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Softening the blow of calcinosis cutis: The promise of intralesional sodium thiosulfate

DII small banner By Warren R. Heymann, MD
Oct. 12, 2017

Calcinosis cutis and pseudoxanthoma elasticum of central abdomen. Firm, erythematous nodules with focal areas of yellow chalky material centrally.
Credit: JAAD

I’m not sure what’s harder about calcinosis cutis (CC), the lesion itself or treating it.

Calcinosis cutis (CC) 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 disorder, most characteristically an autoimmune connective tissue disease. Metastatic calcification has abnormal serum levels of calcium and phosphorus with deposition occurring after the 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 agents that induce precipitation of calcium salts. Calciphylaxis involves calcification of small and medium-sized vessels and is associated with chronic renal failure and dialysis. CC 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)

Among autoimmune connective tissue diseases, CC is seen most commonly with systemic sclerosis and dermatomyositis. As noted in their outstanding review of the topic, Gutierrez and Wetter state that while there is no uniformly effective treatment for CC, several surgical and medical therapies have demonstrated varying degrees of benefit, including surgical excision, laser therapy, extracorporeal shock wave lithotripsy, diltiazem, colchicine, aluminum hydroxide, bisphposphonates, warfarin, ceftriaxone, minocycline, IVIG and topical sodium thiosulfate (STS). (2)

STS is an inorganic salt that has been used intravenously for decades, initially for the treatment of cyanide poisoning. Subsequently it proved to be effective in treating calcium-mediated disorders. According to Strazzula et al: “The mechanism of sodium thiosulfate in the treatment of calcium-related disorders is thought to be multifactorial. Evidence has shown that it acts as an anticalcification agent, with vasodilatory and antioxidant properties. Some research suggests that sodium thiosulfate inhibits the precipitation of calcium in tissues by increasing calcium solubility, and others hypothesize that sodium thiosulfate combines with calcium, forming a salt that can later be dialyzed.” (3)
Recently, intravenous (IV) STS has been used increasingly, and somewhat effectively, for calciphylaxis. Because of adverse reactions associated with IV STS (nausea and vomiting, rhinorrhea, peritonitis, hypotension, anion gap metabolic acidosis, and sepsis) (4), it was inevitable that other forms of delivery of STS would be attempted to improve the benefit-to-risk ratio for calciphylaxis, and expand its use for other forms of CC.

Although topical STS may be effective in very superficial forms of CC, it is the larger, deeper subcutaneous lesions that are most debilitating, warranting therapy. I first became familiar with the concept of intralesional STS after reading the article by Strazzula et al, in which 4 patients with biopsy-proven cutaneous calciphylaxis were treated with IL sodium thiosulfate (250 mg/mL) in areas of clinically active disease (1 patient also received IV STS). The patients tolerated the medication well, with only transient localized discomfort during injection. All 4 patients had complete healing of their ulcers and remission of disease within several months of therapy. (3)
The use of intralesional STS has now expanded into the realm of CC associated with autoimmune connective tissue diseases. Smith reported the successful treatment of an exophytic lesion of CC on the fingertip of a 37 year-old woman with dermatomyositis. A dose of 0.1 ml of 12.5mg/50mL was utilized twice, intradermally, 3 weeks apart, resulting in complete healing. (5) In a study of 5 patients with systemic sclerosis and disabling dystrophic CC, and 1 nephrogenic systemic fibrosis (NSF) patient with severe fibrosis and ulcerations, all were treated with intralesional injections of STS, 150 mg/ml, in the base of the calcification. Calcifications on the fingertips of less than 5-mm diameter were treated with a single injection of STS, More widespread calcifications complicated with ulcerations were treated with repeated injections every week for 4 weeks. The clinical response was evaluated at weeks 4 and 12. CC was reduced by 67% by week 4 and by 90% by week 12. Complete remission was obtained in 50% of patients by week 12 and 80% remission was achieved in the remaining 50% by week 12 compared with baseline lesion size before treatment. Furthermore, the patients all reported improvement in pain and disability. The patient with NSF died shortly after the third treatment due to gastric bleeding, which was unrelated to the STS. (6) Intralesional STS has also been effective in patients with tumoral CC in two patients, one with dermatomyositis and the other with a history of familial hyperphosphatemia. (7) Most recently, subcutaneous CC associated with lupus panniculitis resolved with injections of STS at a dose of 12.5mg/50mL following ring blocks of lidocaine (8) (compared to 12.5 mg/50ml in reference 5 — this is a huge difference; after some inquiry, it was probably 12.5g/50ml, although I cannot be certain of that).

In conclusion, everything about CC is hard — except the decision to try intralesional STS in afflicted patients.

1. Le C, Bedocs PM. Calcinosis cutis . StatPearls [Internet]. Treasure Island (FL). StatPearls Publishing,
2. Gutierrez A Jr, Wetter DA. Calcinosis cutis in autoimmune connective tissue diseases. Dermatol Ther 2012; 25: 195-206.
3. Strazzula L, et al. Intralesional sodium thiosulfate for the treatment of calciphylaxis. JAMA Dermatol 2013; 149: 946-9.
4. Peng T, et al. A systematic review of sodium thiosulfate in treating calciphylaxis in chronic kidney disease patients. Nephrology (Carlton) 2017 Jun 11 [Epub ahead of print]
5. Smith GP. Intradermal sodium thiosulfate for exophytic calcinosis cutis of connective tissue. J Am Acad Dermatol 2013; 69: e146-7.
6. Baumgartner J, Olesen AB. Treatment of skin calcifications with intra-lesional injection of sodium thiosulfate: A case series. Acta Derm Venereol 2016; 96: 257-8.
7. Goossens J, et al. Efficacy of intralesional sodium thiosulfate injections for disabling tumoral calcinosis: Two cases. Semin Arthritis Rheum. 2017 Jun 17 [Epub ahead of print]
8. Gunasekera N, et al. Intralesional sodium thiosulfate treatment for calcinosis cutis in the setting of lupus panniculitis. JAMA Dermatol 2017; 153: 944-5.

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