Recalcitrant digital calcinosis cutis successfully treated with intralesional sodium thiosulfate under digital nerve blockade

Abstract

Dystrophic calcinosis cutis can be associated with severe pain, decreased mobility, increased risk of infection and significantly decreased quality of life. We report a case of recalcitrant calcinosis cutis on the background of eosinophilic fasciitis, which achieved rapid reduction in calcium deposits following a novel injecting protocol of intralesional sodium thiosulfate.

Background

The term calcinosis cutis describes the accumulation of insoluble calcium apatite salts in the epidermis, dermis, subcutaneous tissues or joints and muscles. Subtypes of calcinosis cutis include dystrophic, idiopathic, metastatic, mixed and iatrogenic. Of the five different subtypes, dystrophic calcinosis cutis is the most commonly reported and is often associated with underlying autoimmune connective tissue diseases such as dermatomyositis, systemic sclerosis, lupus erythematosus and mixed connective disease.¹ Dystrophic calcinosis cutis may cause substantial morbidity and pain especially when it is associated with ulceration, close proximity to joints or secondary infection.²

Calcinosis cutis is difficult to treat. Treatments are aimed at dissolution or surgical removal of calcium salts. Options include calcium channel blockers (diltiazem), colchicine, probenecid, minocycline, intravenous immunoglobulin, bisphosphonates, warfarin and surgical excision.² Sodium thiosulfate was first introduced in 2004 by Cicone et al as a promising treatment option for calcinosis cutis. The proposed mechanism of action of sodium thiosulfate is chelation of insoluble calcium apatite crystals into calcium thiosulfate salts, which are 100 000 times more soluble.³ To date, various methods of administering sodium thiosulfate have been reported including intravenous, topical and intralesional injection.^4–6

We report a case of dystrophic digital calcinosis cutis successfully treated with weekly intralesional injections of sodium thiosulfate 250 mg/mL.

Case presentation

A woman in her 60s, with a background of eosinophilic fasciitis, presented with a 5-year history of recalcitrant calcinosis cutis affecting her left elbow and three fingertips bilaterally. The subcutaneous calcifications varied in size from several millimetres on the fingertips (figure 1), to 1–2 cm on the left elbow. The right third finger was the most severely affected, with multiple calcifications associated with the worst oedema, deformity and pain. They were extremely painful, restricting usage of the fingers and the range of motion of the left elbow, significantly impacting on the patient’s quality of life. In collaboration with the patient’s rheumatologist, many different treatments were attempted including dietary modifications (low-phosphate high-aluminium diet), topical sodium thiosulfate 10%, topical tacrolimus 0.1% ointment, clobetasol 0.1% ointment, short courses of oral prednisolone (highest dose was 50 mg weaned over 2–3 weeks), oral diltiazem 180 mg two times a day, colchicine 0.5 mg three times a day and various analgesics such as pregabalin 150 mg mane 300 mg nocte, amitriptyline 75 mg nocte and celecoxib 200 mg daily without success. The patient was also treated with methotrexate 30 mg weekly for eosinophilic fasciitis. Surgical excision and curettage of calcifications was attempted; unfortunately, the patient developed recurrence at the site of surgery within a few weeks postprocedure.

Figure 1.

Photo of the patient’s bilateral fingers with varied sized—calcifications on the right third, right fourth and left fourth fingertips prior to intralesional sodium thiosulfate.

After thorough clinical review, intralesional sodium thiosulfate was applied for and approved by our tertiary centre’s medical therapeutic administration committee. Patient’s consent and photographs were obtained prior to each treatment.

Patient’s consent was obtained prior to treatment including: pain associated with administration of local anaesthetic and hypertonic solution of sodium thiosulfate, increased risk of wound infection, damage to surrounding structures, for example, nerves, tendons and vessels and failure of response to treatment. Photographs were obtained prior to each treatment. An aseptic technique was employed to perform intralesional sodium thiosulfate injections. All affected fingers were thoroughly prepped with chlorhexidine 0.1% solution. Digital nerve blocks were performed with the injection of 2% lidocaine into digital nerves at the base of each affected finger (right third and fourth finger and left fourth finger). A total volume of 5 mls of 2% lidocaine was required for the three digital nerve blocks. Sodium thiosulfate 250 mg/mL solution was then injected into the bases of calcifications on each finger using a 30G insulin syringe. Multiple injections were performed due to the presence of multiple calcifications per finger, using 0.05–0.1 mL per calcification depending on the lesion size. A maximum of 1 mL of sodium thiosulfate 250 mg/mL was injected per finger. After each injection, the patient was advised to seek medical attention in case of development of increased oedema, erythema, warmth and/or pain at the injection sites or systemic symptoms such as fever. The patient tolerated the procedure well with the digital nerve blocks. In total six treatments were delivered at 1–2 weekly intervals. Reduction in calcification sizes was observed as early as after the second injection. Reduction in calcification sizes was observed as early as after the second injection.

