Calcinosis Cutis 

Calcinosis Cutis – Interesting Facts

1. Calcinosis cutis refers to the deposition of insoluble calcium salt within the skin and/or subcutaneous tissue^(1,2)
2. There are 5 main types of calcinosis cutis including^(1,2)
3. Dystrophic – most common type and associated with
4. Normal serum calcium and phosphate levels
5. cConnective tissue conditions and autoimmune diseases such as systemic sclerosis, dermatomyositis, lupus erythematosus, and Calcinosis, Raynaud phenomenon, Esophageal involvement, Sclerodactyly, and Telangiectasia (CREST) syndrome
6. Metastatic – associated with elevated serum calcium and phosphate levels, typically in the setting of chronic kidney failure, hypervitaminosis D, hyperparathyroidism, sarcoidosis, milk and alkali syndrome (excessive consumption of antacids or calcium-containing food), or malignant neoplasms
7. Idiopathic – characterized by unknown etiology and no precipitating metabolic abnormalities or connective tissue damage
8. Iatrogenic – associated with use of calcium- or phosphate-containing substances
9. Calciphylaxis (not covered in the scope of this topic)
10. Debilitating type of calcinosis cutis that occurs due to cutaneous ischemic infarcts caused by total blood vessel occlusion from vascular calcification
11. Most commonly seen in patients with renal failure and associated with high mortality

Synonyms

• Calcification

Types

• 5 main types of calcinosis cutis include dystrophic, metastatic, idiopathic, iatrogenic, and calciphylaxis^(1,2)
• Dystrophic calcification (most common)^(1,2)
  • Associated with normal serum calcium and phosphate levels
  • Secondary to tissue damage to collagen, elastin, or subcutaneous fat leading to hypoxia, or hypovascularization and resulting in deposition of hydroxyapatite and amorphous calcium phosphate
  • Associated with connective tissue conditions and autoimmune diseases, such as systemic sclerosis, Calcinosis, Raynaud phenomenon, Esophageal involvement, Sclerodactyly, and Telangiectasia (CREST) syndrome, dermatomyositis (adult and juvenile), and lupus erythematosus
• Metastatic calcification⁽¹⁾
  • Associated with abnormal calcium and/or phosphate serum levels leading to precipitation of calcium in skin and subcutaneous tissue
  • Associated with chronic kidney failure, hypervitaminosis D, hyperparathyroidism, sarcoidosis, milk and alkali syndrome (excessive consumption of antacids or calcium-containing food), and malignant neoplasms
• Idiopathic calcification⁽¹⁾
  • Occurs in patients without prior damage to skin and without abnormal calcium or phosphate metabolism (which would indicate metastatic calcinosis)
  • 3 main types of idiopathic calcification include
    • Familial tumoral calcinosis (some experts consider this a form of metastatic rather than idiopathic calcinosis due to association with hyperphosphatemia)
    • Calcified subepidermal nodules (nodular calcinosis of Winer)
    • Scrotal calcinosis
• Iatrogenic calcification due to medical treatment or diagnostic procedures; occurs with normal calcium and phosphate levels⁽¹⁾
• Calciphylaxis is calcification of small vessels, typically affecting blood vessels in dermis and subcutaneous fat (not covered in the scope of this topic)⁽¹⁾
• Other rare types of calcinosis cutis (CC) that may be classified as idiopathic or dystrophic include⁽¹⁾
  • CC circumscripta
  • CC universalis
  • Tumoral calcinosis
  • Transplant associated Calcinosis Cutis 

Epidemiology

Who Is Most Affected

• Calcinosis cutis most often affects patients with underlying autoimmune connective tissue diseases^(1,2)

Incidence/Prevalence

• reported prevalence of dystrophic calcinosis cutis among patients with autoimmune connective tissue diseases
  • 18%-49% of patients with systemic sclerosis^(1,2)
  • 20% of adults with dermatomyositis⁽¹⁾
  • 44%-70% of patients with juvenile dermatomyositis⁽¹⁾
  • rare in patients with lupus erythematosus⁽¹⁾

Risk Factors

Dystrophic Calcinosis Cutis Risk Factors

• Dystrophic calcinosis cutis may occur due to or concurrently with many different conditions that affect connective tissues, such as^(1,2)
  • Autoimmune and acquired idiopathic inflammatory diseases
    • Systemic sclerosis
    • Calcinosis, Raynaud phenomenon, esophageal involvement, sclerodactyly, and telangiectasia (CREST) syndrome
    • Dermatomyositis or juvenile dermatomyositis
    • Lupus erythematosus and lupus panniculitis
    • Rheumatoid arthritis
    • Morphea-like or linear localized scleroderma
    • Primary Sjogren syndrome
    • Overlap autoimmune syndromes of connective tissue
    • Undifferentiated and mixed connective tissue disease
  • Skin neoplasms
    • Pilomatrixoma (also known as Malherbe calcifying epithelioma) – reported to present in up to 75% of dystrophic calcification
    • Trichilemmal cyst
  • Collagen or elastic fiber diseases
    • Elastic pseudoxanthoma
    • Werner syndrome
    • Ehlers-Danlos syndrome
  • Infections
    • Onchocercosis
    • Cysticercosis
    • Histoplasmosis
    • Cryptococcosis
    • iIntrauterine herpes simplex
  • Trauma or burns
  • Porphyria cutanea tarda (uncommon cause, most often occurs in patients with scleroderma-like lesions)
  • Pancreatic panniculitis
• Chronic skin graft-versus-host disease (JAMA Dermatol 2020 Jul 1;156(7):814)
• Calcinosis cutis may be associated with repeated inflammation, blister formation, and/or fibrosis in some conditions⁽¹⁾
• Among patients with systemic sclerosis, calcinosis cutis is reported to occur more frequently in patients with anticentromere antibody and/or anti-PM/Scl antibody⁽²⁾

Metastatic Calcinosis Cutis Risk Factors

• Elevated levels of serum calcium and/or phosphorus⁽¹⁾
• conditions that may lead to metastatic calcinosis cutis include⁽¹⁾
  • chronic kidney failure (most common cause)
  • hyperparathyroidism
  • hypervitaminosis D
  • sarcoidosis (production of vitamin D by sarcoidosis granulomas)
  • milk and alkaline syndrome (excessive consumption of antacids or calcium-containing food)
  • malignant neoplasms

Iatrogenic Calcinosis Cutis Risk Factors

• iatrogenic calcinosis cutis has been associated with calcium- or phosphate-containing solutions; reported underlying causes include⁽¹⁾
  • calcium gluconate
  • calcium chloride
  • para-aminosalicylic acid
  • conductive pastes used for electrode placement
  • chemotherapy-induced tumor lysis syndrome
  • postorgan transplant
  • venipuncture sites

