Lindsay Strowd, MD

To the Editor:

Solid-organ transplant recipients can develop a range of dermatologic consequences due to chronic immunosuppression, including frequent skin infections and malignancies. Atopic dermatitis (AD) and psoriasis are relatively rare in this population because many immunosuppressive therapies, such as mycophenolate mofetil and tacrolimus, also are used to treat inflammatory dermatoses.¹ In a large renal transplant population, the prevalence of AD was 1.3%.² The pathogenesis of posttransplantation AD is poorly understood, and standard treatment regimens have not been defined. Dupilumab is a novel biologic medication that has demonstrated efficacy in the treatment of AD.³ Reports of dupilumab use for AD management in solid-organ transplant recipients are limited in the literature.

A 29-year-old woman with a history of a heart transplant 4 years prior presented to our dermatology clinic with an itchy rash over the entire body. Since the transplant, she had been on long-term immunosuppression with prednisone, mycophenolate mofetil, and tacrolimus. The rash appeared after she switched from brand-name to generic versions of the medications. Physical examination revealed erythematous scaly plaques on the lateral face, back, chest, arms, and legs covering approximately 10% of the body surface area. The patient’s total serum IgE level was elevated at 711,500 µg/L (reference range, 0–1500 µg/L). Outside biopsies revealed changes consistent with spongiotic dermatitis, and patch testing performed by an outside physician was positive for sensitivity to the preservative bronopol.

The patient was switched back to brand-name tacrolimus, but the rash did not improve. Topical steroids, phototherapy, and omalizumab were ineffective. The itching was primarily managed with desoximetasone spray, mometasone cream, and loratidine. With approval from the patient’s transplant team outside of our hospital system, she was started on dupilumab 300 mg once every 14 days. Complete clearance of the rash was noted within 3 months of treatment. Besides bilateral conjunctivitis, which was treated with ophthalmic prednisolone and moxifloxacin solutions, dupilumab was well tolerated. No issues related to immunosuppressant levels or graft-related issues, including rejection, were reported at 6-, 12-, and 18-month follow-up visits.

Atopic dermatitis is characterized by activation of type 2 immune responses, skin barrier defects, and increased Staphylococcus aureus colonization.⁴ A potential mechanism for the development of AD in transplant recipients relates to their use of tacrolimus for chronic immunosuppression. Tacrolimus increases intestinal permeability and therefore allows greater absorption of allergens. This influx of allergens promotes hypersensitivity reactions, resulting in elevated IgE levels and eosinophilia. Tacrolimus also facilitates predominance of helper T cells (T_H2 cytokines) through selective inhibition of the T_H1 cytokine IL-2.⁵

Dupilumab is a human monoclonal antibody that blocks IL-4 and IL-13, which are key drivers of T_H2-mediated inflammation. In addition to downregulation of inflammatory mediators, dupilumab also increases production of epidermal barrier proteins, resulting in skin repair. It has demonstrated rapid, dose-dependent efficacy in patients with moderate to severe AD.⁶ Dupilumab boasts a good safety profile with no increase in risk for skin infections compared to placebo⁶; however, its safety has not yet been verified in transplant recipients.

Our case is notable for the severity of the patient’s AD despite considerable immunosuppression with transplant medications. Development of AD was associated with a switch from brand-name to generic drugs, which is not commonly reported. Her condition was refractory to a litany of treatments prior to a trial of dupilumab. The rapid clearance observed with this novel biologic medication highlights its potential to provide relief to patients who have particularly tenacious cases of AD. Prior to starting dupilumab, we do recommend more extensive laboratory testing in immunosuppressed patients including transplant recipients and patients with human immunodeficiency virus. We illustrate that a history of solid-organ transplant need not exclude patients from consideration for dupilumab therapy.

