Update on cutaneous calciphylaxis.

Calciphylaxis is a devastating disorder with a mortality rate of 80% due to sepsis and organ failure. Hallmarks of this rare disease are arteriolar media calcification, thrombotic cutaneous ischemia, and necrotic ulcerations. Different mechanisms of vascular calcification can lead to calciphylaxis. Early diagnosis by deep cutaneous ulcer biopsy is most important for prognosis. Here, dermatologists play a significant role although treatment usually needs an interdisciplinary approach. Surgical procedures had been the cornerstone of treatment in the past including parathyroidectomy, but recently new medical treatments emerged aiming to normalize disturbances of minerals to reduce the serum concentration of sodium phosphate and to prevent precipitation and calcification. Multimodal therapy is warranted but only aggressive surgical debridement of cutaneous ulcers has shown significant outcome improvement.

What was known?

Calciphylaxis is an inflammatory disease of small- and medium-sized arteries characterized by calcification, thromboembolism, and painful cutaneous ulcerations. The most common underlying pathologies include end-stage renal disease, diabetes mellitus, autoimmune disorders, and malignant disorders.

Introduction

The term calciphylaxis had been coined by Selye in the early 1960s of the last century. He understood the disease as a kind of hypersensitivity and identified a number of “calcigens” (in analogy to allergens) involved in subcutaneous calcification.[1]

Nowadays, calciphylaxis is defined as a syndrome of progressive vascular media calcification due to various pathologies. Since the disease can be observed in patients with terminal renal insufficiency, the term calcific uremic arteriolopathy has been coined.[2] But renal pathology is not an essential for the development of calciphylaxis.[3]

Definition

Calciphylaxis can be defined as a chronic progressive syndrome of arteriolar media calcification, thrombotic ischemia, and necrotic ulceration. Calciphylaxis develops when the levels of calcium and phosphate in the blood exceed their solubility range leading to deposits in the arteriolar walls. Systemic and cutaneous calciphylaxis are differentiated. Systemic calciphylaxis may lack ulcerations.[4]

In this review, we will exclusively focus on cutaneous calciphylaxis since this is the part of calciphylaxis the dermatologist may be confronted with. Severe ulcer pain is an important clinical symptom in cutaneous calciphylaxis. Cutaneous calciphylaxis can be subdivided into central and distal types. The distal type seems to have a better prognosis but evidence-based data are lacking.[5]

Epidemiology

In a population-based study from Olmsted, MN, incidence was 4.5 per million inhabitants in a year.[6] The cumulative incidence of calciphylaxis among hemodialysis patients in the Western World is about 1% and prevalence is 4.1-4.4%.[478]

Pathogenesis

The central mechanism in calciphylaxis is calcifying arteriolopathy, where vascular tissue develops into osteoid-like tissue. The smooth muscle cells of the vascular wall transdifferentiate into osteoid-like cells, a phenotypic shift that occurs without increase in proliferation. Several mechanisms may be involved: (a) A loss of inhibitors of calcification, (b) inducers of extra-osseous calcification, (c) circulating precipitating complexes, and (d) cell death.[9]

The initial step consists of inflammation with involvement of macrophages and vascular cells.[10-12] This is followed by paracrine signals mediated due to different signaling molecules such as bone morphogenetic protein-2 (BMP-2), Wnts, parathyroid hormone-related polypeptide, osteopontin, osteoprotegerin, and matrix Gla-protein.[13] A crucial factor in this pathway is phosphate. Phosphate is transported into the smooth muscle cells by type III sodium-dependent phosphate co-transporter Pit-1. BMP-2 stimulates phosphate uptake by smooth muscle cells. During this process, both Pit-1 messenger ribonuclei acid (mRNA) and Pit-1 protein are upregulated.[14]

In patients with terminal renal insufficiency, associated metabolic disturbances contribute to vascular calcification, such as hyperglycemia, hyperphosphatemia, hypercholesterolemia, hypertension, parathormone resistance, and iatrogenic calcitriol excess.[15]