Associated Conditions

• digital ulcers and osteoporosis each associated with calcinosis cutis in patients with systemic sclerosis
  •  based on retrospective cohort study
  • 5,218 patients (84.9% female; mean age 57 years) with systemic sclerosis were evaluated for presence of calcinosis cutis and associated features
  • 24.7% prevalence of calcinosis cutis (1,290 patients)
  • analysis adjusted for disease duration from first non-Raynaud phenomenon symptoms, sex, modified Rankin Skin Score, digital ulcers, telangiectasias, osteoporosis, cardiac disease, gastrointestinal disease, muscle disease, and anticentromere antibody
  • calcinosis cutis associated with
    • osteoporosis (odds ratio [OR] 4.2, 95% CI 2.3-7.9)
    • digital ulcers (OR 3.9, 95% CI 2.7-5.5)
    • telangiectasias (OR 3.6, 95% CI 2.2-5.8)
    • female sex (OR 3.1, 95% CI 1.5-6.2)
    • anticentromere antibody (OR 2.2, 95% CI 1.5-3.2)
    • cardiac disease (OR 1.8, 95% CI 1.1-2.9)
    • gastrointestinal disease (OR 1.7, 95% CI 1.1-2.6)
  • Reference – Semin Arthritis Rheum 2016 Dec;46(3):344full-text
• fingertip ulcers, longer disease duration, and autoantibodies appear associated with calcinosis in adults with dermatomyositis
  •  based on retrospective cohort study
  • 126 adults (mean age 50 years; 73.8% female) with dermatomyositis were evaluated for calcinosis and clinical features
  • 14 patients (11%) had calcinosis; site of calcinosis lesions (9 patients had lesions affecting ≥ 1 site)
    • extremities in 85.7%
    • axilla in 35.7%
    • trunk in 28.6%
    • buttock in 21.4%
    • groin in 21.4%
    • elbow in 14.3%
    • neck in 1 patient (7%)
    • hand in 0 patients
  • comparing clinical features of 14 patients with calcinosis vs. 112 patients without calcinosis
    • median disease duration 6.9 vs. 3.9 years (p = 0.003)
    • Raynaud phenomenon in 46.2% vs. 22.2% (not significant [p = 0.06])
    • fingertip ulcers in 50% vs. 9.3% (p = 0.001)
    • interstitial lung disease (ILD) in 53.9% vs. 15.2% (p = 0.001); results lost significance in multivariate analysis
  • comparing autoantibodies of 14 patients with calcinosis vs. 112 patients without calcinosis
    • MDA-5 in 35.7% vs. 9.8% (p = 0.006); results lost significance when controlling for ILD, disease duration, and fingertip ulcers
    • transcriptional intermediary factor 1-gamma (TIF1-gamma) in 14.3% vs. 45.5% (p = 0.02)
    • Ro-52 in 42.9% vs. 17.9% (p = 0.02)
    • NXP-2 in 28.6% vs. 10.7% (not significant [p = 0.06])
  • factors associated with calcinosis in 3 multivariate analyses for each associated autoantibody
    • fingertip ulcers (odds ratio [OR] range 11-12)
    • longer disease duration (OR range 1.18-1.21)
    • NXP-2 antibodies (OR 15.52, 95% CI 2-120)
    • TIF-1gamma (OR 0.2, 95% CI 0.01-0.99)
  • Reference – JAMA Dermatol 2014 Jul;150(7):724full-text

Etiology and Pathogenesis

Causes

• calcinosis cutis occurs due to the deposition of insoluble calcium salt within the skin and/or subcutaneous tissue^(1,2)
• there are 5 main types of calcinosis cutis including dystrophic, metastatic, iatrogenic, idiopathic and calciphylaxis (calciphylaxis not covered in the scope of this topic)^(1,2)
• each type (except idiopathic) is associated with different underlying metabolic processes and conditions^(1,2)
  • dystrophic calcinosis cutis occurs due to local tissue damage or abnormalities that affect the collagen, elastin or fat components of the dermis and subcutaneous tissues
    •  normal serum calcium and phosphate levels are seen with dystrophic calcinosis cutis
    • dystrophic calcinosis cutis is usually associated with underlying conditions of the connective tissue or dermis, particularly autoimmune and acquired idiopathic inflammatory diseases
      • seen in about 25% of patients with systemic sclerosis, 44%-70% of patients with juvenile dermatomyositis and 20% of adults with dermatomyositis
      • less commonly seen with lupus erythematosus and lupus panniculitis, rheumatoid arthritis, and other connective tissue disorders
    • dystrophic calcinosis cutis may be seen with some inherited collagen or elastic fiber diseases, such as Ehlers-Danlos syndrome; some skin neoplasms, such as pilomatrixoma and trichilemmal cyst; and after trauma or burns
    • see full list of potential underlying conditions in Dystrophic Calcinosis Cutis Risk Factors
  • metastatic calcification
    •  results from abnormal serum calcium and/or phosphate levels leading to calcium deposition in skin and subcutaneous tissue
    • most common cause is chronic kidney failure
    • other causes include hyperparathyroidism, hypervitaminosis D, sarcoidosis (production of vitamin D by sarcoidosis granulomas), milk and alkaline syndrome (excessive consumption of antacids or calcium-containing food), malignant neoplasms
  • familial tumoral calcinosis (form of idiopathic or metastatic calcinosis) may be due to inherited recessive disease of increased phosphate resorption in proximal tubule of kidney
  • iatrogenic calcinosis cutis
    • typically occurs when medical interventions disturb calcium and phosphate metabolism and lead to soft tissue calcification
    • has been reported with
      • IV calcium gluconate, calcium chloride or para-aminosalicylic acid for tuberculosis treatment
      • conductive pastes used for electrode placement
      • chemotherapy-induced tumor lysis syndrome
      • postliver transplant
      • venipuncture

Pathogenesis

• pathogenesis depends on type of calcinosis cutis^(1,2)
• pathogenesis of dystrophic calcinosis cutis ^(1,2)
  • tissue damage (particularly recurrent trauma) to collagen, elastin, or subcutaneous fat and/or vascular hypoxia or hypovascularization in these tissues can trigger necrotic cells to release phosphate-binding proteins which take up phosphate, ultimately leading to calcification
  • abnormalities in bone matrix proteins are thought to be involved
  • chronic inflammation is thought to be involved, specifically proinflammatory cytokines interleukin (IL) 6, IL-1-beta, and tumor necrosis factor
  • calcified deposit comprises hydroxyapatite and amorphous calcium phosphate
  • when associated with porphyria cutanea tarda, lesions occur due to repeated episodes of local inflammation, blistering, and fibrosis
• pathogenesis of metastatic calcinosis cutis⁽¹⁾
  • abnormal levels of calcium and/or phosphorus lead to precipitation of calcium salts in normal tissue
  • once serum levels normalize, lesions remit
  • degree of hyperphosphatemia directly correlates to number and size of calcium deposits

History and Physical

Clinical Presentation

Dystrophic Calcinosis Cutis Presentation

• several underlying conditions are associated with dystrophic calcinosis cutis, which is characterized by deposition of calcium in the skin associated with damage to collagen, elastin, or subcutaneous fat, and normal serum calcium and phosphate levels^(1,2)
• systemic sclerosis^(1,2)
  • dystrophic calcinosis cutis occurs in 18%-49% of patients with systemic sclerosis (SSc)
  • typically occurs > 10 years after diagnosis, but can be seen even prior to diagnosis
  • may be associated with calcinosis, Raynaud phenomenon, esophageal involvement, sclerodactyly, and telangiectasia (CREST) syndrome
  • calcinosis presents as subcutaneous nodules in digits or at pressure points such as knees, elbows, or ischial tuberosities in patients with systemic sclerosis (SSc)⁽²⁾
    • presenting symptoms may include
      • pain
      • soft tissue swelling around nodules
      • digital ulcers, which may be complicated by infection
      • digital pitting
      • deformities of the hand(s) leading to functional limitations
      • “toothpaste-like” material exuding from skin
    • calcinosis most frequently occurs in those with
      • older age
      • longer disease duration
      • limited cutaneous SSc subtype
    • associated with acroosteolysis and telangiectasias
  • lesion sites by reported frequency⁽²⁾
    • hands in 65%-83% of affected patients
    • proximal upper extremity in 27%
    • knees or proximal lower extremity in 10%-22%
    • hip in 6.7%
    • less commonly, calcinosis may also occur on trunk, chest, buttocks, maxillary sinuses, spine, or paraspinal tissues
  • nodules are of varying size and shape and typically occur at sites of recurrent microtrauma (Curr Opin Rheumatol 2015 Nov;27(6):542)
  • associated autoantibodies include
    • positive anticentromere antibody
    • positive anti-PM/Scl antibody
    • positive anticardiolipin antibodies
    • References – Curr Opin Rheumatol 2015 Nov;27(6):542
• juvenile dermatomyositis
  • calcinosis cutis seen in 4%-70% of patients with juvenile dermatomyositis⁽¹⁾
  • onset of calcinosis cutis typically about 2-3 years after diagnosis⁽¹⁾
  • nodules typically found on areas at risk of trauma such as elbows and knees, but may occur anywhere (including intramuscularly or intrafascially)
  • associated with autoantibodies, anti-p155, anti-p140 and anti-MJ (also called anti-NXP-2)
  • may be associated with more severe and active disease course