To the Editor:

Solid-organ transplant recipients can develop a range of dermatologic consequences due to chronic immunosuppression, including frequent skin infections and malignancies. Atopic dermatitis (AD) and psoriasis are relatively rare in this population because many immunosuppressive therapies, such as mycophenolate mofetil and tacrolimus, also are used to treat inflammatory dermatoses.¹ In a large renal transplant population, the prevalence of AD was 1.3%.² The pathogenesis of posttransplantation AD is poorly understood, and standard treatment regimens have not been defined. Dupilumab is a novel biologic medication that has demonstrated efficacy in the treatment of AD.³ Reports of dupilumab use for AD management in solid-organ transplant recipients are limited in the literature.

A 29-year-old woman with a history of a heart transplant 4 years prior presented to our dermatology clinic with an itchy rash over the entire body. Since the transplant, she had been on long-term immunosuppression with prednisone, mycophenolate mofetil, and tacrolimus. The rash appeared after she switched from brand-name to generic versions of the medications. Physical examination revealed erythematous scaly plaques on the lateral face, back, chest, arms, and legs covering approximately 10% of the body surface area. The patient’s total serum IgE level was elevated at 711,500 µg/L (reference range, 0–1500 µg/L). Outside biopsies revealed changes consistent with spongiotic dermatitis, and patch testing performed by an outside physician was positive for sensitivity to the preservative bronopol.

The patient was switched back to brand-name tacrolimus, but the rash did not improve. Topical steroids, phototherapy, and omalizumab were ineffective. The itching was primarily managed with desoximetasone spray, mometasone cream, and loratidine. With approval from the patient’s transplant team outside of our hospital system, she was started on dupilumab 300 mg once every 14 days. Complete clearance of the rash was noted within 3 months of treatment. Besides bilateral conjunctivitis, which was treated with ophthalmic prednisolone and moxifloxacin solutions, dupilumab was well tolerated. No issues related to immunosuppressant levels or graft-related issues, including rejection, were reported at 6-, 12-, and 18-month follow-up visits.

Atopic dermatitis is characterized by activation of type 2 immune responses, skin barrier defects, and increased Staphylococcus aureus colonization.⁴ A potential mechanism for the development of AD in transplant recipients relates to their use of tacrolimus for chronic immunosuppression. Tacrolimus increases intestinal permeability and therefore allows greater absorption of allergens. This influx of allergens promotes hypersensitivity reactions, resulting in elevated IgE levels and eosinophilia. Tacrolimus also facilitates predominance of helper T cells (T_H2 cytokines) through selective inhibition of the T_H1 cytokine IL-2.⁵

Dupilumab is a human monoclonal antibody that blocks IL-4 and IL-13, which are key drivers of T_H2-mediated inflammation. In addition to downregulation of inflammatory mediators, dupilumab also increases production of epidermal barrier proteins, resulting in skin repair. It has demonstrated rapid, dose-dependent efficacy in patients with moderate to severe AD.⁶ Dupilumab boasts a good safety profile with no increase in risk for skin infections compared to placebo⁶; however, its safety has not yet been verified in transplant recipients.

Our case is notable for the severity of the patient’s AD despite considerable immunosuppression with transplant medications. Development of AD was associated with a switch from brand-name to generic drugs, which is not commonly reported. Her condition was refractory to a litany of treatments prior to a trial of dupilumab. The rapid clearance observed with this novel biologic medication highlights its potential to provide relief to patients who have particularly tenacious cases of AD. Prior to starting dupilumab, we do recommend more extensive laboratory testing in immunosuppressed patients including transplant recipients and patients with human immunodeficiency virus. We illustrate that a history of solid-organ transplant need not exclude patients from consideration for dupilumab therapy.

