Successful Treatment of Single Infected Calciphylaxis Lesion With Intralesional Injection of Sodium Thiosulfate at High Concentration

Introduction. Calciphylaxis is a very complicated disease that usually presents in patients with end-stage renal disease (ESRD). Treatment for calciphylaxis is not well standardized and typically involves a multidisciplinary approach. One of the common medications used in calciphylaxis treatment is sodium thiosulfate (STS). However, its intravenous injection is associated with multiple side effects. Case Report. The authors present a case report of an intralesional injection of STS followed by a literature review of the common treatment modalities and possible further use of intralesional injections. A 51-year-old man with ESRD on peritoneal dialysis presented with a right calf biopsy-proven calciphylaxis lesion measuring 3.1 cm x 3.9 cm. About the same time, he had Pseudomonas-associated peritoneal catheter peritonitis. The calciphylaxis lesion was treated with bimonthly intralesional injections of STS. The lesion had a complete resolution by week 9. Conclusions. The authors believe a higher local concentration of STS leading to a faster resolution and requiring less frequent injections needs to be further evaluated. Following additional studies, they also propose a greater use of intralesional STS injections in a select set of patients in the future. 

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Calciphylaxis is a very serious and potentially fatal disease. It usually occurs in the setting of end-stage renal disease (ESRD) and severe secondary hyperparathyroidism.^1,2 However, it has been reported in early kidney disease and even in patients with normal kidney function.³ Histologically, calciphylaxis, also known as calcific uremic arteriolopathy, involves diffuse calcification of the medial layer of small cutaneous arteries and arterioles, leading to microthrombosis and fibrointimal hyperplasia.⁴ Clinically, calciphylaxis presents early as exquisitely tender purpuric subcutaneous plaques or nodules; later, it progresses into ischemic necrotic ulcers.⁵ Once suspected, workup begins with a laboratory evaluation, which includes measuring serum calcium, phosphate, electrolytes, blood urea nitrogen (BUN), creatinine, parathyroid hormone (PTH), and coagulation factors including prothrombin time (PT), activated partial thromboplastin time (aPTT), antithrombin III, proteins C and S, anticardiolipin, and antiphospholipid. Subsequently, a skin biopsy is the standard diagnostic method. The biopsy usually is taken peripherally from the area adjacent to the necrosis, preferably an area with early erythema or purpura. A biopsy from the center of the lesion is rarely helpful. Typical findings are arteriolar calcification, subintimal fibrosis, and thrombotic occlusion.⁴ An excisional biopsy rarely is indicated. Treatment for calciphylaxis is not well standardized. It involves different medications, wound care modalities, and possible hemodialysis session adjustments. Herein, the authors present a case of successful treatment of a single biopsy-proven calciphylaxis lesion using intralesional sodium thiosulfate (STS) injection. 

A 51-year-old man with known ESRD secondary to diabetic nephropathy presented as an outpatient referral to the Integrated Wound Healing Center at MedStar Franklin Square Medical Center (Rossville, MD). By the time he presented, he had been on peritoneal dialysis for 18 months. His past medical history is notable for dilated noncoronary cardiomyopathy with diastolic dysfunction, uncontrollable hypertension, and diabetic retinopathy. 

Previously, he presented to an outside facility’s wound clinic with a right lateral mid-calf ulcer. The ulcer started a few weeks prior to presentation with no apparent trauma. On exam at the outside facility, the right calf ulcer measured 2.2 cm x 2.8 cm and was covered with a significant amount of necrotic tissue. There was mild nonblanching irritation erythema around the skin edges and no purulent discharges, subcutaneous air, crepitus, or fluctuance. The treatment provided at the outside facility was directed toward a suspected venous ulcer, which included bedside weekly sharp debridement, daily enzymatic debridement with collagenase, and compression therapy. During the following weeks, the ulcer increased in size to 3.1 cm x 3.9 cm. He then was referred to the authors for further evaluation. 

Due to concerns for either malignancy or calciphylaxis, a punch biopsy was performed, and it confirmed the diagnosis of calciphylaxis. Once the diagnosis was established, further workup was done. The results of the workup included creatinine of 13.70 mg/dL, BUN of 71 mg/dL, PTH of 278.1 pg/mL, calcium of 7.8 mg/dL, and phosphorus of 7.0 mg/dL. 

