Calcinosis cutis: Management

INTRODUCTION — The term "calcinosis cutis" describes the deposition of insoluble calcium salts in the skin and subcutaneous tissue. There are five subtypes of calcinosis cutis (see "Calcinosis cutis: Etiology and patient evaluation", section on 'Subtypes'):

●Dystrophic calcinosis cutis

●Metastatic calcinosis cutis

●Idiopathic calcinosis cutis

●Iatrogenic calcinosis cutis

●Calciphylaxis

The treatment of calcinosis cutis is often challenging, and the subtype influences the approach to treatment. Potential interventions include treatment for an underlying disease, medication to reduce calcium deposits or associated inflammation, and surgical removal of calcium deposits.

The management of the various subtypes of calcinosis cutis will be reviewed here. The diagnosis and evaluation of patients with calcinosis cutis is discussed separately. (See "Calcinosis cutis: Etiology and patient evaluation".)

DYSTROPHIC CALCINOSIS CUTIS — Dystrophic calcinosis cutis, the most common form of calcinosis cutis, results from local tissue injury. Dystrophic calcinosis cutis most frequently occurs in association with autoimmune connective tissue diseases (particularly systemic sclerosis and dermatomyositis); therefore, the treatment of this presentation will be reviewed here. Less common causes include lobular panniculitides, porphyria cutanea tarda, select genodermatoses, cutaneous neoplasms, traumatic injury, and parasitic infections. (See "Calcinosis cutis: Etiology and patient evaluation", section on 'Dystrophic calcinosis cutis'.)

Treatment principles — The treatment of dystrophic calcinosis cutis associated with autoimmune connective tissue disease is often difficult. Therefore, for many patients, the primary goal of treatment is to minimize symptoms and alleviate functional limitations rather than the complete resolution of cutaneous calcification [1].

Management typically begins with consideration of two questions:

●Is the underlying autoimmune connective tissue disease adequately treated?

●Do the signs and symptoms of calcinosis cutis warrant treatment?

Treatment of underlying disease — Suppression of activity of the associated autoimmune disease is suggested based upon the theory that autoimmune disease-related tissue injury contributes to risk for cutaneous calcification (algorithm 1) [2].

Treatment of calcinosis — Treatment of calcinosis cutis associated with autoimmune connective tissue diseases involves careful consideration of the need for treatment and the selection of an appropriate treatment regimen.

Approach

●Decision to treat – Consideration of the severity of the signs and symptoms of calcinosis cutis is important because the response to treatment is variable and unpredictable, and there is risk for treatment-related adverse effects. Clinical follow-up without intervention to reduce calcium deposits is a reasonable option for calcinosis cutis that is asymptomatic, nonprogressive, unassociated with internal involvement, and of minimal concern to the patient.

●Treatment selection – Once the decision is made to pursue treatment, the challenge is to determine the best initial treatment regimen. Although responses to a wide variety of therapies are documented in the literature, data are insufficient for determining the most effective treatment pathway. Patient-specific factors, such as comorbidities and tolerance for specific interventions, influence treatment selection:

•Drug therapy – Pharmacologic options include drugs that influence calcium or phosphorus metabolism, reduce associated inflammation, or act through unclear mechanisms. Compared with larger calcium deposits, small calcium deposits may respond better to pharmacologic therapy [3]. (See 'Drug therapy' below.)

•Surgery – Surgical removal of calcinosis may be useful for patients with discrete, symptomatic areas of calcinosis cutis as the primary treatment or as an adjunct to medical therapy. Although early reports documenting poor wound healing and sinus track formation led to the historical avoidance of surgical procedures for dystrophic calcinosis cutis, subsequent reports suggest that surgery can be effective for some patients. (See 'Role of surgery' below.)

●Duration of therapy – Patients who respond to systemic pharmacologic therapies for calcinosis cutis are often maintained on continuous or intermittent treatment for months to years in an attempt to reduce risk for recurrence of disease. The ideal duration of medical treatment for calcinosis cutis is unclear.