To the Editor:

Solid-organ transplant recipients can develop a range of dermatologic consequences due to chronic immunosuppression, including frequent skin infections and malignancies. Atopic dermatitis (AD) and psoriasis are relatively rare in this population because many immunosuppressive therapies, such as mycophenolate mofetil and tacrolimus, also are used to treat inflammatory dermatoses.¹ In a large renal transplant population, the prevalence of AD was 1.3%.² The pathogenesis of posttransplantation AD is poorly understood, and standard treatment regimens have not been defined. Dupilumab is a novel biologic medication that has demonstrated efficacy in the treatment of AD.³ Reports of dupilumab use for AD management in solid-organ transplant recipients are limited in the literature.

A 29-year-old woman with a history of a heart transplant 4 years prior presented to our dermatology clinic with an itchy rash over the entire body. Since the transplant, she had been on long-term immunosuppression with prednisone, mycophenolate mofetil, and tacrolimus. The rash appeared after she switched from brand-name to generic versions of the medications. Physical examination revealed erythematous scaly plaques on the lateral face, back, chest, arms, and legs covering approximately 10% of the body surface area. The patient’s total serum IgE level was elevated at 711,500 µg/L (reference range, 0–1500 µg/L). Outside biopsies revealed changes consistent with spongiotic dermatitis, and patch testing performed by an outside physician was positive for sensitivity to the preservative bronopol.

The patient was switched back to brand-name tacrolimus, but the rash did not improve. Topical steroids, phototherapy, and omalizumab were ineffective. The itching was primarily managed with desoximetasone spray, mometasone cream, and loratidine. With approval from the patient’s transplant team outside of our hospital system, she was started on dupilumab 300 mg once every 14 days. Complete clearance of the rash was noted within 3 months of treatment. Besides bilateral conjunctivitis, which was treated with ophthalmic prednisolone and moxifloxacin solutions, dupilumab was well tolerated. No issues related to immunosuppressant levels or graft-related issues, including rejection, were reported at 6-, 12-, and 18-month follow-up visits.

Atopic dermatitis is characterized by activation of type 2 immune responses, skin barrier defects, and increased Staphylococcus aureus colonization.⁴ A potential mechanism for the development of AD in transplant recipients relates to their use of tacrolimus for chronic immunosuppression. Tacrolimus increases intestinal permeability and therefore allows greater absorption of allergens. This influx of allergens promotes hypersensitivity reactions, resulting in elevated IgE levels and eosinophilia. Tacrolimus also facilitates predominance of helper T cells (T_H2 cytokines) through selective inhibition of the T_H1 cytokine IL-2.⁵

Dupilumab is a human monoclonal antibody that blocks IL-4 and IL-13, which are key drivers of T_H2-mediated inflammation. In addition to downregulation of inflammatory mediators, dupilumab also increases production of epidermal barrier proteins, resulting in skin repair. It has demonstrated rapid, dose-dependent efficacy in patients with moderate to severe AD.⁶ Dupilumab boasts a good safety profile with no increase in risk for skin infections compared to placebo⁶; however, its safety has not yet been verified in transplant recipients.

Our case is notable for the severity of the patient’s AD despite considerable immunosuppression with transplant medications. Development of AD was associated with a switch from brand-name to generic drugs, which is not commonly reported. Her condition was refractory to a litany of treatments prior to a trial of dupilumab. The rapid clearance observed with this novel biologic medication highlights its potential to provide relief to patients who have particularly tenacious cases of AD. Prior to starting dupilumab, we do recommend more extensive laboratory testing in immunosuppressed patients including transplant recipients and patients with human immunodeficiency virus. We illustrate that a history of solid-organ transplant need not exclude patients from consideration for dupilumab therapy.

Calciphylaxis, also known as calcific uremic arteriolopathy, is a painful skin condition classically seen in patients with end-stage renal disease (ESRD), particularly those on chronic dialysis.^1,2 It also has increasingly been reported in patients with normal renal function and calcium and phosphate homeostasis.^3,4 Effective diagnosis and management of calciphylaxis remains challenging for physicians.^2,5 The condition is characterized by tissue ischemia caused by calcification of cutaneous arteriolar vessels. As a result, calciphylaxis is associated with high mortality rates, ranging from 60% to 80%.^5,6 Excruciating pain and nonhealing ulcers often lead to recurrent hospitalizations and infectious complications,⁷ and poor nutritional status, chronic pain, depression, and insomnia can further complicate recovery and lead to poor quality of life.⁸

We provide an update on calciphylaxis etiopathogenesis, diagnosis, and management. We also highlight some challenges faced in managing this potentially fatal condition.