Initially, the calciphylaxis treatment plan was to use a combination of local wound care and medical treatment that included intravenous STS and sevelamer carbonate (Renvela; SANOFI, Bridgewater Township, NJ). However, about the same time, he presented to the Franklin Square MedStar hospital with severe sepsis. He was found to have a peritoneal catheter infection and subsequent peritonitis. He underwent an emergent exploratory laparotomy and removal of the infected peritoneal catheter. The removed catheter grew Pseudomonas aeruginosa. He was started on ceftazidime 2 g intravenously every 12 hours. Simultaneously, his right leg calciphylaxis ulcer developed surrounding blanching erythema indicating cellulitis. After a rather prolonged hospital course, he was discharged to a rehabilitation center with instructions to continue ceftazidime for 14 days at the same aforementioned dosage and frequency. 

During a follow-up visit, a multidisciplinary discussion of the existing treatment regimen raised concerns regarding the potential side effects of intravenous STS, such as gastrointestinal upset, metabolic acidosis, and sodium overload. Specifically, there were concerns of the gastrointestinal side effects given his recent peritonitis and subsequent surgery. After further discussions with the patient about the current options, they collectively decided to proceed with the experimental treatment of intralesional STS. 

Intralesional STS injections were performed once every 2 weeks. A total of 4 cc to 5 cc of STS was injected at each session. The STS was mixed with lidocaine 1% plain at a 1:1 ratio for local anesthetic effect. The medication was injected in the periphery of the ulcer. The patient was seen in the wound center on a weekly basis. Sharp debridement was stopped permanently, and enzymatic debridement was started instead. Collagenase 250 units per gram ointment (SANTYL; Smith & Nephew, Inc, Fort Worth, TX) was applied twice daily by the patient, followed by a dry sterile ALLEVYN dressing (Smith & Nephew, Inc). The patient’s 2-week regimen of ceftazidime antibiotics ran its course, and he received his final dose 2 weeks into the STS intralesional injections. By that time, the cellulitis had resolved. Weekly comprehensive metabolic panels were monitored for metabolic acidosis. 

By week 9 post STS treatment, there was complete resolution of the ulcer (Figure). The STS injections and collagenase ointment applications were halted at this time. Follow-up continued for 6 months and showed no recurrent ulcer formation. 

To date, there has not been any clinical trial to standardize the treatment for calciphylaxis. Broadly speaking, the current prevalent treatment consists of medical treatment and wound care.^6,7 Medical treatment has been centered on correcting calcium dysregulation, including low calcium dialysis, phosphate binders, and possible parathyroidectomy.^8,9 Intravenous STS has been used with variable success.¹⁰ Other medical interventions have been reported and usually tailored towards each individual patient.¹¹ Examples of such options include cessation of all possible trigger agents (warfarin, vitamin D, iron, and calcium supplements),^12,13 intensified daily hemodialysis of up to 4-hour runs,¹⁴ daily oxygen therapy of 10-L face mask for 2 hours,¹¹ daily cinacalcet for patients with PTH > 369.2 pg/mL, and sevelamer carbonate for phosphate control.^8,9 Wound care options are limited but include gentle debridement, if necessary.¹⁵ Hyperbaric oxygen therapy also may be considered for very painful ulcers.¹⁶ 

The use of intravenous STS was first reported for treatment of recurrent calcium urolithiasis in 1985.¹⁷ It was then used intravenously for calciphylaxis by Cicone et al¹⁸ in 2004. Currently, STS is considered the main medical treatment for calciphylaxis. Mataic and Bastani¹⁹ reported favorable results for administering intraperitoneal STS to ESRD patients on peritoneal dialysis. The main side effects of intravenous STS are nausea, vomiting, metabolic acidosis, volume overload, hypocalcaemia, and prolonged QT interval.^5,20 The mechanism of action is not well understood. There have been many speculations about possible antioxidant or calcium-chelating capacity.^21,22 However, a more in-depth in vitro study by O’Neill and Hardcastle²³ has appropriately questioned these speculations. They²³ evaluated the effects of STS on the medial layer of ex vivo rat aortas with and without aortic wall injuries. Then, further in vitro studies were done to compare the effects of STS with sodium chloride and sodium sulfate on calcification, calcium concentration, calcium crystallization, calcium binding, and overall medium pH.²³ Although an exact mechanism has not been identified specifically, this study²³ established new ideas that could reshape the understanding of the mechanism of action of STS. Since STS had inhibited calcification in an in vitro aorta, it appears STS has direct extracellular action on the aorta wall.²³ This extracellular action was independent of the direct calcium interaction/binding and the medium pH. Interestingly, the STS inhibition happened only on injured aortas and did not occur with uninjured aortas or purified elastin. This suggests some element of intracellular involvement complicating the understanding of the mechanism of action. 