Drug therapy — Efficacy data for all therapies for calcinosis cutis are limited. Our preferred initial treatment for dystrophic calcinosis cutis associated with autoimmune connective tissue disease is topical or intralesional sodium thiosulfate based upon the limited data that suggest efficacy and relative safety of this intervention (algorithm 1). (See 'Topical or intralesional sodium thiosulfate' below.)

Systemic therapies, such as diltiazem, colchicine, and minocycline, are an option for patients in whom the number or extent of lesions makes local therapy impractical and patients who do not respond to or cannot access topical or intralesional sodium thiosulfate. (See 'Alternative drug therapies' below.)

Topical or intralesional sodium thiosulfate — Sodium thiosulfate, an industrial chemical used in the treatment of disorders such as cyanide poisoning, calciphylaxis, and cisplatin toxicity, may be of benefit for calcinosis cutis. Improvement is thought to result from potent antioxidant and vasodilatory properties:

●Administration and precautions – Treatment regimens for sodium thiosulfate vary. Topical and intralesional administration are the primary modes of therapy.

Topical treatment generally consists of twice-daily application of compounded 10 to 25% sodium thiosulfate to the affected areas [4]. Use of higher concentrations has also been reported [5].

Generally, a partial response is seen within the first month or two of therapy, but several months of treatment may be necessary to achieve a complete response [4]. Topical therapy may be most beneficial for very small lesions [5].

Intralesional sodium thiosulfate (150 to 250 mg/mL) is generally administered to individual lesions every one to four weeks until resolution or cessation of improvement. A reasonable initial regimen consists of 150 mg/mL given monthly, with the option to increase the concentration and frequency based on patient tolerance and response [6]. Improvement may be evident within one to four treatments [6-8].

Examples of reported adverse effects of topical or intralesional sodium thiosulfate therapy include skin irritation and pain [4,7,9]. Local infection has also been reported with intralesional therapy, likely due to the development of ulceration in association with softening of calcifications [7]. Adverse effects reported in a case series of three patients who received intravenous sodium thiosulfate therapy for calcinosis cutis include headache, nausea, weakness, fatigue, and central catheter line infections [10]. Metabolic acidosis and other side effects of intravenous sodium thiosulfate are discussed separately. (See "Calciphylaxis (calcific uremic arteriolopathy)", section on 'Side effects'.)

●Efficacy – Data on the efficacy of sodium thiosulfate are limited to case reports and case series [4-6,9,11].

In a systematic review of the literature that identified 42 patients with calcinosis cutis (including 36 patients with dystrophic calcinosis cutis) treated with 10 or 25% topical sodium thiosulfate (or 20 or 25% sodium metabisulfate [which forms a metabolite of sodium thiosulfate in vivo]), 20 percent had a complete response, 58 percent had a partial response, and 22 percent had no response [4]. Mean durations of treatment to achieve complete and partial responses were five and four months, respectively.

In a subsequent, retrospective study of outcomes from topical, intralesional, or intravenous sodium thiosulfate in 80 lesions of calcinosis cutis, lesion size appeared to influence the response to topical therapy [5]. Although twice-daily application of topical sodium thiosulfate serum compounded 50:50 with petrolatum or a bland emollient was associated with resolution of all 53 treated lesions <0.2 cm in size, lower resolution rates occurred for larger lesions.

Reports of intralesional injection of sodium thiosulfate describe varying results [5-7]. In the retrospective study mentioned above, intradermal injection of undiluted sodium thiosulfate (0.1 to 1 mL of sodium thiosulfate 250 mg/mL) administered every three weeks was associated with resolution of 13 of 13 lesions ≤2 cm in size and no response in three larger lesions [5]. In contrast, in a study in which four patients received a total of three, once-monthly treatments with diluted sodium thiosulfate (0.1 mL/cm² of sodium thiosulfate 40 mg/mL) into one calcinosis cutis lesion and saline injection into a second lesion (maximum lesion size 2x2 cm), only one patient had improvement in a sodium thiosulfate-treated lesion [12].