Epidemiology

Calciphylaxis is considered a rare dermatosis with an estimated annual incidence of 1% to 4% in ESRD patients on dialysis. Recent data suggest that incidence of calciphylaxis is rising,^5,7,9 which may stem from an increased use of calcium-based phosphate binders, an actual rise in disease incidence, and/or increased recognition of the disease.⁵ It is difficult to estimate the exact disease burden of calciphylaxis because the diagnostic criteria are not well defined, often leading to missed or delayed diagnosis.^3,10 Furthermore, there is no centralized registry for calciphylaxis cases.³

Etiology and Pathogenesis

Calciphylaxis is thought to have a multifactorial etiology with the exact cause or trigger unknown.⁷ A long list of risk factors and triggers is associated with the condition (Table 1). Calciphylaxis primarily affects small arteries (40–600 μm in diameter) that become calcified due to an imbalance between inhibitors and promoters of calcification.^2,11 Fetuin-A and matrix Gla protein inhibit vascular calcification and are downregulated in calciphylaxis.^12,13 Dysfunctional calcium, phosphate, and parathyroid hormone regulatory pathways provide an increased substrate for the process of calcification, which causes endothelial damage and microthrombosis, resulting in tissue ischemia and infarction.^14,15 Notably, there is growing interest in the role of vitamin K in the pathogenesis of calciphylaxis. Vitamin K inhibits vascular calcification, possibly by increasing the circulating levels of carboxylated matrix Gla protein.¹⁶

Clinical Features

Calciphylaxis is most commonly seen on the legs, abdomen, and buttocks.² Patients with ESRD commonly develop proximal lesions affecting adipose-rich sites and have a poor prognosis. Distal lesions are more common in patients with nonuremic calciphylaxis, and mortality rates are lower in this population.²

Early lesions present as painful skin nodules or indurated plaques that often are rock-hard or firm to palpation with overlying mottling or a livedoid pattern (Figure, A). Early lesions progress from livedo reticularis to livedo racemosa and then to retiform purpura (Figure, B). Purpuric lesions later evolve into black eschars (Figure, C), then to necrotic, ulcerated, malodorous plaques or nodules in later stages of the disease (Figure, D). Lesions also may develop a gangrenous sclerotic appearance.^2,5

Although most patients with calciphylaxis have ESRD, nonuremic patients also can develop the disease. Those with calciphylaxis who do not have renal dysfunction frequently have other risk factors for the disease and often report another notable health problem in the weeks or months prior to presentation.⁴ More than half of patients with calciphylaxis become bedridden or require use of a wheelchair.¹⁷ Pain is characteristically severe throughout the course of the disease; it may even precede the appearance of the skin lesions.¹⁸ Because the pain is associated with ischemia, it tends to be relatively refractory to treatment with opioids. Rare extracutaneous vascular calcifications may lead to visual impairment, gastrointestinal tract bleeding, and myopathy.^5,9,19,20

Diagnosis

Considering the high morbidity and mortality associated with calciphylaxis, it is important to provide accurate and timely diagnosis; however, there currently are no validated diagnostic criteria for calciphylaxis. Careful correlation of clinical and histologic findings is required. Calciphylaxis biopsies have demonstrated medial calcification and proliferation of the intima of small- to medium-sized arteries.²¹ Lobular and septal panniculitis and extravascular soft-tissue calcification, particularly stippled calcification of the eccrine sweat glands, also has been seen.^2,22 Special calcium stains (eg, von Kossa, Alizarin red) increase the sensitivity of biopsy by highlighting subtle areas of intravascular and extravascular calcification.^5,23 Sufficient sampling of subcutaneous tissue and specimen evaluation by an experienced dermatopathologist are necessary to ensure proper interpretation of the histologic findings.

