Calcinosis Cutis


Article Author:
Cuong Le


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Paul Bedocs


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Sisira Reddy
Joseph Nahas
Chokkalingam Siva


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James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
9/5/2019 4:04:29 PM

Introduction

Calcinosis cutis is a condition in which calcium salts are deposited in the skin and subcutaneous tissue. It is classified into five main types: dystrophic, metastatic, idiopathic, iatrogenic, and calciphylaxis. Dystrophic calcification is the most common cause of calcinosis cutis and is associated with normal laboratory values of calcium and phosphorus. There is an underlying disease, systemic sclerosis, dermatomyositis, mixed connective tissue disease, or lupus, that induces tissue damage and creates a nidus for calcification. Metastatic calcification has abnormal serum levels of calcium and phosphorus with deposition occurring after calcium phosphate product exceeds 70. Idiopathic calcification has no underlying tissue damage or abnormal laboratory values. It includes tumoral calcinosis, subepidermal calcified nodules, and scrotal calcinosis. Iatrogenic calcification is caused by administration of calcium or phosphate containing agent and inducing precipitation of calcium salts. Calciphylaxis involves calcification of small and medium-sized vessels and is associated with chronic renal failure and dialysis. The disorder is classified as calcinosis circumscripta if it is limited to an extremity or joint. Calcinosis universalis occurs when there is diffuse involvement of subcutaneous and fibrous structures of muscles and tendons. [1]

Etiology

Calcinosis may be caused by trauma, inflammation, varicose veins, tumors, infections, connective tissue disease, hyperphosphatemia, and hypercalcemia. Calcinosis cutis is associated with systemic sclerosis.

Epidemiology

Calcinosis cutis commonly occurs in patients with systemic sclerosis, especially the limited form (CREST). Twenty-five percent to 40% of patients with limited systemic sclerosis will develop calcinosis cutis ten years after the onset of disease. Calcinosis cutis is seen in 30% of adults and up to 70% of children and adolescents with dermatomyositis. Patients with systemic lupus erythematosus can present with periarticular calcification in 33% of cases and soft tissue calcification in 17%. [2]

Pathophysiology

Dystrophic Calcification

Dystrophic calcification is the most common type of calcinosis cutis. Serum calcium and phosphorus levels are normal. This condition is characterized by tissue damage that leads to the release of phosphate-binding proteins by dying cells. The phosphate-binding protein binds phosphate and results in calcification. This tissue damage also results in chronic inflammation and vascular hypoxia. High mitochondrial calcium and phosphate levels are released that further lead to crystal formation and cell necrosis. Tumor necrosis factor (TNF), IL-6, IL-1B, contribute to the formation of the calcium salts. The calcium salts are composed of hydroxyapatite and amorphous calcium phosphate. Dystrophic calcification is associated with diseases that lead to connective tissue damage. The most common diseases are systemic sclerosis, dermatomyositis, and systemic lupus erythematosus. It has also been reported in rheumatoid arthritis, scleroderma, and Sjogren syndrome. Rarely it is seen in porphyria cutanea tarda. Dystrophic calcification is seen in elastic pseudoxanthoma, Werner syndrome, Ehlers-Danlos, pilomatrixoma, trichilemmal cyst, basal cell carcinoma, trichoepitheliomas, pancreatic and lupus panniculitis, onchocerciasis, cysticercosis, histoplasmosis, cryptococcosis, trauma, and burns.

Metastatic Calcification

Metastatic calcification is deposition of calcium salts in the presence of abnormal serum calcium and phosphorus levels. Calcium deposition occurs when the calcium phosphate product exceeds 70 mg^2/dL^2. These abnormal levels precipitate the calcium salts and resolve with correction of the calcium and phosphorus levels. These deposits are usually located in periarticular regions. The most common cause of metastatic calcification is chronic kidney failure. Other causes include hypervitaminosis D, hyperparathyroidism, sarcoidosis, milk-alkali syndrome, and malignant neoplasms. Milk-alkali syndrome occurs with excessive ingestion of foods or antacids that contain calcium.