Local STS use was introduced for cutaneous calcium depositions about 2 decades later. Wolf et al²⁴ reported a case of dystrophic calcification (also known as calcinosis cutis) in the presence of systemic lupus erythematosus disease. The ulcer failed multiple debridement attempts with aggressive local wound care and systemic antibiotics. Twice-weekly applications of 10% STS solution compresses were administered. The ulcer eventually healed 8 months later. Similar results were reported in a 6-year-old boy with iatrogenic calcinosis cutis secondary to calcium gluconate intravenous infusion through peripheral veins.²⁵ Goossens et al²⁶ reported 2 cases of intralesional STS in tumoral calcinosis (TC). The first was done for a 44-year-old woman with dermatomyositis associated with Sjögren’s syndrome. Her initial disease was treated with steroids and methotrexate. However, she later developed disabling TC-like lesions in the elbow and forearm. The elbow TC was treated with weekly STS injections for 6 months. The patient had significant clinical improvement and radiological evidence of TC elbow reduction. Interestingly, her other TC lesions remained the same clinically and radiologically. The second case was of a 42-year-old man with familial hyperphosphatemic TC around the left tibia and right buttock. Maximal medical treatment to reduce the overall phosphate body load failed to improve the symptoms. Topical application of STS lead to an almost complete resolution of the tibial lesion but not of the buttock lesion. The buttock lesion therefore was treated with alternate weekly/biweekly STS injections for 21 months. Overall, the patient had a modest, yet noticeable, clinical improvement. 

The first case report of STS intralesional injection for calciphylaxis was reported by Strazzula et al²⁷ in 2013. In their series of 4 patients,²⁷ biopsy-proven calciphylaxis lesions were treated with weekly injections of 1 cc to 3 cc of STS. All 4 patients had complete resolution of their ulcers by 5 to 6 months. 

The present case report documents the successful treatment of biopsy-proven calciphylaxis using intralesional injections of STS. This protocol had few differences from the aforementioned case report.²⁷ The authors used a significantly higher local dose for a smaller lesion — 4 cc to 5 cc of STS compared with their²⁷ 1 cc to 3 cc. The other major difference is the frequency of the injections. The present authors injected STS every 2 weeks instead of every week. Their hypothesis for making those changes was that a more concentrated saturation of STS in the wound bed would result in faster healing and, inevitably, a less frequent injection interval. Supporting this hypothesis was the aforementioned findings by O’Neill and Hardcastle²³ that indicated the direct extracellular effect of STS on the calcification process.

This is a single case report and the findings cannot be used to draw a definite conclusion. A prospective, randomized study is needed to prove this hypothesis specifically and the efficacy of intralesional STS injection for calciphylaxis in general. 

The authors do not propose the intralesional utilization of STS as the sole future therapy for calciphylaxis. Rather, they believe this is another option to be added to the current available treatment protocols. There are 2 groups that could benefit the most from this modality choice. The first is nonuremic patients or those who are not on hemodialysis; this group of patients does not have established intravenous access nor do they require frequent visits to the dialysis units. The second group is the set of patients who already have severe gastrointestinal symptoms or who cannot tolerate the intravenous injection side effects. The intralesional utilization of STS for calcified cutaneous lesion should be further investigated with prospective, randomized studies. 

Note: Authors acknowledge the logistical support of Daniel Joseph Hakim, PT, Director of Clinical Operations at the Integrated Wound Healing Center at MedStar Franklin Square Medical Center (Rossville, MD). 

Authors: Bara Zuhaili, MD¹; and Khalid Al-Talib, MD, FACP²

Affiliations: ¹Johns Hopkins School of Medicine, Division of Vascular Surgery and Endovascular Therapy, Columbia, MD; and ²MedStar Franklin Square Medical Center, Rossville, MD

Correspondence: Bara Zuhaili, MD, Assistant Professor of Surgery, Johns Hopkins School of Medicine, Division of Vascular Surgery and Endovascular Therapy, 11085 Little Patuxent Parkway, Suite 103, Columbia, MD 21044; bzuhail1@jhu.edu 

Disclosure: The authors disclose no financial or other conflicts of interest.