Despite these measures, skin biopsies may be nondiagnostic or falsely negative; therefore, when there is high clinical suspicion, it may be appropriate to move forward with a presumptive diagnosis of calciphylaxis even if the histologic findings are nondiagnostic.^1,9,24 It also is worth noting that localized progression and ulceration may occur following skin biopsy, such that biopsy may even be contraindicated in certain cases (eg, penile calciphylaxis).

Standard laboratory workup for calciphylaxis includes evaluation for associated risk factors as well as exclusion of other conditions in the differential diagnosis (Table 2). Blood tests to evaluate for risk factors include liver and renal function tests, a complete metabolic panel, parathyroid hormone level, and serum albumin level.⁵ Elevated calcium and phosphate levels may signal disturbed calcium and phosphate homeostasis but are neither sensitive nor specific for the diagnosis.²⁵ Complete blood cell count, blood cultures, thorough hypercoagulability workup (including but not limited to antiphospholipid antibodies, proteins C and S, factor V Leiden, antithrombin III, homocysteine, methylenetetrahydrofolate reductase mutation, and cryoglobulins), rheumatoid factor, antineutrophil cytoplasmic antibodies, and antinuclear antibody testing may be relevant to help identify contributing factors or mimickers of calciphylaxis.⁵ Various imaging modalities also have been used to evaluate for the presence of soft-tissue calcification in areas of suspected calciphylaxis, including radiography, mammography, computed tomography, ultrasonography, nuclear bone scintigraphy, and spectroscopy.^2,26,27 Unfortunately, there currently is no standardized reproducible imaging modality for reliable diagnosis of calciphylaxis. Ultimately, histologic and radiographic findings should always be interpreted in the context of relevant clinical findings.^2,9

Prevention

Reduction of the net calcium phosphorus product may help reduce the risk of calciphylaxis in ESRD patients, which can be accomplished by using non–calcium-phosphate binders, adequate dialysis, and restricting use of vitamin D and vitamin K antagonists.^2,5 There are limited data regarding the benefits of using bisphosphonates and cinacalcet in ESRD patients on dialysis to prevent calciphylaxis.^28,29

Management

Management of calciphylaxis is multifactorial. Besides dermatology and nephrology, specialists in pain management, wound care, plastic surgery, and nutrition are critical partners in management.^1,5,9,30 Nephrologists can help optimize calcium and phosphate balance and ensure adequate dialysis. Pain specialists can aid in creating aggressive multiagent pain regimens that target the neuropathic/ischemic and physical aspects of calciphylaxis pain. When appropriate, nutrition specialists can help establish high-protein, low-phosphorus diets, and wound specialists can provide access to advanced wound dressings and adjunctive hyperbaric oxygen therapy. Plastic surgeons can provide conservative debridement procedures in a subset of patients, usually those with distal stable disease.

The limited understanding of the etiopathogenesis of calciphylaxis and the lack of data on its management are reflected in the limited treatment options for the disease (Table 3).^2,5,9 There are no formal algorithms for the treatment of calciphylaxis. Therapeutic trials are scarce, and most of the current treatment recommendations are based on small retrospective reports or case series. Sodium thiosulfate has been the most widely used treatment option since 2004, when its use in calciphylaxis was first reported.³¹ Sodium thiosulfate chelates calcium and is thought to have antioxidant and vasodilatory properties.³² There are a few promising clinical trials and large-scale studies (Table 4) that aim to evaluate the efficacy of existing treatments (eg, sodium thiosulfate) as well as novel treatment options such as lanthanum carbonate, SNF472 (hexasodium phytate), and vitamin K.^33-36