Idiopathic Calcification

Idiopathic calcification occurs when there is deposition of calcium salts without underlying tissue damage or abnormal calcium or phosphorus levels. There are three types: familial tumoral calcinosis, subepidermal calcified nodules, and scrotal calcinosis. Familial tumoral calcinosis is seen in healthy adolescent patients. There is increased uptake of phosphate in the proximal tubule of the kidney. Calcification occurs around major joints and can be subcutaneous or intramuscular. Subepidermal calcified nodules or Winder nodular calcinosis presents in children and can present at birth. It occurs on the head and extremities as solitary, hard, white-yellow papules. Scrotal calcinosis presents as nodules and masses on the scrotum. There is controversy about its etiology and whether the nodules are from calcification of epidermal cysts. Patients are usually asymptomatic, but pruritis or white chalky discharge can occur.

Iatrogenic Calcification

Iatrogenic calcification occurs in patients that are receiving calcium or phosphate containing substances. It has been seen with intravenous calcium gluconate, calcium chloride, and para-aminosalicylic acid during the treatment of pulmonary tuberculosis. It is also seen after administration of electrodes with pastes containing calcium chloride for electroencephalography. Tumor lysis syndrome and calcinosis cutis after organ transplant fall under this category. Iatrogenic calcification can be prevented by diluting the calcium solution and lowering phosphorus levels before administration. [3][4][5]

Histopathology

Calcium deposits stain dark blue with hematoxylin and eosin (H and E) and black with von Kossa stains. Fine granules can be seen in the dermis, and large, irregular calcium masses can be seen in the subcutaneous tissue.

History and Physical

Lesions can occur gradually and be asymptomatic, or it can be generalized and more severe. The nodules can vary in shape and size and can be painful leading to functional impairment. The lesions in dystrophic calcification are localized based on the underlying disease. The areas most commonly affected in systemic sclerosis are the forearms, elbows, fingers, and knees. Calcification occurs in elbows and knees and areas of previous inflammatory lesions in dermatomyositis. The extremities, buttocks, underneath lupus lesions, and periarticular areas are affected in lupus erythematosus. Lesions are located periarticular in metastatic calcification. The lesions are located around joints in tumoral calcinosis and on children's faces in subepidermal calcified nodules in idiopathic calcification. The calcification is located at sites of venipuncture in iatrogenic calcification.

Evaluation

Laboratory studies and imaging should be done to evaluate the condition and the extent of the disease as well as the possible etiology. A complete blood count should be obtained for lupus erythematosus and possible malignant neoplasms. A basic metabolic panel with creatinine and urea can be obtained to evaluate for chronic kidney failure. Parathyroid hormone and vitamin D level are done to rule out hyperparathyroidism and hypervitaminosis D. Calcium, phosphate, total proteins, albumin, 24 h urine excretion of calcium/inorganic phosphate levels should be obtained for metastatic calcification. Creatine phosphokinase (CPK), lactate dehydrogenase (LDH), glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and aldolase levels should be obtained to evaluate for dermatomyositis. Antinuclear antibodies (ANA), anti-dsDNA, and anti-ENA for lupus and systemic sclerosis. Anti-ENA looks at Ro, La, Sm, RNP, Scl-70, Jo1. Bicarbonate and arterial pH can be obtained to rule out milk and alkali syndrome.

Other studies should include x-ray, skin ultrasound, bone scintigraphy, CT and MRI, and skin biopsy.[6]

Treatment / Management

Treatment for calcinosis cutis can be challenging. Steps can be taken to help facilitate treatment and increase blood flow to the extremities. These include avoiding trauma, smoking cessation, decrease stress and exposure to the cold. Smaller lesions have been reported to respond to warfarin, ceftriaxone, and intravenous immunoglobulin (IVIG). Surgical excision and carbon dioxide laser can also be used. Larger lesions respond to diltiazem, bisphosphonates, probenecid, aluminum hydroxide, and surgical excision or curettage. Patients with small and localized lesions are good candidates for surgical treatment whereas more generalized disease will require medical management.