• adult-onset dermatomyositis
  • calcinosis cutis seen in about 20% of patients with adult-onset dermatomyositis (less common with adult onset dermatomyositis than juvenile dermatomyositis)⁽¹⁾
  • onset of calcinosis cutis typically about 8 years after diagnosis
  • consists of soft tissue calcifications that appear as hard, painful nodules; typically found on areas at risk of trauma such as elbows and knees, but may occur anywhere
  • may develop into draining fistulae to surface of skin
  • generally associated with advanced disease
• lupus erythematosus and lupus panniculitis⁽¹⁾
  • calcinosis cutis occurs rarely with lupus and generally only after ≥ 20 years of lupus
  • typical sites include extremities, buttocks, beneath cutaneous lupus lesions, and periarticular (J Am Acad Dermatol 2011 Jul;65(1):1)
  • may be initially detected on x-ray as a chance finding
• less commonly, dystrophic calcinosis cutis may present with other connective diseases such as⁽¹⁾
  • rheumatoid arthritis
  • primary Sjogren syndrome
  • overlap autoimmune syndromes of connective tissue
  • undifferentiated and mixed connective tissue disease
• porphyria cutanea tarda (PCT)⁽¹⁾
  • calcinosis cutis occurs uncommonly with PCT
  • associated with scleroderma-like lesions, and appears at sites of repeated inflammation, blister formation, and/or fibrosis
• dystrophic calcinosis cutis may be seen in localized skin neoplasms, such as⁽¹⁾
  • pilomatrixoma (also known as Malherbe calcifying epithelioma)
  • trichilemmal cyst
• inherited conditions of connective tissue associated with dystrophic calcinosis cutis include⁽¹⁾
  • Ehlers-Danlos Syndrome (EDS)
  • elastic pseudoxanthoma
  • Werner syndrome
• dystrophic calcinosis cutis may be seen within sites of trauma or burns⁽¹⁾
• dystrophic calcinosis cutis may be seen in localized infections, including with⁽¹⁾
  • onchocercosis
  • cysticercosis
  • histoplasmosis
  • cryptococcosis
  • intrauterine herpes simplex
• pancreatic panniculitis is dystrophic calcinosis cutis associated with a pancreatic condition, such as acute or chronic pancreatitis or pancreatic carcinoma (Rev Esp Enferm Dig 2019 Oct;111(10):812)

Metastatic Calcinosis Cutis Presentation

• metastatic calcinosis cutis presents in individuals with abnormal calcium and/or phosphate metabolism⁽¹⁾
• calcium precipitation occurs in normal skin, usually in periarticular regions, and resolves when calcium and phosphate levels return to normal⁽¹⁾
• underlying conditions associated with metastatic calcinosis such as⁽¹⁾
  • chronic kidney failure (most common cause)
  • hyperparathyroidism
  • hypervitaminosis D
  • sarcoidosis (production of vitamin D by sarcoidosis granulomas)
  • milk and alkaline syndrome (excessive consumption of antacids or calcium-containing food)
  • malignant neoplasms

History

Chief Concern (CC)

• calcinosis cutis refers to calcified deposits under skin, which may be asymptomatic or debilitating^(1,2)

History of Present Illness (HPI)

• calcinosis cutis lesions typically develop gradually and are asymptomatic⁽¹⁾
• lesions may be localized and asymptomatic, or involve areas of body surface and lead to^(1,2)
  • muscular atrophy
  • joint contracture
  • cutaneous ulceration (associated with increased risk for infection)
• dystrophic calcinosis reported typical onset timing by underlying disease⁽¹⁾
  • systemic sclerosis: > 10 years, but may also occur prior to sclerosis diagnosis
  • adult dermatomyositis: 8 years after diagnosis
  • juvenile dermatomyositis: 2-3 years after diagnosis
  • lupus erythematous: ≥ 20 years
• ask about effect of calcification on life including functionality and clinical significance to help guide management strategy; ask about presence of⁽¹⁾
  • pain
  • recurrent infections
  • ulceration
  • impaired mobility

Medication History

• ask about use of calcium- or phosphate-containing substances for interventional or diagnostic purposes⁽¹⁾
• iatrogenic causes reported to have included⁽¹⁾
  • calcium gluconate
  • calcium chloride
  • para-aminosalicylic acid
  • conductive pastes used for electrode placement
  • chemotherapy-induced tumor lysis syndrome
  • organ transplant
  • venipuncture

Past Medical History (PMH)

• ask about/assess for ^(1,2)
  • underlying conditions including associated with dystrophic calcinosis such as
    • autoimmune connective tissue disorders including
      • systemic sclerosis
      • dermatomyositis
      • lupus erythematosus
    • skin neoplasms
    • collagen or elastic fiber diseases
    • infections
    • trauma or burns
    • porphyria cutanea tarda (uncommon cause, most often occurs in patients with scleroderma-like lesions)
    • pancreatic panniculitis
  • underlying conditions associated with metastatic calcinosis such as
    • chronic kidney failure (most common cause)
    • hyperparathyroidism
    • hypervitaminosis D
    • sarcoidosis (production of vitamin D by sarcoidosis granulomas)
    • milk and alkaline syndrome (excessive consumption of antacids or calcium-containing food)
    • malignant neoplasms
  • recent procedures or therapies involving calcium- or phosphate-containing solutions (associated with iatrogenic calcinosis)
• in patients with systemic sclerosis and calcinosis, co-occurring conditions may include
  • cardiac disease
  • gastrointestinal disease
  • osteoporosis
  • pulmonary hypertension
  • arthritis
  • Reference – Curr Opin Rheumatol 2015 Nov;27(6):542

Physical

Skin

• location of calcinosis cutis may help determine the type of calcinosis cutis, as some associated conditions more likely to develop lesions in specific sites
  • trauma-induced calcinosis cutis appears on site of prior trauma
  • dystrophic calcinosis cutis
    • calcinosis lesions in systemic sclerosis typically appear on
      • fingers, especially fingertips
      • forearms
      • elbows
      • knees
    • calcinosis in dermatomyositis
      • appears as subcutaneous calcification on previous inflammatory lesions; commonly on the elbows and knees
      • muscle calcification may be present
    • typical calcinosis locations in lupus erythematosus
      • extremities
      • buttocks
      • beneath cutaneous lupus lesions
      • periarticular
    • calcinosis in porphyria cutanea tarda typically appears on
      • scalp
      • neck
      • periauricular
      • dorsal aspects of hands
    • calcinosis in pancreatic panniculitis appears on lower extremities around ankles and knees
    • calcinosis in lupus panniculitis appears on
      • upper arms
      • shoulders
      • face
      • buttocks
  • cutaneous neoplasms
    • pilomatricoma calcinosis appears on head, neck, and extremities
    • trichilemmal (pilar) cyst calcinosis appears on scalp
  • inherited conditions
    • pseudoxanthoma elasticum-associated calcinosis appears on
      • neck
      • axillar
      • antecubital and popliteal fossa
      • abdomen
      • groin
    • Werner syndrome calcinosis cutis appears on tendons and periarticular areas
    • Ehlers-Danlos syndrome calcinosis appears on periarticular areas
  • idiopathic calcification
    • tumoral calcinosis occurs around joints
    • calcified subepidermal nodules (nodular calcinosis of Winer) are present at birth, and appear as hard, solitary white-yellowish papules typically on head and limbs
  • iatrogenic calcinosis cutis may be seen at sites of venipuncture
  • metastatic calcinosis may appear in periarticular regions
  • calciphylaxis occurs typically on lower limbs
  • References – ^(1,2), J Am Acad Dermatol 2011 Jul;65(1):1
• among patients with systemic sclerosis, findings reported frequently with calcinosis cutis include⁽²⁾
  • digital ulcers
  • digital pitting scars
  • acro-osteolysis
  • telangiectasias

Genital Exam

• scrotal calcinosis lesions are variable in size and number⁽¹⁾
  • deposits are palpable and marble-like
  • typically asymptomatic but may be associated with pruritus

Diagnosis

Making the Diagnosis

• diagnosis of calcinosis cutis is typically apparent from clearly palpable or visible deposits under the skin in individuals at risk due to underlying conditions such as systemic sclerosis, dermatomyositis or chronic renal failure^(1,2)
• diagnosis made definitively with biopsy^(1,2)
• serum testing of calcium and phosphate, and imaging may be required to identify type of calcinosis and underlying etiology^(1,2)