Alternative drug therapies — Systemic therapies, including diltiazem, colchicine, and minocycline, are alternative therapies for calcinosis cutis associated with autoimmune connective tissue disease (algorithm 1).

Selection — Diltiazem is a common systemic treatment for dystrophic calcinosis cutis associated with autoimmune connective tissue disease [13]. Diltiazem inhibits calcium influx in cells, which may support a role in decreasing dystrophic calcification.

Colchicine or minocycline is generally preferred over diltiazem for patients presenting with prominent inflammation or ulceration. Inflammation contributes significantly to the morbidity associated with calcinosis cutis, and limited data suggest the anti-inflammatory effects of these drugs may improve associated symptoms or ulceration [2,14,15]. Varying degrees of improvement in calcium deposits have also been reported in some patients.

Diltiazem

●Administration and precautions – Diltiazem is prescribed most often at a dose of 2 to 4 mg/kg per day and has appeared to be of benefit for patients with dystrophic calcinosis associated with adult and juvenile dermatomyositis [16-18], systemic sclerosis [19], systemic lupus erythematosus [20], lupus panniculitis [21], and mixed connective tissue disease [22]. Our typical dose for adults is 240 mg per day. Improvement may be evident within the first few months of treatment.

Examples of adverse effects of diltiazem include edema, headache, atrioventricular block, bradycardia, hypotension, dizziness, and gastrointestinal symptoms. Risk for adverse effects of diltiazem may be greatest in patients with reduced ventricular function or cardiac conduction abnormalities.

●Efficacy – Efficacy data for diltiazem are limited to case reports and case series, with conflicting conclusions on efficacy [13]. A 2014 review of published cases found benefit of diltiazem documented in slightly more than one-half of reported cases [13].

Support for the drug stems from a retrospective study of patients with calcinosis cutis associated with autoimmune connective tissue disease in which 17 patients were given diltiazem (≤480 mg per day) [1]. Of the 17 patients, 9 had a partial response to diltiazem, 3 had insufficient documentation of the outcome, and the remainder did not respond to therapy. A lower rate of response (as assessed with radiologic examination) was documented in a separate series of adults treated with diltiazem 180 mg per day for subcutaneous calcinosis cutis associated with systemic sclerosis [23]. Slight improvement was evident in only 3 of 12 patients.

There are fewer data on the efficacy of other calcium channel blockers for calcinosis cutis associated with autoimmune connective tissue disease. Partial improvement during amlodipine therapy has been reported in at least one patient [1]. Verapamil (120 mg per day) failed to yield improvement in another patient [24].

Colchicine

●Administration and precautions – Dosing of colchicine for calcinosis cutis is not standardized; our typical regimen for adults is 0.6 mg twice daily.

A clinical response to colchicine may be evident within a few months. Gastrointestinal distress is a common side effect of colchicine that can limit use in some patients. (See "Colchicine: Drug information".)

●Efficacy – Case reports document both treatment success and failure of colchicine for calcinosis cutis [13]. As examples, improvement in inflammation and healing of ulcerations secondary to calcinosis cutis occurred within two months of the start of colchicine (1 mg per day) in a child with systemic sclerosis as well as a child with dermatomyositis [25]. In a separate retrospective study of patients with calcinosis cutis associated with autoimmune connective tissue disease, one of eight patients treated with colchicine (≤1.2 g per day) achieved complete resolution of calcinosis, and two patients achieved a partial response [1].

Minocycline

●Administration and precautions – Doses of minocycline for calcinosis cutis range from 50 to 200 mg per day [26]. Our typical regimen for adults is 100 mg twice daily. Minocycline should not be used for children under the age of nine years because of a potential for permanent tooth discoloration with long-term treatment. Responses may occur within the first several months of treatment [14].

In addition to blue-black discoloration of calcium deposits, other potential side effects of minocycline therapy include dizziness, skin discoloration, a hypersensitivity syndrome, and a lupus-like syndrome. (See "Minocycline (systemic): Drug information".)