Calcification of vascular walls increases stiffness, pulse wave velocity, and ischemic events, and increases cardiovascular morbidity and mortality.[16]

Associated disorders and risk factors

Terminal renal insufficiency is the most important disease associated with calciphylaxis.[245] There is a variety of identified risk factors in such patients for calciphylaxis development, including hyperphosphatemia; Ca phosphorous product, >70 mg2/dl2; blood sedimentation rate, >30 mm/h; aluminum, >25ng/ml; increase in calcium levels; and decrease in serum albumin.[51718] Concomitant medications such as calcium-based phosphate binders, vitamin K antagonists, and heparin are further risk factors.[51819]

Another important group of associated diseases are autoimmune disorders, such as systemic lupus, rheumatoid arthritis, giant cell arteritis, and others.[20-23]

In this group of disorders, renal involvement is not necessary for calciphylaxis. Precipitating factors could be systemic corticosteroid therapy and associated protein C or S deficiency.[524]

Further associated disorders are hyperparathyroidism (adenoma or carcinoma; in case of secondary type, there is association with end-stage renal disease), diabetes mellitus, and hepatobiliary diseases.[52324] Multiple myeloma, Hodgkin's disease, and lymphomatoid papulosis have been reported to be rarely associated with calciphylaxis.[2526]

Clinical presentation and diagnostics

Cutaneous calciphylaxis starts with non-characteristic cutaneous symptoms including subcutaneous nodules and infiltrated plaques. Purpuric- and livedo-like lesions may occur. Later stage is characterized by the development of progressive necrotic ulcers often with a bizarre shape and severe pain [Figure 1a and b]. Cutaneous ulceration is a strong negative prognostic factor. Ulcerations may be a starting point for septic complications associated with high mortality of 50-80%.[52324] Distal cutaneous calciphylaxis is responsible for about 1.1% of leg ulcers seen in Germany.[27] Less common sites of cutaneous ulcerations are breasts and genitals. A deep skin biopsy (no punch biopsy) with subcutaneous adipose tissue is necessary to confirm diagnosis. The calcified arterioles are placed within the subcutaneous fat. A von Kossa stain is a reliable method to visualize calcified vascular walls for routine. The most common histopathological finding is a septal calcifying panniculitis.[523]

Figure 1

Clinical presentation of distal cutaneous calciphylaxis. (a) A more recent ulceration with reddish wound ground and serous discharge. (b) A long-standing ulcer with fibrin coverage but no signs of re-epithelialization. (c) Situation after deep ulcer shaving with split-skin mesh-graft transplantation in the same setting

A net-like pattern of calcification has been described as characteristic for calciphylaxis in plain radiographs and may aid diagnosis.[28] Laboratory findings are non-specific and dependent on underlying pathologies.

Differential diagnoses

The initial stages of nephrogenic systemic fibrosis may resemble calciphylaxis, sometimes with extra-osseous calcification.[29] Calcinosis cutis is seen mainly with autoimmune collagen-vascular diseases, but ulceration is rare. Autoimmune vasculitis or panniculitis has to be considered.[173031] Winiwarter–Buerger disease and ergotism can cause painful digital ulcerations.[3132] Calciphylaxis may clinically resemble pyoderma gangrenosum, but histopathology is different.[33]

Treatment

In general, treatment of calciphylaxis is a multimodal and interdisciplinary approach. The major targets are interruption and/or reversal of vascular calcification and prevention of fatal septic complications.

Medical treatment

In case of end-stage renal disease, intensified hemodialysis and preference of products with a lower Ca content are essential. Primary goals of medical treatment are normalization of hyperparathyroidism, hypercalcemia, and hyperphosphatemia. None can reduce the risk of septic fatalities.