Differential Diagnosis

• rule out gouty tophi (Cureus 2020 Mar 30;12(3):e7471full-text)
• consider other causes of potentially painful cutaneous tumors such as
  • metastases
  • osteoma cutis (heterotropic deposition of bone within the dermis)
  • foreign body or foreign body reaction
  • thrombus
  • keloid
  • leiomyoma or leiomyosarcoma
  • eccrine spiradenoma
  • neuroma
  • glomus tumor
  • leiomyoma
  • angiolipoma
  • neurilemmoma
  • dermatofibroma
  • References – Cureus 2020 Feb 11;12(2):e6955full-text, Cureus 2019 Jun 20;11(6):e4959full-text
• subcutaneous granuloma annulare mimicking calcinosis cutis in case report (Pediatr Dermatol 2020 Jul;37(4):687)

Testing Overview

• all patients with calcinosis cutis require the following blood tests to determine type of calcinosis⁽¹⁾
  • serum calcium
  • inorganic phosphate
  • alkaline phosphatase
  • albumin
• complementary tests to determine underlying etiology may include
  • testing for autoimmune or other disorders⁽¹⁾
  • imaging to assess site and extent of calcification^(1,2)
  • biopsy of affected site for definitive diagnosis⁽¹⁾

Blood Tests

• tests to determine type of calcinosis cutis⁽¹⁾
  • serum calcium
  • inorganic phosphate
  • alkaline phosphatase
  • albumin
  • considerations include
    • abnormal calcium and phosphate levels suggest metastatic calcinosis, calciphylaxis (levels may also be normal), or tumoral calcinosis (type of idiopathic calcinosis cutis associated with hyperphosphatemia)
    • parathyroid hormone may be elevated if calcium-phosphorus metabolism is disturbed
    • if total calcium is measured, adjust for albumin (or plasma protein levels) as calcium binds strongly to proteins
    • ideally, ionized calcium should be measured if possible (difficult sample processing and high costs may limit availability)
• complementary blood tests to consider for identifying underlying etiology⁽¹⁾
  • hematology and biochemistry labs
    • complete blood count
    • electrolytes
    • creatinine
    • liver function tests
    • lactate dehydrogenase (LDH)
  • parathyroid hormone for hyperparathyroidism
  • vitamin D levels for hypervitaminosis D
  • serum bicarbonate and arterial pH to assess for milk and alkaline syndrome
  • autoantibodies for lupus erythematosus, systemic sclerosis and/or dermatomyositis
  • for dermatomyositis known or suspected, test for the following
    • muscle enzymes creatine phosphokinase (CPK), LDH, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and aldolase
    • antibodies
      • Mi-2
      • Jo-1
      • PM-Scl
      • Reference – J Am Acad Dermatol 2011 Jul;65(1):1
  • systemic lupus erythematosus and systemic sclerosis autoantibodies
    • ANA
    • anti-DNA
    • anti-ENA
    • dsDNA
    • Sm
    • Ro/SSA
    • La/SSB
    • U1RNP
    • References – ¹, J Am Acad Dermatol 2011 Jul;65(1):1
  • see also:
    • Juvenile Dermatomyositis
    • Dermatomyositis and Polymyositis in Adults
    • Systemic Sclerosis
    • Complications of Chronic Kidney Disease (CKD)
• myositis autoantibodies
  • in adults with dermatomyositis and in juvenile dermatomyositis, an increased risk of calcinosis is associated with the following
    • anti-NXP2
    • anti-PM/Scl
  •  a decreased risk of calcinosis in adults with dermatomyositis is associated with
  • Reference – Autoimmun Rev 2020 Jun;19(6):102533

Urine Studies

• consider 24-hour urine excretion of calcium and inorganic phosphate to determine if metastatic calcinosis⁽¹⁾

Imaging

• complementary testing to characterize calcinosis cutis may include
  • x-ray to determine site and extension of calcification^(1,2)
    • x-ray is first-line imaging for evaluation of patients with autoimmune connective tissue disorders
    • in patients with juvenile dermatomyositis and calcinosis, plain x-ray is recommended to characterize calcification (Expert Grade 3C) by Single Hub and Access Point for Pediatric Rheumatology in Europe (SHARE) consensus recommendations (Ann Rheum Dis 2017 Feb;76(2):329full-text)
  • skin ultrasound^(1,2)
    • shows hyperechoic image of calcinosis, sometimes with posterior acoustic shadow
    • may help determine thickness, longitudinal extension, and site of calcification
    • may help identify surrounding inflammation which may help guide management decisions
  • bone scintigraphy is reported to be more sensitive than x-ray and potentially useful in assessment of calcification in nonvisceral soft tissue⁽¹⁾
  • computed tomography not typically used for calcinosis evaluation, but may help detect malignant neoplasms if suspected⁽¹⁾
  • magnetic resonance imaging not generally useful for calcinosis evaluation⁽¹⁾

Biopsy and Pathology

• skin biopsy of affected site enables definitive diagnosis of calcinosis cutis⁽¹⁾
• calcinosis cutis histology⁽¹⁾
  • deposit is composed of hydroxyapatite and amorphous calcium phosphate
  • appears dark blue with hematoxylin-eosin staining and with a blackish tone with Von Kossa staining
  • foreign body reactions and fibrosis may be present around calcium deposits in dystrophic calcinosis

Management

Management Overview

• there are no specific, universally effective treatments for calcinosis cutis and evidence for treatments is limited to mostly case reports and case series^(1,2)
• for all types of calcinosis cutis
  • individualize management to patient and clinical extent of calcinosis and treat underlying causes, if present^(1,2)
  • manage pain with analgesia; options may include acetaminophen, nonsteroidal anti-inflammatory agents, or opioids if appropriate⁽²⁾
  • advise avoidance of trauma, stress, and cold exposure^(1,2)
  • for suspected superinfections of calcinosis lesions, administer antibiotic regimens covering streptococci and staphylococci ⁽²⁾
• for dermatomyositis-associated calcinosis, recommendations from professional organizations include medications such as warfarin, IV immunoglobulins (IVIG), bisphosphonates, or others; and surgical excision (all based on limited evidence)
• surgical excision is an option for patients with calcinosis cutis and pain, recurrent infections, ulceration, impaired mobility and/or large, localized, symptomatic calcinosis lesions particularly if located over tendons, blood vessels, or nerves
• for dystrophic calcinosis not amenable to surgical excision, medication therapy may be an option
  • bisphosphonates reported to improve calcinosis cutis in most patients with dermatomyositis (level 3 [lacking direct] evidence)
  • diltiazem reported to improve calcinosis cutis in 0%-64% of adults with systemic sclerosis or dermatomyositis (level 3 [lacking direct] evidence)
  • minocycline reported to help improve calcinosis cutis in patients with systemic sclerosis (level 3 [lacking direct] evidence)
  • sodium thiosulfate
    • intralesional sodium thiosulfate reported potentially helpful for calcinosis cutis in patients with systemic sclerosis or dermatomyositis (level 3 [lacking direct] evidence); limited evidence for topical or IV sodium thiosulfate
    • topical sodium thiosulfate is reported effective for calcinosis cutis in case reports (level 3 [lacking direct] evidence)
  • IVIG reported to have mixed evidence for benefit in calcinosis cutis in patients with dermatomyositis (level 3 [lacking direct] evidence)
  • rituximab may not improve calcinosis cutis in post-hoc analysis of randomized trial (level 2 [mid-level] evidence)
  • infliximab reported to have some benefit in case series (level 3 [lacking direct] evidence)
  • very limited evidence for colchicine or probenecid (level 3 [lacking direct] evidence)
• other options for calcinosis cutis with limited evidence include
  • CO₂ laser therapy (level 3 [lacking direct] evidence)
  • extracorporeal shock wave lithotripsy (ESWL) (level 3 [lacking direct] evidence)
  • hematopoietic stem cell transplant (level 3 [lacking direct] evidence)

Recommendations for Dystrophic Calcinosis Cutis

Japanese Society of Neurology/Japanese Dermatological Association/Japan College of Rheumatology (JSN/JDA/JCR) 2019 Recommendations