Diltiazem

Diltiazem is the most commonly used treatment for calcinosis cutis. It decreases the amount of calcium that enters cells and macrophages of the damaged tissues. High doses at 2 mg/kg/d to 4 mg/kg/d are necessary for therapeutic response.

Warfarin

Vitamin K levels have been measured to be high in some patients with calcinosis cutis, and the use of warfarin 1 mg/d normalizes the levels and has some improvement for small lesions. 

Bisphosphonates

Bisphosphonates work on macrophages which are active at the affected sites. It prevents the release of proinflammatory cytokines. It also reduces calcium turnover and resorption. Bisphosphonates show good response mainly in dermatomyositis and systemic sclerosis. Etidronate is used at 800 mg/d. Oral alendronate is used at 70 mg/wk, and pamidronate is used at 90 mg/wk. Their side effects include osteonecrosis of the jaw, fever, infusion site reaction, and low levels of calcium, phosphate, and magnesium.

Minocycline

Minocycline inhibits matrix metalloproteinases which reduce inflammation and ulceration and also chelates calcium. The drug is used at 50 mg to 100 mg/d and is seen to be effective in systemic sclerosis.

Ceftriaxone

Ceftriaxone effects matrix metalloproteinases, chelates calcium, and is anti-inflammatory. It is used at 2 g/d for 20 days and is best used in morphea profunda.

Aluminum Hydroxide 

Aluminum hydroxide binds phosphorus and reduces the intestinal absorption of phosphorus. It is used at doses of 2.24 g/d, 2.4 g/d, and 1.8 g/d for calcinosis cutis in dermatomyositis and lupus.

Probenecid

Probenecid inhibits uric acid reuptake in the proximal tubule and increases renal phosphate excretion. It is used at 1.5 g/d and response is seen in juvenile dermatomyositis.

Topical Sodium Thiosulfate

Sodium thiosulfate is used because it increases calcium solubility. Topical sodium thiosulfate mixed with zinc oxide has been used successfully in ulcerated dystrophic calcification. Intralesional injections of sodium thiosulfate were shown to be successful in calcinosis cutis in a patient with lupus panniculitis. Intravenous sodium thiosulfate has been effective in treatment calciphylaxis and calcinosis cutis but is associated with more adverse side effects.

Other Treatments

Colchicine has been used due to its anti-inflammatory properties. IVIG at a dose of 2 g/kg has been shown to work in digital calcification in CREST syndrome and dermatomyositis. Intralesional corticosteroid injections have been used for limited systemic sclerosis. Extracorporeal shockwave lithotripsy has been used with good clinical response. Surgical excision is the most common method used. Carbon dioxide laser light has been effective in treating small lesions and lesions on the digits.[7][8][9]

Pearls and Other Issues

Calciphylaxis is a disease of calcification of small and medium-sized vessels that lead to ischemia and necrosis of the overlying skin. It is seen in patients with chronic renal failure and on dialysis but can also occur in those with normal kidney functions. This disease entity will be discussed elsewhere.

Enhancing Healthcare Team Outcomes

The diagnosis and management of calcinosis cutis are not simple because there are many causes. It is best managed by an interprofessional team that includes an internist, nephrologist, primary care provider, a rheumatologist, endocrinologist, and specialty care nurse. The interprofessional team can optimize the treatment of these patients through communication and coordination of care. Primary care physicians, dermatologist, and nurse practitioners provide diagnoses and care plans. Specialty care nurses should work with the team for coordination of care and are involved in patient education. Pharmacists should evaluate medications prescribed, recognize drug-drug interactions, provide patient education, and monitor compliance. The interprofessional team can thus improve outcomes for patients with calcinosis cutis. 

