Non‐healing leg ulcers in a patient with dystrophic calcification and crest syndrome: a challenging clinical case

Abstract

The management of non‐healing leg ulcers in patients with CREST syndrome and subdermal calcification is rarely reported in medical literature. Only one similar case was found in the literature (1). Dealing with such patients can be a challenge for wound specialists. In this article, we discuss the clinical progress of an interesting case of extensive non‐healing leg ulcers in a CREST patient with dystrophic calcification. The combination of systemic physiological deficits and immune compromise, along with the local physical abnormalities associated with the wound pose a complex multifactorial aetiological mix. There is no conclusive data on the optimal management of these wounds in CREST patients. It seems that ablation of the calcific deposits may offer some hope.

INTRODUCTION

Systemic scleroderma is characterised by two types: CREST syndrome and progressive (diffuse) systemic sclerosis. CREST is an acronym which describes a specific constellation of symptoms; Calcinosis cutis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly and Telangiectasia. CREST syndrome, also known as Thibierge–Weissenbach syndrome, is a particular form of systemic scleroderma with usually only limited systemic organ involvement. Presence of anticentromere antibodies is highly specific for patients with CREST syndrome.

Patients with CREST syndrome or limited systemic sclerosis/scleroderma often have better long‐term prognosis in comparison with patients with progressive (diffuse) systemic sclerosis/scleroderma. This relatively benign clinical course of CREST syndrome rarely contributes to renal or pulmonary involvement.

The pathogenesis of CREST syndrome is complex and there is no complete understanding of this process. It involves several types of autoimmune and possibly alloimmune reactions, resulting in damage of microvasculature and connective tissue fibrosis in the specific organs.

Pathophysiologic processes of calcinosis cutis in CREST syndrome and calcium deposits within non‐healing wounds may have similar mechanisms with inflammatory reaction and calcium efflux from damaged cells. Calcium deposits, whether in the dermis or subcutaneous fat tissue in CREST syndrome, or within non‐healing wounds, is the result of dystrophic calcification. This type of calcification is characteristic for areas of tissue damage or even necrosis. Remarkably, patient's serum levels of calcium and phosphorus remain normal.

Dystrophic calcification in a wound creates chronic foreign body inflammatory reaction that contributes to a non‐healing ulcer if calcific deposits are not removed 2, 3, 4, 5. However, the removal of calcium deposits can be a real challenge due to severe pain for the patient and the adherence of calcium deposits to fascia and within fibrous tissue.

CASE REPORT

A 68‐year‐old lady with a complaint of pain in non‐healing ulcers on her distal third of the right lower leg was first referred to the vascular outpatient clinic in November 2006. She had been known as a patient with severe calcinosis cutis for seven years.

Her medical history includes CREST syndrome diagnosed 22 years ago, hypertension, ischemic heart disease, hypercholesterolemia, hyperhomocysteinemia, hyperuricemia and chronic renal impairment. Past surgical history comprises coronary artery bypass graft (CABG) and aortic valve replacement performed in 2004, thyroidectomy, cholecystectomy and appendicectomy. Medications included thyroxine, allopurinol and high dose folic acid.

Clinical examination revealed two chronic leg ulcers: 1·5 × 1·0 cm ulcer on the lateral aspect of the right leg just above the lateral malleolus, and 4·0 × 2·5 cm ulcer on the posterior aspect of the right lower leg.

Both ulcers had a strong odour, yellow discharge, active bleeding and chalky deposits of calcium crystals in the ulcer bed. These deposits were analysed and found to compose of 60% calcium phosphate, 25% calcium oxalate and 15% magnesium nitric hydroxide. X‐ray images revealed extensive subcutaneous calcification in an ‘amulet’ distribution. This was asymmetrically much worse in the right leg (Figure 1).

Figure 1.

Ankle X‐ray with severe dystrophic subdermal calcification of both ankles, 2007 (prior to the development of extensive ulceration).

The patient's blood test comprised normal levels of calcium and phosphorus. However, she had positive antinuclear antibodies (ANA) and anticentromere antibodies (1:2560). Extractable Nuclear Antigens (ENA), C‐ANCA and P‐ANCA were negative.

A venous duplex ultrasound study demonstrated venous insufficiency. A comment was made of abnormal appearance of vein wall and valves ‘possibly due to scleroderma’. The saphenofemoral junction and great saphenous vein was incompetent. However, small saphenous and popliteal veins were within normal limits. She had a competent deep venous system.

Her ankle‐brachial index (ABI) on the right was found to be 1·0. The absolute ankle pressure and index ratio were prone to artefact due to the circumferential calcification of her leg. Arterial duplex was also difficult because of dense subcutaneous calcification. Later MR angiogram confirmed no significant arterial disease. There were slightly ulcerated right common iliac artery plaques but no significant stenosis (Figure 2).

Figure 2.

Lower limb MRA, 2007.

Given the possibility of a ‘venous’ aetiology of these ulcers, the patient was advised to use Profore Lite compression bandaging and Ichthopaste (medicated paste bandage) on the wounds. After several weeks Ichthopaste was ceased and there was minimal response to mild compression therapy, but full compression was intolerable. She was put on colchicine tablets 0·5 mg once a day.

Over the ensuing four years, many different therapeutic and surgical treatments were undertaken. The patient's ulcers deteriorated and eventually the procedure of right above the knee amputation (AKA) had to be performed.