• JSN/JDA/JCR 2019 recommendations for management of persistent calcinosis refractory to conventional treatments for dermatomyositis including considering the following options as interventions (JSN/JDA/JCR Grade C1)
  • low-dose warfarin (JSN/JDA/JCR Level II)
  • diltiazem hydrochloride (JSN/JDA/JCR Level V)
  • aluminum hydroxide (JSN/JDA/JCR Level V)
  • bisphosphonates (JSN/JDA/JCR Level V)
  • probenecid (JSN/JDA/JCR Level V)
  • IV immunoglobulin (IVIG) (no level reported)
  • surgical therapy (JSN/JDA/JCR Level V)
  • Reference – JSN/JDA/JCR treatment consensus statement on management of polymyositis and dermatomyositis among rheumatologists, neurologists and dermatologists can be found in J Dermatol 2019 Jan;46(1):e1
• for conventional treatments of dermatomyositis, see Dermatomyositis and Polymyositis in Adults

Single Hub and Access Point for Pediatric Rheumatology in Europe (SHARE) Consensus-Based 2016 Recommendations on Management of Juvenile Dermatomyositis

• in patients with juvenile dermatomyositis, calcinosis may be associated with inadequate response to corticosteroid therapy and greater disease duration
• SHARE recommendations for calcinosis management in patients with juvenile dermatomyositis
  • IV immunoglobulin may be useful as adjunctive therapy in patients with disease resistant to conventional therapy, particularly if skin features are prominent (Expert Grades 2B-4C)
  • mycophenolate mofetil may be useful for muscle and skin disease including calcinosis (Expert Grade 3C)
  • intensify immunosuppressive therapy in presence of developing or established calcinosis (Expert Grade 3C)
  • no specific recommendations for calcinosis are made due to limited evidence (case reports or series), but options may include
    • bisphosphonates such as pamidronate or alendronate
    • infliximab
    • abatacept
    • diltiazem
    • probenecid
    • IV immunoglobulin
    • intralesional steroids
    • surgical resection
• Reference – Single Hub and Access Point for Pediatric Rheumatology in Europe (SHARE) consensus-based recommendations on management of juvenile dermatomyositis can be found in Ann Rheum Dis 2017 Feb;76(2):329full-text
• for conventional treatments of juvenile dermatomyositis, see Juvenile Dermatomyositis

2016 European Guidelines (S1) on High-Dose IV Immunoglobulin in Dermatology

• CLINICIANS’ PRACTICE POINT: Calcinosis cutis is not specifically mentioned in this guideline, but the scope of the guideline covers severe forms of potential underlying conditions such as dermatomyositis.
• European Dermatology Forum/European Academy of Dermatology and Venereology (EDF/EADV) guideline on use of high-dose IVIG use in dermatomyositis
  • high-dose IVIG is indicated in all severe forms of dermatomyositis including inclusion body myositis and polymyositis (includes idiopathic, paraneoplastic, or juvenile forms)
  • recommendation is based on individual case reports, small case series, and 1 small randomized trial (the randomized trial showed improvement in muscle strength [N Engl J Med 1993 Dec 30;329(27):1993])
  • Reference – EDF/EADV guideline on use of high-dose IV immunoglobulin in dermatology can be found in J Eur Acad Dermatol Venereol 2016 Oct;30(10):1657full-text

Medications

Diltiazem and Other Calcium Channel Blockers

• diltiazem^(1,2)
  • dosing for calcinosis cutis is 2-4 mg/kg/day (high-dose used for calcinosis cutis)
  • mechanism of action is reduction of cellular calcium uptake
  • mainly reported in case reports of patients with dermatomyositis
• diltiazem reported to improve calcinosis cutis in 0%-64% of adults with systemic sclerosis or dermatomyositis (level 3 [lacking direct] evidence)
  •  based on systematic review of observational studies without comparison groups
  • systematic review of 30 studies evaluating interventions for calcinosis cutis in 288 patients with systemic sclerosis or dermatomyositis
  • studies with < 3 patients were excluded
  • complete response defined as resolution of calcinosis cutis, and partial response defined as any improvement according to study protocol including reduced size of calcium deposits and ulcer healing; studies reporting only pain reduction were included as treatment failures
  • diltiazem evaluated in 3 retrospective case series with 38 adults (32% with dermatomyositis, 32% with systemic sclerosis, and 37% unspecified); follow-up ranged from 78 to 201 months
    • dosing ranged from 60 mg 3 times daily to 480 mg/day
    • partial response rate reported in 0%-64% among studies (0% in 1 study, 25% in 1 study, and 64% in 1 study)
    • no complete responses reported among studies
  • Reference – J Am Acad Dermatol 2020 Feb;82(2):317

Bisphosphonates

• bisphosphonates that have been reported as used for calcinosis cutis include⁽¹⁾
  • oral Etidronate, reported dosing is 800 mg/day
  • oral Alendronate, reported dosing is 70 mg/week
  • IV Pamidronate, reported dosing is 90 mg/week
• adverse events reported to include hypocalcemia, hypophosphatemia, hypomagnesium, fever, infusion-site reactions, and osteonecrosis of the jaw⁽¹⁾
• mechanism of action is inhibition of macrophages activated by calcification and inhibition of associated proinflammatory cytokines⁽¹⁾
• bisphosphonates reported to improve calcinosis cutis in most patients with dermatomyositis (level 3 [lacking direct] evidence)
  •  based on systematic review of observational studies without comparison groups
  • systematic review of 30 studies evaluating interventions for calcinosis cutis in 288 patients with systemic sclerosis or dermatomyositis
  • studies with < 3 patients were excluded
  • complete response defined as resolution of calcinosis cutis, and partial response defined as any improvement according to study protocol including reduced size of calcium deposits and ulcer healing; studies reporting only pain reduction were included as treatment failures
  • bisphosphonates evaluated in 4 retrospective cohort studies with 17 patients (2 adults and 15 pediatric patients; all pediatric patients had dermatomyositis and diagnosis in adults was unspecified)
    • no response reported in 2 of 12 pediatric patients (both with dermatomyositis) in 1 study
    • partial response reported in 11 patients in 4 studies with total of 17 patients
    • complete response reported in 3 patients in 2 studies with total of 9 patients
  • Reference – J Am Acad Dermatol 2020 Feb;82(2):317

Minocycline

• Minocycline (Systemic)⁽¹⁾
  • reported dosing is 50-100 mg/day
  • mechanisms involve proteolysis, calcium binding, and anti-inflammatory effect
  • mainly reported in patients with systemic sclerosis
• minocycline reported to help improve calcinosis cutis in patients with systemic sclerosis (level 3 [lacking direct] evidence)
  •  based on systematic review of observational studies without comparison groups
  • systematic review of 30 studies evaluating interventions for calcinosis cutis in 288 patients with systemic sclerosis or dermatomyositis
  • studies with < 3 patients were excluded
  • complete response defined as resolution of calcinosis cutis, and partial response defined as any improvement according to study protocol including reduced size of calcium deposits and ulcer healing; studies reporting only pain reduction were included as treatment failures
  • minocycline 50-200 mg/day evaluated in 2 studies with 12 patients (9 with systemic sclerosis and 3 unspecified) (largest study summarized below)
    • partial response reported in 9 of 12 patients
    • adverse events included nausea (1 patient), dizziness (1 patient), and conversion of calcinosis deposits into blue-black color (frequency not reported)
  • Reference – J Am Acad Dermatol 2020 Feb;82(2):317
• minocycline reported help reduce ulceration and inflammation in calcinosis cutis associated with limited systemic sclerosis in women (level 3 [lacking direct] evidence)
  •  based on uncontrolled trial
  • 9 women (mean age 66 years) with limited cutaneous systemic sclerosis complicated by calcinosis cutis with pain and/or ulceration received minocycline 50 or 100 mg/day
  • mean duration of treatment was 3.5 years
  • 8 patients reported to respond to minocycline (1 died of esophageal carcinoma) and 1 patient was intolerant to minocycline due to unacceptable nausea and dizziness; 7 patients continued to receive minocycline through follow-up
  • improvement reported to occur at ≥ 1 month of treatment (mean 4.8 months)
    • most common improvement reported was reduced ulceration and inflammation of calcium deposits
    • size of calcium deposits also reported to be reduced
  • 2 patients discontinued treatment had recurrence and worsening of calcinosis in 2-3 months; treatment was restarted and calcinosis improved
  • long-term follow-up
    • some patients cyclically receive minocycline in 4-8 week durations, which is reported to control calcinosis for about 3-4 months before worsening
    • some patients receive low dose minocycline continuously
  • side effects include black/blue discoloration of calcium deposits
  • Reference – Ann Rheum Dis 2003 Mar;62(3):267PDF