●Efficacy – In an open-label study in which nine adult female patients with limited cutaneous systemic sclerosis were treated with minocycline (50 or 100 mg per day), improvement primarily occurring as reduced inflammation or ulceration was noted in eight [14]. More modest reductions in calcium deposits were also detected. Most patients exhibited improvement within several months, and improvement was noted within one month in two patients. Of note, blue-black discoloration of the calcium deposits occurred as a side effect of therapy.

The efficacy of minocycline was also reviewed in a retrospective study that included six patients with calcinosis cutis associated with autoimmune connective tissue disease treated with minocycline (≤200 mg per day) [1]. One patient achieved a partial response, two patients failed to respond, and the response to treatment was unknown for three patients.

Other drug therapies — Multiple other treatments have been used for dystrophic calcinosis cutis. Like diltiazem, colchicine, and minocycline, these treatments have limited or conflicting efficacy data. Examples include warfarin [27], bisphosphonates [28-31], intravenous immune globulin [32,33], oral aluminum hydroxide [2], intralesional corticosteroids [34], ceftriaxone [35], probenecid [36], infliximab [37], rituximab [26], and intravenous immunoglobulins [38,39].

Intravenous sodium thiosulfate therapy is documented in case reports, with varying responses to therapy [5,10,40,41]. The limited and conflicting efficacy data preclude a recommendation for the routine use of this therapy.

Role of surgery — Surgery is an additional primary or adjunctive treatment option for discrete, symptomatic areas of calcinosis cutis (algorithm 1) [1]. Surgical procedures may yield pain relief and improvement in functional limitations [42].

Data on surgical therapy are primarily limited to small case series and case reports. Surgical procedures that have been beneficial include surgical excision [43], surgical excision with local fasciocutaneous flap [3], debulking with a high-speed burr [44], incision and drainage [45], and carbon dioxide (CO₂) laser vaporization [46]. Risks of surgical intervention include recurrence, poor wound healing, infection, and sinus formation [3].

METASTATIC CALCINOSIS CUTIS — Metastatic calcinosis cutis results from an underlying defect in the metabolism of calcium or phosphorus, leading to precipitation of calcium in cutaneous or subcutaneous tissues and other sites. The most common cause of metabolic calcinosis cutis is chronic renal failure.

Because the underlying defect is the cause of metastatic calcinosis cutis, treatment focuses on correcting the calcium phosphate product [47]. The management of mineral disorders in chronic kidney disease is reviewed separately. (See "Overview of the management of chronic kidney disease in adults", section on 'Mineral and bone disorders (MBD)' and "Pediatric chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

IDIOPATHIC CALCINOSIS CUTIS — Idiopathic calcinosis cutis consists of a group of disorders in which calcium deposition occurs in the skin in the absence of tissue injury or a metabolic disorder. Examples include idiopathic calcification of the scrotum, subepidermal calcified nodule, and tumoral calcinosis. (See "Calcinosis cutis: Etiology and patient evaluation", section on 'Idiopathic calcinosis cutis'.)

Treatment of idiopathic calcinosis cutis is not necessary in asymptomatic patients who are not bothered by the condition. If treatment is desired, surgical excision is the treatment of choice. Of note, subepidermal calcified nodules often spontaneously resolve when the nodule ulcerates and eliminates calcium transepidermally.

IATROGENIC CALCINOSIS CUTIS — Iatrogenic calcinosis most frequently results from extravasation of intravenous calcium gluconate, calcium chloride, or phosphate-containing solutions into the skin. Observation without intervention is a reasonable initial approach for asymptomatic lesions because of the potential for spontaneous resolution within six months [48,49].

Treatments for dystrophic calcinosis cutis may be attempted for symptomatic iatrogenic calcinosis cutis; however, data confirming the efficacy of these interventions are lacking. Topical sodium thiosulfate therapy has been suggested based upon case reports that describe resolution of new-onset iatrogenic calcinosis cutis within four to six months during treatment with 10 or 25% topical sodium thiosulfate [50-52]. (See 'Topical or intralesional sodium thiosulfate' above.)