The treatment is challenging and depends on the cause. The key is to avoid trauma, smoking cessation, decrease stress and exposure to the cold. Smaller lesions have been reported to respond to warfarin, ceftriaxone, and intravenous immunoglobulin (IVIG). Surgical excision and carbon dioxide laser can also be used. Larger lesions respond to diltiazem, bisphosphonates, probenecid, aluminum hydroxide, and surgical excision or curettage. Patients with small and localized lesions are good candidates for surgical treatment whereas more generalized disease will require medical management. The outcomes for most patients are guarded because the condition has no cure.[10][11] (Level V)


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Calcinosis Cutis - Questions

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A 56-year-old female with renal failure was hospitalized because she missed two of her dialysis days due to lack of transport. The patient received her first dialysis treatment the day before and is doing much better in the hospital, but she developed a rash on her flank that is tender to the touch. She states it started four days ago and was much smaller than it was now. Physical exam shows a 4 cm x 5 cm black-purple retiform purpura with central eschar on the left flank that is tender to touch. Which of the following is the next best step in the management of this patient?



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A 65-year-old female with a past medical history of chronic kidney disease presents with muscle weakness and palpitations. On the physical exam, she is diaphoretic but otherwise doing well. An EKG and blood work is done, revealing a potassium level of 7.7 mEq/L. The patient is treated accordingly with intravenous medications. Four days later, the patient complains of abdominal pain. The physical exam, reveals a purple retiform plaque with a central ulcer measuring 1.5x1 cm on the right lower abdomen. What is the most likely cause of this patient's symptoms?



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A 33-year-old white female presents to the clinic because her hands are changing color. She states that it started when she was a teenager but has gotten worse. It is exacerbated by the cold. Her hands go from pale white to blue to red, and it involves the third, fourth, and fifth fingers bilaterally. Physical exam shows multiple hard 8 mm papules on both arms. White chalky material is expressed from the papules. Her arms have a taut shiny appearance. What antibodies are most likely to be present in this patient?



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Calcinosis Cutis - References

References

Calcinosis Cutis and Calciphylaxis., Jiménez-Gallo D,Ossorio-García L,Linares-Barrios M,, Actas dermo-sifiliograficas, 2015 Dec     [PubMed]
Calcinosis: pathophysiology and management., Valenzuela A,Chung L,, Current opinion in rheumatology, 2015 Nov     [PubMed]
Intralesional Sodium Thiosulfate Treatment for Calcinosis Cutis in the Setting of Lupus Panniculitis., Gunasekera NS,Maniar LEG,Lezcano C,Laga AC,Merola JF,, JAMA dermatology, 2017 May 31     [PubMed]
Iatrogenic Calcinosis Cutis Successfully Treated with Topical Sodium Thiosulfate., García-García E,López-López R,Álvarez-Del-Vayo C,Bernabeu-Wittel J,, Pediatric dermatology, 2017 May     [PubMed]
Scrotal calcinosis: pathogenetic link with epidermal cyst., Solanki A,Narang S,Kathpalia R,Goel A,, BMJ case reports, 2015 Sep 23     [PubMed]
Extensive calcinosis cutis universalis in a patient with systemic lupus erythematosus: 10-year treatment experience., Huang HL,Wu WT,Ou TT,, The Kaohsiung journal of medical sciences, 2014 Dec     [PubMed]
Diffuse idiopathic calcinosis cutis in an adult: a rare case., Prabhu R,Sarma YS,Phillip K,Sadhu S,, The Eurasian journal of medicine, 2014 Jun     [PubMed]
Calcinosis cutis: part II. Treatment options., Reiter N,El-Shabrawi L,Leinweber B,Berghold A,Aberer E,, Journal of the American Academy of Dermatology, 2011 Jul     [PubMed]
Calcinosis cutis: part I. Diagnostic pathway., Reiter N,El-Shabrawi L,Leinweber B,Berghold A,Aberer E,, Journal of the American Academy of Dermatology, 2011 Jul     [PubMed]
Li G,Adachi JD,Cheng J,Thabane L,Hudson M,Fritzler MJ,Lorenzi S,Baron M,Larché M, Relationship between calcium channel blockers and skin fibrosis in patients with systemic sclerosis. Clinical and experimental rheumatology. 2017 Sep-Oct;     [PubMed]
Valenzuela A,Chung L,Casciola-Rosen L,Fiorentino D, Identification of clinical features and autoantibodies associated with calcinosis in dermatomyositis. JAMA dermatology. 2014 Jul;     [PubMed]

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