Sodium Thiosulfate

• sodium thiosulfate IV, topically or intralesionally has been reported as used for the management of calcinosis cutis⁽²⁾
  • the mechanism appears to involve an antioxidant effect and vasodilation
  • it may also be involved in chelation and dissolution of calcium deposits
• efficacy of topical and intralesional thiosulfate
  • topical sodium thiosulfate reported to induce complete response in 19% and partial response in 63% of patients with calcinosis cutis (level 3 [lacking direct] evidence)
    •  based on noncomparative data in systematic review of mostly observational studies
    • systematic review of 40 studies (1 pilot trial, 7 case series, 27 case reports, and 5 conference abstracts) evaluating interventions for calcinosis cutis in 136 patients
    • 52% of patients had systemic sclerosis, 12% had dermatomyositis or juvenile dermatomyositis, and 5% had overlap syndrome
    • treatments evaluated were topical and intralesional sodium thiosulfate, extracorporeal shockwave lithotripsy (ESWL), and laser treatment
    • complete response was defined as 100% resolution of calcifications; partial response was defined as any response other than 0% and 100% resolution
    • topical sodium thiosulfate was evaluated in 13 studies with 48 patients (maximum lesion diameter was 13 cm); formulation included cold cream, zinc ointment, or soaked compresses
    • topical sodium thiosulfate associated with
      • complete response in 19%
      • partial response in 63%
    • adverse events with topical sodium thiosulfate included skin irritation in 2 patients and transient pruritus, recurrence, and zinc ointment allergy in 1 patient each
    • Reference – Arch Dermatol Res 2022 Aug;314(6):515full-text
  • intralesional sodium thiosulfate reported to induce complete response in 36% and partial response in 38% of patients with calcinosis cutis (level 3 [lacking direct] evidence)
    •  based on noncomparative data in systematic review of mostly observational studies
    • systematic review of 40 studies (1 pilot trial, 7 case series, 27 case reports, and 5 conference abstracts) evaluating interventions for calcinosis cutis in 136 patients
    • 52% of patients had systemic sclerosis, 12% had dermatomyositis or juvenile dermatomyositis, and 5% had overlap syndrome
    • treatments evaluated were topical and intralesional sodium thiosulfate, ESWL, and laser treatment
    • complete response was defined as 100% resolution of calcifications; partial response was defined as any response other than 0% and 100% resolution
    • intralesional sodium thiosulfate was evaluated in 9 studies with 53 patients (maximum lesion diameter was 65 cm); intralesional sodium thiosulfate concentration ranged from 0.1 to 250 mg/mL, with application ranging from single session to once monthly
    • intralesional sodium thiosulfate associated with
      • complete response in 36%
      • partial response in 38%
    • adverse events with intralesional sodium thiosulfate included injection pain in 6 patients, infection in 5 patients, and blistering in 1 patient
    • Reference – Arch Dermatol Res 2022 Aug;314(6):515full-text
    • similar findings in older systematic review (J Am Acad Dermatol 2020 Feb;82(2):317)

IV Immunoglobulin (IVIG)

• IVIG reported to have mixed evidence for benefit in calcinosis cutis in patients with dermatomyositis (level 3 [lacking direct] evidence)
  •  based on systematic review of observational studies without comparison groups
  • systematic review of 30 studies evaluating interventions for calcinosis cutis in 288 patients with systemic sclerosis or dermatomyositis
  • studies with < 3 patients were excluded
  • complete response defined as resolution of calcinosis cutis, and partial response defined as any improvement according to study protocol including reduced size of calcium deposits and ulcer healing; studies reporting only pain reduction were included as treatment failures
  • IVIG evaluated for calcinosis cutis in 2 retrospective studies with 15 patients with dermatomyositis
    • partial response reported in 62% of patients in 1 case series with 8 patients
    • no response reported in 1 case series with 7 patients (1 patient reported pain improvement in this study)
  • Reference – J Am Acad Dermatol 2020 Feb;82(2):317

Monoclonal Antibodies

• mixed evidence of benefit for rituximab on calcinosis cutis in patients with systemic sclerosis or dermatomyositis (level 2 [mid-level] evidence); infliximab reported to improve calcinosis in some pediatric patients with juvenile dermatomyositis (level 3 [lacking direct] evidence)
  •  based on systematic review of mostly observational studies
  • systematic review of 30 studies evaluating interventions for calcinosis cutis in 288 patients with systemic sclerosis or dermatomyositis
  • studies with < 3 patients were excluded
  • complete response defined as resolution of calcinosis cutis, and partial response defined as any improvement according to study protocol including reduced size of calcium deposits and ulcer healing; studies reporting only pain reduction were included as treatment failures
  • rituximab evaluated in 7 studies (3 prospective studies, 3 retrospective studies, and 1 randomized trial evaluating various skin lesions including calcinosis) with 32 children with dermatomyositis and 27 adults (dermatomyositis in 9 and systemic sclerosis in 18)
  • rituximab associated with
    • overall, complete response in 6 patients (10%) in 4 studies (1 small randomized trial with no significant improvement and 3 observational studies); range 0% (0 patients in 3 studies with 14 patients) to 100% (3 patients in 1 study with 3 patients)
    • partial response reported overall in 20 patients (34%) in 5 observational studies; range of 0% (1 study with 6 patients) to 100% (3 studies with 16 patients)
    • relapse rate 0% at 12-60 month follow-up in 2 observational studies with 7 patients
    • adverse events reported in 4 patients overall in 3 studies
  • infliximab evaluated in 3 observational studies without comparison groups and was associated with
    • partial response rate range from 0% (0 of 2 patients) to 80% (4 of 5 pediatric patients with juvenile dermatomyositis)
    • no complete responses reported in any study
  • Reference – J Am Acad Dermatol 2020 Feb;82(2):317
• rituximab may not improve calcinosis in patients with refractory adult or juvenile dermatomyositis (level 2 [mid-level] evidence)
  •  based on post-hoc analysis of randomized trial
  • 200 patients with refractory myositis received rituximab (dosing based on surface area) and placebo and were randomized to order of intervention (early group received rituximab at weeks 0/1 and placebo at weeks 8/9; late group received placebo at weeks 0/1 and rituximab at weeks 8/9)
  • 200 patients ≥ 5 years old (mean age 42 years) with refractory dermatomyositis or polymyositis were randomized to early rituximab (rituximab at weeks 0 and 1 then placebo at weeks 8 and 9) vs. late rituximab (placebo at weeks 0 and 1 and then rituximab at weeks 8 and 9) and followed to 44 weeks in RIM trial
    • from this trial 72 adults with dermatomyositis and 48 patients with juvenile dermatomyositis were evaluated for cutaneous disease activity in 14 visits over 44 weeks
    • stable concomitant therapies continued throughout trial
  • baseline Myositis Damage Index (MDI) calcinosis score was 24.3 compared to MDI calcinosis score at last visit of 32 (not significant)
  • calcinosis was present in 10% of adults and 46% of pediatric patients at baseline; no major changes reported after rituximab intervention in either group
  • Reference – Rheumatology (Oxford) 2017 Feb;56(2):247full-text
• rituximab reported ineffective for preventing progression of calcinosis in case series of 54-year-old woman with scleromyositis and 38-year-old man with anti-Pm/Scl-positive polymyositis/scleroderma overlap syndrome (BMJ Case Rep 2016 May 31;2016full-text)

Warfarin

• Warfarin⁽¹⁾
  • dosing for calcinosis cutis is low and generally 1 mg/day
  • mechanism of action is inhibited carboxylation and reduction of enzyme matrix gamma-carboxyglutamate Gla protein (MGP) levels
• mixed evidence for warfarin for calcinosis cutis in patients with dermatomyositis or systemic sclerosis, and warfarin does not appear effective for most patients (level 2 [mid-level] evidence)
  •  based on systematic review of mostly observational studies
  • systematic review of 30 studies evaluating interventions for calcinosis cutis in 288 patients with systemic sclerosis or dermatomyositis
  • studies with < 3 patients were excluded
  • complete response defined as resolution of calcinosis cutis, and partial response defined as any improvement according to study protocol including reduced size of calcium deposits and ulcer healing; studies reporting only pain reduction were included as treatment failures
  • warfarin evaluated in 1 randomized trial with 5 patients (2 adults with systemic sclerosis [SSc], 1 pediatric patient with dermatomyositis plus SSc, and 2 pediatric patients with SSc), and 4 retrospective observational studies with 14 patients
    • treatment failure reported in 1 randomized trial with 5 patients and 2 studies with 8 patients
    • complete response reported in 2 of 3 patients in 1 study
    • partial response reported in 4 patients in 2 studies with 6 patients
  • Reference – J Am Acad Dermatol 2020 Feb;82(2):317