CALCIPHYLAXIS — Calciphylaxis is a life-threatening, calcific vasculopathy that can affect skin, subcutaneous tissue, and internal organs. The disorder usually occurs in the setting of end-stage kidney disease. Treatment of calciphylaxis is difficult, and many patients die within a few months of diagnosis. Infection of ulcerated areas leading to sepsis is a common cause of mortality. (See "Calciphylaxis (calcific uremic arteriolopathy)".)

The treatment of patients with calciphylaxis requires a multi-interventional approach that includes wound care, pain control, prompt treatment of infection, correction of abnormalities in plasma calcium and phosphorus concentrations, avoidance of local tissue trauma, and other interventions. The treatment of calciphylaxis is reviewed separately. (See "Calciphylaxis (calcific uremic arteriolopathy)", section on 'Treatment' and "Calciphylaxis (calcific uremic arteriolopathy)", section on 'Prognosis'.)

SUMMARY AND RECOMMENDATIONS

●Overview – Calcinosis cutis is a disorder characterized by the deposition of insoluble calcium salts in the skin or subcutaneous tissue. There are five subtypes of calcinosis cutis: dystrophic, metastatic, idiopathic, iatrogenic, and calciphylaxis. (See 'Introduction' above.)

●Dystrophic calcinosis cutis – Dystrophic calcinosis cutis most often occurs in association with autoimmune connective tissue disease. Treatment of this presentation consists of suppression of the associated autoimmune disease and interventions to improve lesions of calcinosis cutis and associated symptoms (algorithm 1). Data on therapies for dystrophic calcinosis cutis are limited, leading to uncertainty about the best approach to the management of this disease (see 'Dystrophic calcinosis cutis' above):

•Whom to treat – Not all patients require treatment beyond suppression of the associated autoimmune disease. Clinical follow-up without intervention to reduce calcium deposits is a reasonable option for calcinosis cutis that is asymptomatic, nonprogressive, unassociated with internal involvement, and of minimal concern to the patient. (See 'Treatment principles' above.)

•Patients proceeding with treatment – For patients with autoimmune connective tissue disease-associated dystrophic calcinosis that is symptomatic, progressive, or of other concern to the patient, we suggest topical or intralesional sodium thiosulfate as initial treatment rather than systemic therapy (algorithm 1) (Grade 2C). (See 'Topical or intralesional sodium thiosulfate' above.)

Systemic treatment with diltiazem, colchicine, or minocycline is an alternative for patients in whom the number or extent of lesions makes local therapy impractical and patients who do not respond to or cannot access topical or intralesional sodium thiosulfate. Surgical removal is an additional option for discrete, symptomatic areas of calcinosis cutis (algorithm 1). (See 'Alternative drug therapies' above and 'Role of surgery' above.)

●Metastatic calcinosis cutis – Metastatic calcinosis cutis primarily occurs in the setting of chronic renal disease. The management of these patients focuses on treatment of the underlying defect in the metabolism of calcium or phosphorus. (See 'Metastatic calcinosis cutis' above.)

●Idiopathic calcinosis cutis – Idiopathic calcification of the scrotum, subepidermal calcified nodule, and tumoral calcinosis are forms of idiopathic calcinosis cutis. If treatment is desired, the calcium deposits can be removed with surgical excision. (See 'Idiopathic calcinosis cutis' above.)

●Iatrogenic calcinosis cutis – Iatrogenic calcinosis cutis most often results from extravasation of intravenous calcium gluconate, calcium chloride, or phosphate-containing solutions into the skin. Iatrogenic calcinosis cutis often resolves spontaneously over the course of several months. (See 'Iatrogenic calcinosis cutis' above.)

●Calciphylaxis – Calciphylaxis is a life-threatening, calcific vasculopathy that usually occurs in the setting of end-stage kidney disease. Management consists of a multi-interventional approach involving wound care, pain control, prompt treatment of infection, correction of abnormalities in plasma calcium and phosphorus concentrations, avoidance of local tissue trauma, and other interventions. (See 'Calciphylaxis' above and "Calciphylaxis (calcific uremic arteriolopathy)", section on 'Treatment'.)