Non-calcium/non-aluminum-containing phosphate binders

Non-calcium/non-aluminum-containing phosphate binders like sevelamer hydrochloride or lanthanum carbonate should be preferred in calciphylaxis patients with end-stage renal disease. They may reduce arterial calcification in context with intensified hemodialysis.[3435]

Bisphosphonates

Amino-bisphosphonates inhibit soft tissue calcification. In animal models, bisphosphonates act on macrophages and bind to calcified vascular smooth muscle cells, thereby inhibiting progression of the process. Both oral etidronate disodium and intravenous pamidronate have been used successfully in individual calciphylaxis patients.[3637] The following dosages are used: Ibandronate, 150 mg monthly; alendronate, 70 mg weekly; or risedronate, 35 mg weekly.

Cinacalcet

Cinacalcet is a calcimimetic antagonist of parathormone which can normalize secondary hyperparathyroidism. The action is mediated by increasing sensitivity of Ca-sensing receptor on parathyroid glands. Doses are titrated from 30 to 180 mg/d. Wound pain is reduced in single cases but on long term, the drug can decrease bone mineral density.[3839]

Cinacalcet does not induce a long lasting of the autonomous growth of parathyroids. The effect is limited to the time of treatment.

Paricalcitol

Paricalcitol is a selective activator of vitamin D receptors. In animal models, aortic calcification was reduced. Anti-calcification factors such as osteopontin and klotho were upregulated.[40] There are case reports on positive effects on hemodialysis-associated calciphylaxis when used together with other drugs.[4142]

Sodium thiosulfate

Sodium thiosulfate is a chelating agent with anti-oxidant efficacy. The drug is used intravenously in calcifying nephrolithiasis and tumor-induced calcinosis.[43] In a literature review, 41 calciphylaxis patients treated in > 90% successfully have been identified.[44] In hemodialysis patients, improvement in cutaneous ulcers and pain was observed in about 70%. It is given intravenously in 25% in dextrose solution with a dosage of 25 g/1.73 m2 after hemodialysis. Nevertheless, sodium thiosulfate was unable to reduce high mortality rate of 71%.[45]

Farnesoid X receptor agonists

Nuclear Farnesoid X receptor (FXR) is involved in regulation of lipid, carbohydrate, and bile acid metabolism. In cell culture and animal studies, FXR agonist, 6α-ethyl-chenodeoxycholic acid inhibits phosphate-induced mineralization of cells and ameliorate renal vascular calcification.[46] In the future, FXR agonist may represent a new class of drugs for medical treatment of calciphylaxis.

Pain control

Pain control is a significant part in the attempts to improve patient's quality of life.[47] A multimodal preventive analgesia with sufficient dosages of opioids, ketamine, or benzodiazepines is recommended.[48] In case of opioid-resistant pain, levomethadone has been used successfully.[49]

Wound debridement and surgery

Parathyroidectomy

The classical surgical attempt to calciphylaxis is hyperparathyroidism. Parathyroidectomy is curative in primary hyperparathyroidism. On the other hand, the procedure alone is not effective in secondary or tertiary hyperparathyroidism to improve outcome of calciphylaxis patients.[50] Patients after bariatric surgery need particular care since life-threatening hypocalcemia has been observed after parathyroidectomy.[51]

Surgery of cutaneous ulcers

Whether or not aggressive wound debridement should be performed in calciphylaxis, has been a matter of debate. Those who argue against debridement fear an aggravation of cutaneous ulceration or believe that medical drug therapy is capable to prevent catastrophic outcome.[5253]

Wound debridement with sterile maggots has been used in individual cases successfully, but it is not always sufficient to induce complete ulcer healing.[54] Considering histopathology, debridement should aim not only to remove eschar and bacterial biofilms but also inflamed adipose tissue. The only legitimation for aggressive debridement is improvement of outcome by reduction of wound infection, sepsis, and organ failure.