Other Medications

• colchicine reported to partially improve calcinosis cutis in 11%-43% of patients with systemic sclerosis or dermatomyositis (level 3 [lacking direct] evidence)
  •  based on systematic review of observational studies without comparison groups
  • systematic review of 30 studies evaluating interventions for calcinosis cutis in 288 patients with systemic sclerosis or dermatomyositis
  • studies with < 3 patients were excluded
  • complete response defined as resolution of calcinosis cutis, and partial response defined as any improvement according to study protocol including reduced size of calcium deposits and ulcer healing; studies reporting only pain reduction were included as treatment failures
  • colchicine reported associated with partial response in 2 observational studies
    • 3 of 7 patients (43%) in 1 study (including 1 complete response)
    • 1 of 9 patients (11%) in 1 study
  • Reference – J Am Acad Dermatol 2020 Feb;82(2):317
• cyclophosphamide reported to resolve calcinosis cutis at 12-24 months in 9 of 14 patients (64%) with refractory or severe juvenile dermatomyositis in cohort study; no other studies evaluating cyclophosphamide found in systematic review of 30 studies (J Am Acad Dermatol 2020 Feb;82(2):317)
• IV ceftriaxone 2 g/day for 20 days reported to resolve calcinosis cutis on arms, chest, and left thigh within weeks in 16-year-old boy with morphea profunda in case report (J Am Acad Dermatol 2010 Aug;63(2):e53) – see also Ceftriaxone
• probenecid reported to improve calcinosis and normalize serum phosphorus and disability (reduced range of motion in knees) at 17 months in 11-year-old boy with juvenile dermatomyositis in case report (J Rheumatol 2006 Aug;33(8):1691)

Surgery and Procedures

Excision or Curettage

• surgical excision of calcinosis cutis may be indicated in patients with^(1,2)
  • localized calcium deposits
  • idiopathic calcinosis cutis (first-line treatment)
  • pain
  • recurrent infections
  • ulceration
  • impaired mobility
  • large, localized, and symptomatic calcinosis lesions particularly if located over tendons, blood vessels, or nerves
• surgical excision reported to improve and resolve calcinosis cutis in most patients with systemic sclerosis or dermatomyositis (level 3 [lacking direct] evidence)
  •  based on systematic review of mostly observational studies without comparison groups
  • systematic review of 30 studies evaluating interventions for calcinosis cutis in 288 patients with systemic sclerosis or dermatomyositis
  • studies with < 3 patients were excluded
  • complete response defined as resolution of calcinosis cutis, and partial response defined as any improvement according to study protocol including reduced size of calcium deposits and ulcer healing; studies reporting only pain reduction were included as treatment failures
  • surgical excision evaluated in 2 studies with 38 adults (10 with systemic sclerosis, 28 unspecified underlying condition); follow-up range duration range was 104 months in 1 study with 28 adults and 0.1 month in 1 study with 10 adults)
  • excision reported associated with
    • partial response in 80%-96% of patients in 2 studies
    • complete response in 22 of 28 patients (79%) in 1 study (not reported in other study)
  • Reference – J Am Acad Dermatol 2020 Feb;82(2):317
• high-speed burr debulking reported to yield patient satisfaction ratings of “very satisfied” or “somewhat satisfied” in 44.4% of patients with digital calcinosis and scleroderma; satisfaction reported associated with single digit involvement
  •  based on retrospective case series
  • 9 adults with scleroderma received high-speed burr debulking procedure for digital calcinosis and were followed for mean 2 years (range 18-30 months)
    • high speed burr introduced into calcium deposit to fragment or liquefy deposit
    • remnants extracted by expression, micro-curettes and irrigation
  • calcinosis was bilateral in 8 patients, mean number of digits involved was 2 (range 1-4 digits); 7 patients had ulceration
  • disability assessed with Disabilities of the Arm, Shoulder, and Hand (DASH; score range 0-100)
  • outcomes at follow-up
    • no patient had complete resolution of calcinosis
    • 4 of 9 patients (44.4%) were very or somewhat satisfied with procedure
    • patient satisfaction associated with single-finger involvement compared to multidigit involvement (p = 0.02)
    • 7 patients reported decreased load of calcinosis; recurrence occurred in all 7 patients, of these
      • late recurrence to small degree in 3 patients
      • early complete recurrence in 3 patients
      • recurrence with unknown onset in 1 patient
    • complications reported in 6 patients (8 total complications) including weakness, decreased motion, numbness, and superficial wound infection
  • Reference – J Hand Surg Am 2014 Mar;39(3):503
• excision of isolated calcified masses, bisphosphonate for 6 months, ceftriaxone for 30 days, diltiazem for > 1 year, and intralesional corticosteroids reported not effective for preventing progression of extensive calcinosis cutis universalis in 37-year-old woman with systemic lupus erythematosus in case report (Kaohsiung J Med Sci 2014 Dec;30(12):639full-text)

Laser Treatment

• ablative treatment laser therapy reported as a treatment strategy for management of small and digital calcinosis⁽¹⁾
• laser treatment reported to induce complete response in 57% and partial response in 14% of patients with calcinosis cutis (level 3 [lacking direct] evidence)
  •  based on noncomparative data in systematic review of mostly observational studies
  • systematic review of 40 studies (1 pilot trial, 7 case series, 27 case reports, and 5 conference abstracts) evaluating interventions for calcinosis cutis in 136 patients
  • 52% of patients had systemic sclerosis, 12% had dermatomyositis or juvenile dermatomyositis, and 5% had overlap syndrome
  • treatments evaluated were topical and intralesional sodium thiosulfate, extracorporeal shockwave lithotripsy (ESWL), and laser treatment
  • complete response was defined as 100% resolution of calcifications; partial response was defined as any response other than 0% and 100% resolution
  • laser treatment was evaluated in 12 studies with 21 patients (maximum lesion diameter was ≤ 2 cm where reported); therapy was given using CO₂ laser, erbium-doped yttrium aluminium garnet (Er:YAG) laser, or picosecond plus CO₂ laser
  • laser treatment associated with
    • complete response in 57%
    • partial response in 14%
  • adverse events with laser treatment included scarring or hyperkeratosis in 10 patients and infection, recurrence, hypopigmentation, and itching or burning in 2 patients each
  • Reference – Arch Dermatol Res 2022 Aug;314(6):515full-text
  • similar results in older systematic review (J Am Acad Dermatol 2020 Feb;82(2):317)

Extracorporeal Shock Wave Lithotripsy (ESWL)

• ESWL is reported to reduce pain associated with calcinosis in observational studies⁽¹⁾
• ESWL reported to induce complete response in 9% and partial response in 55% of patients with calcinosis cutis (level 3 [lacking direct] evidence)
  •  based on noncomparative data in systematic review of mostly observational studies
  • systematic review of 40 studies (1 pilot trial, 7 case series, 27 case reports, and 5 conference abstracts) evaluating interventions for calcinosis cutis in 136 patients
  • 52% of patients had systemic sclerosis, 12% had dermatomyositis or juvenile dermatomyositis, and 5% had overlap syndrome
  • treatments evaluated were topical and intralesional sodium thiosulfate, ESWL, and laser treatment
  • complete response was defined as 100% resolution of calcifications; partial response was defined as any response other than 0% and 100% resolution
  • ESWL was evaluated in 4 studies with 11 patients (maximum lesion diameter was < 20 cm)
  • ESWL associated with
    • complete response in 9%
    • partial response in 55%
  • adverse events with ESWL included transient fever in 1 patient
  • Reference – Arch Dermatol Res 2022 Aug;314(6):515full-text
  • similar results in older systematic review (J Am Acad Dermatol 2020 Feb;82(2):317)