The patient reported thick yellow chalky discharge draining from injection sites, with mild residual discomfort lasting two to 3 days postinjection. Interestingly, this has not been previously described and may account for the accelerated response seen in our case. After the fifth injection, she developed erythema, oedema and pain of the right third finger. Pathology work up showed normal white cell and neutrophil counts with a mildly elevated CRP of 23. A wound swab was completed which was positive for Staphylococcus aureus. In view of the pathology results, the patient’s symptoms were most likely due to a localised infection superimposed on a secondary reaction to dissolving calcium and hypertonic sodium thiosulfate solution. These symptoms resolved after 24 hours of intravenous cefazolin, rest and limb elevation. No systemic adverse effects were observed. She was discharged on 5-day course of oral cefalexin.

Outcome and follow-up

Overall after six injections, there were substantial reductions in numbers of calcifications and calcification sizes of the fingertips (figure 2). The patient later developed new calcifications involving untreated body regions such as the left shoulder, hips and elbows. She returned to her renal and rheumatology physicians for consideration of intravenous sodium thiosulfate. She continues to have intravenous sodium thiosulfate every 3 weeks with slow resolution of calcifications of the left shoulder, hips and elbows (over 100 infusions thus far). With regard to her hands, her pain has resolved and the patient has regained full function of all fingers. This has had a remarkable positive impact on her psychological health.

Figure 2.

Photo of the patient’s hands after six weekly-fortnightly injections with intralesional sodium thiosulfate 250 mg/mL to the right third, right fourth and left forth fingertips.

Discussion

Sodium thiosulfate has been successfully used in the management of patients with calcinosis cutis. Its side effect profile and efficacy are influenced by its route of administration. Topical sodium thiosulfate is well tolerated without systemic side effects. However, it may not penetrate adequately to result in dissolution of calcium salts and application directions must be strictly adhered to.⁵ Intravenous sodium thiosulfate may cause systemic adverse effects such as headache, nausea, vomiting and serious metabolic acidosis.⁴ Intralesional sodium thiosulfate limits systemic adverse effects by providing local delivery while maintaining accessibility to deep lesions.^{6 7}

To date, various concentrations (12.5 mg/50 mL–250 mg/mL) and injecting schedules (weekly to 3-monthly) of intralesional sodium thiosulfate have been reported.^6–8 Most recently, Winter et al, in a double-blind, placebo-controlled pilot study investigated the efficacy of 3-monthly sodium thiosulfate 40 mg/mL, 0.1 mL/cm² injections for management of calcinosis cutis in 5 patients. However, this treatment failed to improve the condition in four out of five patients.⁸ Baumgartner-Nielsen and Olesen reported the use of sodium thiosulfate 150 mg/mL weekly for up to 4 weeks in 6 patients with calcinosis cutis on the background of systemic sclerosis and nephrogenic systemic fibrosis. By week 4, 67% reduction in average lesion size was observed, and 90% reduction at week 12.⁹ López-Sundh et al reported a successful treatment of bilateral axillary calcinosis cutis plaques in a patient with systemic sclerosis. Sodium thiosulfate 250 mg/mL was given at 3-monthly intervals, resulting in complete resolution of plaques.¹⁰

A weekly injection schedule of higher concentration sodium thiosulfate was chosen in our protocol, to facilitate rapid reduction in number and size of calcium deposits per fingertip. Sodium thiosulfate 250 mg/mL is an extremely hypertonic solution and painful to inject, however, due to the digital nerve blocks tolerability was excellent, allowing for a larger volume and multiple injections to be delivered. This combination procedure has not previously been described, but should be considered in all cases of digital calcinosis cutis. Vibrating devices, topical anaesthesia, ice and distraction can all be employed to improve comfort during administration of multiple digital nerve blocks.¹¹

It should be noted that the patient was receiving concurrent oral methotrexate. Taking into consideration the difficult anatomical location and large number of lesions per fingertip, a slightly lower concentration, for example, 150 mg/mL may have been better tolerated. In our patient, an abscopal effect (regression of lesions outside of the treatment field of a locally controlled lesions) was not observed with intralesional sodium thiosulfate. Previous reports have not commented on the presence (or absence) of such an effect, as patients may not have had other areas of disease. Larger studies are needed to investigate the ideal treatment interval and concentration of sodium thiosulfate, which may vary with lesion location and size.

As discussed, our patient responded well to intralesional sodium thiosulfate 250 mg/mL at weekly-fortnightly intervals. Digital nerve blocks were employed to successfully improve tolerability of treatment. As the digits are frequently involved in dystrophic calcinosis cutis,² we believe regional anaesthesia prior to intralesional sodium thiosulfate should become standard of care.

Learning points.

• Dystrophic calcinosis cutis may cause significant morbidity impact on a patient’s quality of life, and can be challenging to treat.

• Weekly to fortnightly injections of intralesional sodium thiosulfate 250 mg/mL into digital calcifications under digital nerve blockade is effective and well tolerated, with a rapid onset of action.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).