Available data support this idea: Aggressive debridement improves the outcome of calciphylaxis patients. Debridement and parathyroidectomy resulted in a better outcome than parathyroidectomy alone.[41]

In a retrospective trial, patients who underwent surgical debridement showed a significant better 1-year survival rate compared to controls: 61.6% versus 27.6% (P = 0.008).[5]

Aggressive surgical debridement can be combined with split-skin mesh-graft transplantation [Figure 1c]. In a retrospective 3-year analysis of our patients with calciphylaxis, terminal renal insufficiency, and diabetes mellitus, the individual skin graft take rate was 30-90%. A complete wound closure was achieved in six of seven patients. We observed no surgery-related complications, no wound infection or sepsis. Patients reported about rapid improvement of quality of life and decreased pain.[55]

Negative pressure wound therapy can increase the take rate of skin grafts in chronic leg ulcers.[56] Whether its use in calciphylaxis offers an additional benefit for the patients can yet not be decided because of small numbers of published cases.[57]

Revascularization by vascular surgery, repeated aggressive debridement, and skin transplantation can improve the limb salvage rate.[58]

Hyperbaric oxygen therapy

Improved to wound healing of calciphylaxis patients was reported when hyperbaric oxygen therapy (HOT) was delivered as an adjuvant treatment in multiple sessions.[5960] The number of patients treated with HOT is small and the treatment has never been investigated as either single option or in a comparative trial.

Conclusions

There is no doubt that calciphylaxis patients need interdisciplinary care. Multimodal therapy for renal end-stage-related calciphylaxis includes intensified hemodialysis with non-calcium/non-aluminum phosphate binders, sodium thiosulfate, cinacalcet, HOT, and parathyroidectomy without aggressive wound debridement resulted in failure of wound healing in 50% of patients with a mortality rate of 83%.[61]

There is still no consensus on the optimum treatment of calciphylaxis, but treatment should aim to close all cutaneous ulcers. Aggressive debridement and skin grafting may reduce the time until complete wound closure. Without aggressive debridement, the multimodal approach remains incomplete and the risk of sepsis remains high despite systemic antibiotic therapy.

CME-Questions

Calciphylaxis is a potentially life-threatening disorder. What are the known risk factors?

Obesity.

End-stage renal disease.

Psoriasis.

Hodgkin's lymphoma.

Calciphylaxis is often associated with underlying pathologies. Which one right?

Helicobacter pylori causing gastritis.

Hepatitis C infection.

Systemic lupus erythematosus.

Leprosy.

Calciphylaxis diagnosis is based on which parameters?

Histopathology of deep ulcer biopsies.

Rapid growing painful skin ulcers.

Increased blood glucose level.

Increased serum iron level.

What seems to be the best imaging technique for diagnosis of calciphylaxis?

Thoracic X-ray.

Mammography.

Computerized tomography.

Diagnostic ultrasound.

Which stain is preferred to visualize vascular calcification?

Hematoxylin-eosin.

Alcian blue.

Congo red.

Von Kossa.

When is parathyroidectomy curative in calciphylaxis?

In any case of calciphylaxis.

In renal end-stage related calciphylaxis.

In primary hyperparathyroidism.

Never.

Which medical drugs have been identified as possible inducers or aggravators of calciphylaxis?

Calcium-containing phosphate binders.

Vitamin-K antagonists.

Systemic corticosteroids.

Levamisole.

Which medical drugs seem to be beneficial in multimodal therapy of calciphylaxis?

Heparin.

Cinacalcet.

Systemic corticosteroids.

Sodium thiosulfate.

What are the major causes of mortality in calciphylaxis?

Cardiovascular events.

Skin cancer.

Massive bleeding.

Sepsis.

Which treatment has been shown to reduce the mortality risk?

Cinacalcet.

Sodium thiosulfate.

Intensified hemodialysis.

Aggressive surgical wound debridement.

What is new?

The major clue to understanding of calciphylaxis is the discovery of vascular smooth muscle cell transdifferentiation. No targeted therapy has been developed, yet FXR receptor antagonists are on the horizon. Multimodal therapy is incomplete without aggressive surgical debridement.