Described below is a chronologic record of the patient management:

2007

• •The dosage of colchicine was increased to 0·5 mg twice a day and reduction of inflammation around ulcer wounds was observed. However, the patient did not tolerate colchicine because of side‐effects.
• •Nanocrystalline Silver Impregnated dressings and amorphous hydrogel were trialled.
• •Oral prednisone 10 mg daily was introduced instead of colchicine.
• •Surgical debridement of the wounds was recommended during warmer months. There was an observation that patients with Raynaud's phenomenon have better tolerance of procedures in warmer conditions. The patient had partial surgical debridement. The ulcer size was recorded as 15·0 cm length × 6·0 cm width ×1·0 cm depth.
• •The patient was referred to urologist for consideration of extracorporeal shock wave lithotripsy – ESWL, as a similar and a related case were reported by Sparsa et al. (1) and Chan et al. (6) and they had satisfying ESWL results. ESWL was not considered financially feasible for this patient and therefore never performed (Figure 3).

Figure 3.

Lower left leg CT, 2007.

2008

• •Topical clioquinol cream was recommended. At this stage, the wound size was recorded as 9·0 × 9·0 cm.
• •Diluted acetic acid bandages were poorly tolerated because of pain. The best tolerated dressing regime was topical Glyceryl trinitrate ointment during daytime and Silver Sulfadiazine cream (SSD) at night time both under compression bandaging, but this was extremely labour‐intensive.
• •The patient was referred to the plastic surgical team for radical excision of the wound with split skin grafting (SSG). She was deemed unfit for this procedure because of pulmonary hypertension, aortic stenosis and angina. Unfortunately, the ulcer (now 12.0 × 11.0 cm) was heavily colonised and became episodically infected so that smaller SSG procedures were not effective (Figure 4).

Figure 4.

Right leg ulcers, 2008.

2009

• •The inflammation and infection persisted. It was noted when calcific plaques from the wound margins broke away, the patient had transient alleviation of her wound pain. The patient was offered surgical debridement of sheets of calcinosis, but once again she refused the procedure under spinal anaesthesia (Figure 5).

Figure 5.

Right leg ulcers, 2009.

2010

• •In January, the procedure of right above knee amputation (AKA) was offered as wounds were deteriorating. The patient continued to receive Nanocrysalline Silver impregnated dressings and Glyceryl trinitrate ointment 0·2%. Four months later, the patient consented to proceed with AKA (Figure 6).
• •In June, two ulcers 1·0 × 1·0 cm on the left leg above lateral and medial malleoli were noted by the patient.
• •In October, these ulcers became infected. Methicillin‐Resistant Staphilococcus Aureus (MRSA) and Pseudomonas infection was diagnosed. The patient was treated with Ciprofloxacillin IV and 1% SSD locally. These wounds on the left leg had less extensive calcinosis but were still expected to be difficult to treat.

Figure 6.

Right leg ulcers were not able to heal for more than three years, May 2010.

Sadly, in November 2010 the patient died of respiratory failure and right‐sided heart failure secondary to pulmonary hypertension.

DISCUSSION

Leg ulcers in patients with CREST syndrome are always challenge to treat. There is little understanding how the process of calcification of the wounds occurs, and more important, how we can modify this pathological process – Enoch et al. (7), Vayssairat et al. (8), Smith et al. (9). Descriptions in the medical literature and our observations suggest calcinosis cutis and dystrophic calcification might have similar traits but their pathophysiology differs. Similar dystrophic calcification has been observed in several patients with and without wounds, who do not have CREST syndrome. There are also many CREST patients who never develop dystrophic calcification except digital calcinosis. CREST may not be aetiologically relevant and other factors may be largely responsible such as repetitive trauma, soft tissue infection, venous hypertension and ischaemia. Irrespective of the aetiology, the combination of CREST syndrome and leg ulcers remains very difficult to treat.

It is hypothesised that calcium deposits within a wound bed create a foreign body which leads to low grade infection, up‐regulation of inflammation processes, copious wound exudate and impaired healing.

Surgical debridement and mechanical removal of calcium deposits has been suggested as the procedure of choice. However, this procedure is not always possible because of severe pain, patient comorbidities and also because of the extensive distribution, as in this case.

Colchicine therapy demonstrated positive anti‐inflammatory effect, but was poorly tolerated by the patient described above. Oral corticosteroids, in spite of expected anti‐inflammatory effect, have not demonstrated significant improvement.

In this case, we were not able to perform ESWL or SSG procedure that might have helped, based on the experience described in other clinical cases – Sparsa et al. (1), Chan et al. (6), Schmeller et al. 10, 11.

Local wound care with several ointments or gels did not demonstrate valuable improvement. However, compression bandages seemed helpful at the onset, particularly because of co‐existent venous pathology.

CONCLUSION

Extensive subdermal calcium deposits in these wounds were dystrophic calcifications. This type of calcification resides in tissue and can cause severe damage and eventual skin necrosis. Calcium crystals create a foreign body reaction within a wound, persistent inflammation and non‐healing ulcers.

The removal of the calcium deposits is expected to facilitate the healing process. There are two options: surgical debridement and ESWL. Unfortunately, extended surgery was not possible because of comorbidities and ESWL was judged too expensive. Both procedures are promising and could be valuable options if technically and medically feasible.

Another observation was that these non‐healing ulcers remained infected and demonstrated poor response to topical and systemic antibiotic therapy. Removal of foreign calcific material allowing de‐colonisation of the wound bed and eventual coverage of the wound with a skin graft would seem to be an extensive but appropriate treatment for these complicated leg ulcers.