Hematopoietic Stem Cell Transplant (HSCT)

• HSCT has been a proposed strategy for calcinosis cutis based on results extrapolated from other severe and recalcitrant connective tissue diseases (J Am Acad Dermatol 2012 Jun;66(6):1004)
• HSCT reported to resolve soft tissue calcification in patients with severe refractory systemic lupus erythematosus and calcinosis or calciphylaxis (level 3 [lacking direct] evidence)
  •  based on uncontrolled trial
  • 3 patients (ages 15, 17, and 35 years; all female) with severe and refractory skin manifestations of system lupus erythematosus (SLE) received high-dose cyclophosphamide, antithymocyte globulin, and HSCT and were followed for 26-38 months
  • 1 patient with end-stage renal disease (ESRD) had calciphylaxis (bilateral proximal and distal on all extremities), 2 patients had bilateral calcinosis cutis in multiple areas (indication for HSCT in these patients was cutaneous vasculitis, plus cerebritis in 1 patient)
  • excellent clinical response to HSCT reported in all 3 patients; HSCT reported to
    • resolve calciphylaxis at 18 months in 15-year-old girl with ESRD and SLE; at 2 year follow-up (after kidney transplant) scars present but no wounds or ulcerations, no analgesia, and normal performance status reported
    • persistently resolve or significantly improve calcinosis in other 2 patients at 1 year follow-ups
  • Reference – Nephrol Dial Transplant 2008 Aug;23(8):2679
• autologous stem cell transplant for pulmonary hypertension reported to completely resolve diffuse calcinosis with persistent results at 2 year follow-up in 12-year-old girl with severe autoimmune disease (Bone Marrow Transplant 2004 Jun;33(12):1257)
• autologous stem cell transplant reported to persistently resolve disease in 2 pediatric patients with severe progressive juvenile dermatomyositis in case series (Scand J Rheumatol 2010;39(1):88)
• review of HSCT for autoimmune diseases can be found in Nat Rev Rheumatol 2017 Apr;13(4):244

Complications

• calcinosis cutis involving large areas of body surface may lead to any of the following⁽¹⁾
  • muscle atrophy
  • joint contracture
  • cutaneous ulceration, which may lead to secondary infection
• calcinosis associated with juvenile dermatomyositis may lead to calcinosis universalis, which describes widespread calcinosis and exoskeleton formation that may lead to severe impairment of mobility ⁽¹⁾

Prognosis

• the prognosis of calcinosis cutis depends on the type and underlying condition (if present)
• overall mortality of 5.7% reported among adults hospitalized with dermatomyositis with calcinosis
  •  based on retrospective cohort study
  • 627 adults hospitalized with dermatomyositis were assessed
  • 5.6% (71% female) had calcinosis
    • locations of calcinosis cutis were proximal limbs (60%), trunk (40%), buttock (20%), axilla (14.3%), groin (8.6%), joint (2.9%), and neck (2.9%)
    • all patients were treated with prednisone and ≥ 1 immunosuppressant
  • median follow-up of 5.4 years
  • among patients with calcinosis, overall mortality 5.7%
  • comparing clinical features in patients with calcinosis vs. without calcinosis
    • mean age at disease onset 35.8 years vs. 48.6 years (odds ratio [OR] 0.95, 95% CI 0.93-0.97)
    • dysphagia in 68.6% vs. 24.5% (OR 2.61, 95% CI 1.19-5.73)
    • skin ulcer in 42.9% vs. 10.6% (OR 5.71, 95% CI 3.04-10.71)
    • presence of antinuclear matrix protein 2 antibody in 57.1% vs. 5.1% (OR 5.92, 95% CI 2.75-12.71)
  • no significant difference in mortality in patients with dermatomyositis with or without calcinosis
  • among 33 surviving patients with calcinosis, secondary complications reported in 17.1% including local pain, skin ulcer, and secondary skin infection
  • Reference – Rheumatology (Oxford) 2021 Jun 18;60(6):2958

Prevention and Screening

Prevention

• no specific measures to prevent calcinosis cutis except adequate prevention and treatment of underlying causes and risk factors^(1,2)

Screening

• actively evaluate all patients with juvenile dermatomyositis for calcinosis cutis (Expert Grade 4D)
  • palpation is recommended for assessment (Single Hub and Access Point for Pediatric Rheumatology in Europe [SHARE] consensus-based recommendations on management of juvenile dermatomyositis)
  • Reference – Ann Rheum Dis 2017 Feb;76(2):329full-text

Guidelines

United States Guidelines

• American Academy of Neurology evidence-based guideline on IV immunoglobulin in treatment of neuromuscular disorders can be found in Neurology 2012 Mar 27;78(13):1009, commentary can be found in Neurology 2012 Sep 25;79(13):1411;author reply 1411full-text

European Guidelines

• European Dermatology Forum/European Academy of Dermatology and Venereology (EDF/EADV) guideline on use of high-dose IV immunoglobulin in dermatology can be found in J Eur Acad Dermatol Venereol 2016 Oct;30(10):1657full-text
• Single Hub and Access Point for Pediatric Rheumatology in Europe (SHARE) consensus-based recommendations on management of juvenile dermatomyositis can be found in Ann Rheum Dis 2017 Feb;76(2):329full-text

Asian Guidelines

• Japanese Society of Neurology/Japanese Dermatological Association/Japan College of Rheumatology (JSN/JDA/JCR) treatment consensus statement on management of polymyositis and dermatomyositis among rheumatologists, neurologists and dermatologists can be found in J Dermatol 2019 Jan;46(1):e1
• Japanese Dermatological Association (JDA) guideline on wounds/burns: management of skin ulcers associated with connective tissue disease/vasculitis can be found in J Dermatol 2016 Jul;43(7):729

Review Articles

• reviews can be found in
  • Actas Dermosifiliogr 2015 Dec;106(10):785
  • Curr Opin Rheumatol 2015 Nov;27(6):542
• review of treatment of calcinosis cutis in systemic sclerosis and dermatomyositis can be found in J Am Acad Dermatol 2020 Feb;82(2):317
• review of calcinosis in scleroderma can be found in Curr Opin Rheumatol 2018 Nov;30(6):554
• review of idiopathic calcinosis cutis of the vulva can be found in J Low Genit Tract Dis 2019 Jan;23(1):75
• review of skin manifestations of systemic sclerosis can be found in Clin Dermatol 2018 Jul ;36(4):459
• review of calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia (CREST syndrome) can be found in J Clin Rheumatol 2017 Aug;23(5):285
• review of calcinosis biomarkers in dermatomyositis can be found in Autoimmun Rev 2020 Jun;19(6):102533
• case report of magnetic resonance imaging findings of calcinosis cutis in primary Sjogren syndrome in 47-year-old woman can be found in Radiol Case Rep 2020 Jul;15(7):1029full-text
• case report of calcinosis cutis associated with chronic sclerodermoid graft versus host disease in 59-year-old man can be found in 
•  Case Rep Dermatol Med 2020;2020:9250923full-text
• case presentation of facial calcinosis cutis associated with systemic lupus erythematosus in 25-year-old woman can be found in JAAD Case Rep 2017 Sep;3(5):460full-text
• idiopathic calcinosis cutis case reports
  • case report of idiopathic calcinosis cutis in both hands of 52-year-old woman can be found in Cureus 2020 Mar 30;12(3):e7471full-text
  • case report of idiopathic scrotal calcinosis can be found in Open Access Maced J Med Sci 2018 Jan 25;6(1):108 full-text
  • case report of diffuse idiopathic calcinosis cutis in 59-year-old woman can be found in Eurasian J Med 2014 Jun;46(2):131full-text
• MEDLINE Search
• to search MEDLINE for (Calcinosis cutis) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis
• Patient Information
• handout from DermNet NZ
• handout on dystrophic calcinosis from Myositis Association
• References
• General References Used
• Jiménez-Gallo D, Ossorio-García L, Linares-Barrios M. Calcinosis Cutis and Calciphylaxis. Actas Dermosifiliogr. 2015 Dec;106(10):785-94.
• Valenzuela A, Song P, Chung L. Calcinosis in scleroderma. Curr Opin Rheumatol. 2018 Nov;30(6):554-561.