, suggesting no treatment effects of RTX on calcinosis. ¹¹⁶

As summarized above, RTX in DM and SSc-associated calcinosis has shown inconsistent efficacy, and further research is necessary to delineate its role.

Abatacept

Abatacept, a fully human soluble fusion protein between the extracellular domain of cytotoxic T-lymphocyte antigen-4 and the Fc portion immunoglobulin [79], exerts anti-inflammatory effects by down-regulating T-cell activation. A recent case report of a 16-year-old JDM patient with calcinosis and skin ulcerations showed complete resolution without radiologic progression or new lesions after 3 months of abatacept. ¹⁰⁷

Tofacitinib

Tofacitinib, a JAK-1 inhibitor that targets multiple proinflammatory cytokines, has been used for the treatment of cutaneous DM. A report of two DM patients with calcinosis showed that tofacitinib 5-mg twice daily halted the progression of calcifications in all locations (with some completely disappearing after 28 weeks of treatment) and resolved accompanying inflammatory changes rapidly within a few weeks. ¹⁰⁸ Another recent case series of three patients with DM found that tofacitinib resulted in clinical improvement in calcinosis. The authors hypothesized that dysregulated mitochondrial calcium storage and release mediated by the STAT 3 pathway may be inhibited by tofacitinib and therefore improve calcinosis. ¹¹⁷ A report of two patients with JDM treated with tofacitinib showed that the extent of calcinosis decreased from 14.4% to 7% involved body surface area 12 months post-treatment in one patient. ¹⁰⁹

IV immunoglobulins

The use of intravenous immunoglobulins (IVIG) in the treatment of calcinosis is mostly restricted to DM patients, based on multiple case reports,^110,118 and retrospective studies.^34,119 However, it does not appear to be universally successful. In a retrospective cohort study of eight adult DM and JDM patients treated with IVIG for refractory cutaneous or muscle disease, five experienced clinical improvement, whereas three patients demonstrated stable or worsened calcinosis. ¹²⁰ There is one report of a patient with lcSSc and disabling calcinosis of the left index finger who was free of symptoms after 5 months of IVIG. ¹²¹ The potential mechanism in reducing calcinosis is unclear but may include the suppression of activated macrophages.^38,121

Minocycline

This tetracycline antibiotic may influence the calcinosis process by altering osteoclast function, chelating calcium, and inhibiting matrix metalloproteinase function. Interestingly, minocycline also has been shown to suppress PARP-1 and inhibit mineralization of human vascular smooth muscle cells in vitro. ¹²²

In a case series of 9 SSc patients with calcinosis, low doses of minocycline (50 or 100 mg/day) for a mean of 3.5 years resulted in reduced ulceration and inflammation, with a modest decrease in the size of deposits in eight patients. Patients had recurrence of calcinosis when the treatment was stopped, so authors recommended cyclic long-term use of minocycline (treatment for 4–8 weeks followed by discontinuation for 3–4 months). ¹²³ The largest series of 78 SSc patients with calcinosis treated with minocycline 50–200 mg/day for 6–12 weeks in repeated courses showed that 34 patients (43.6%) reported clinical improvement in calcinosis-related symptoms with acceptable tolerability. ¹²⁴ Another retrospective study of 78 ACTD patients with calcinosis cutis found that 1/3 had a partial response to minocycline. ⁴⁴

Others

Probenecid and aluminum hydroxide decrease serum phosphate levels and thus reduce the calcification process. These agents have shown improvement in calcinosis deposits of DM and JDM patients,^43,125 but experience with both for treatment of SSc-related calcinosis has been anecdotal. ¹²⁶ Similarly, scattered case reports have documented the efficacy of low-dose warfarin^44,127–129 and colchicine^44,130–132 for the treatment of ACTD-related calcinosis.

Extracorporeal shock wave lithotripsy

Extracorporeal shock wave lithotripsy (ESWL), which uses acoustic shock waves to break apart mineral deposits, reduced the size and pain from calcinosis at 6 months in 9 patients with DM, SSc or chronic venous insufficiency-associated calcinosis. ¹³³ A 12-week study of 3 weekly sessions of ESWL on calcinosis lesions in four SSc patients found a reduction in lesion size in three patients and pain improvement in two patients. ¹³⁴ In a case report of an SSc female with extensive leg ulcerations and calcifications, ESWL was well tolerated and reduced the size of ulcers and pain. ¹³⁵ Another DM patient treated with ESWL had decreased pain and discharge, but without much change in the size of lesions. ¹³⁶

Surgery

Despite all the options discussed above, surgical excision of calcium deposits remains the mainstay of treatment. Patients with large, localized, and symptomatic lesions that are unresponsive to medical therapy, especially located over tendons, blood vessels, and nerves should be referred for surgery.^137,138 Early studies reported frequent complications such as recurrence, neurovascular damage, and impaired wound healing; ¹³⁹ however, several more recent case reports/small case series described increasing success with surgical intervention. ³⁸ In the Mayo Clinic experience, all 11 patients who underwent surgical excision alone and 16 out of 17 patients who received medical and surgical therapy responded to treatment. In contrast, only 7 of 19 patients treated with medical therapy alone had any response. ⁴⁴

Conclusion

Calcinosis is a significant clinical problem for patients with ACTD, especially SS and DM. Although SSc and DM-related calcinosis are both of the dystrophic subtype, they have similar clinical appearance and share the same complications and impact on quality of life, but they differ in distribution, composition, and some pathogenic mechanisms. Multiple treatment strategies for DM and SSc-related calcinosis have been used; however, none has consistently prevented or reduced calcinosis. A better understanding of the physiopathology of calcinosis is needed to improve treatment options.

The Editor/ Editorial Board Member of JSRD is an author of this paper; therefore, the peer-review process was managed by alternative members of the Board and the submitting Editor/Board member had no involvement in the decision-making process.