Prognosis

Calciphylaxis is a potentially fatal condition with a poor prognosis and a median survival rate of approximately 1 year following the appearance of skin lesions.^37-39 Patients with proximal lesions and those on peritoneal dialysis (as opposed to hemodialysis) have a worse prognosis.⁴⁰ Mortality rates are estimated to be 30% at 6 months, 50% at 12 months, and 80% at 2 years, with sepsis secondary to infection of cutaneous ulcers being the leading cause of death.^37-39 The impact of calciphylaxis on patient quality of life and activities of daily living is severe.^8,17

Future Directions

Multi-institution cohort studies and collaborative registries are needed to provide updated information related to the epidemiology, diagnosis, treatment, morbidity, and mortality associated with calciphylaxis and to help formulate evidence-based diagnostic criteria. Radiographic and histologic studies, as well as other tools for early and accurate diagnosis of calciphylaxis, should be studied for feasibility, accuracy, and reproducibility. The incidence of nonuremic calciphylaxis points toward pathogenic pathways besides those based on the bone-mineral axis. Basic science research directed at improving understanding of the pathophysiology of calciphylaxis would be helpful in devising new treatment strategies targeting these pathways. Establishment of a collaborative, multi-institutional calciphylaxis working group would enable experts to formulate therapeutic guidelines based on current evidence. Such a group could facilitate initiation of large prospective studies to establish the efficacy of existing and new treatment modalities for calciphylaxis. A working group within the Society for Dermatology Hospitalists has been tasked with addressing these issues and is currently establishing a multicenter calciphylaxis database.

Calciphylaxis, also known as calcific uremic arteriolopathy, is a painful skin condition classically seen in patients with end-stage renal disease (ESRD), particularly those on chronic dialysis.^1,2 It also has increasingly been reported in patients with normal renal function and calcium and phosphate homeostasis.^3,4 Effective diagnosis and management of calciphylaxis remains challenging for physicians.^2,5 The condition is characterized by tissue ischemia caused by calcification of cutaneous arteriolar vessels. As a result, calciphylaxis is associated with high mortality rates, ranging from 60% to 80%.^5,6 Excruciating pain and nonhealing ulcers often lead to recurrent hospitalizations and infectious complications,⁷ and poor nutritional status, chronic pain, depression, and insomnia can further complicate recovery and lead to poor quality of life.⁸

We provide an update on calciphylaxis etiopathogenesis, diagnosis, and management. We also highlight some challenges faced in managing this potentially fatal condition.

Epidemiology

Calciphylaxis is considered a rare dermatosis with an estimated annual incidence of 1% to 4% in ESRD patients on dialysis. Recent data suggest that incidence of calciphylaxis is rising,^5,7,9 which may stem from an increased use of calcium-based phosphate binders, an actual rise in disease incidence, and/or increased recognition of the disease.⁵ It is difficult to estimate the exact disease burden of calciphylaxis because the diagnostic criteria are not well defined, often leading to missed or delayed diagnosis.^3,10 Furthermore, there is no centralized registry for calciphylaxis cases.³

Etiology and Pathogenesis

Calciphylaxis is thought to have a multifactorial etiology with the exact cause or trigger unknown.⁷ A long list of risk factors and triggers is associated with the condition (Table 1). Calciphylaxis primarily affects small arteries (40–600 μm in diameter) that become calcified due to an imbalance between inhibitors and promoters of calcification.^2,11 Fetuin-A and matrix Gla protein inhibit vascular calcification and are downregulated in calciphylaxis.^12,13 Dysfunctional calcium, phosphate, and parathyroid hormone regulatory pathways provide an increased substrate for the process of calcification, which causes endothelial damage and microthrombosis, resulting in tissue ischemia and infarction.^14,15 Notably, there is growing interest in the role of vitamin K in the pathogenesis of calciphylaxis. Vitamin K inhibits vascular calcification, possibly by increasing the circulating levels of carboxylated matrix Gla protein.¹⁶

Clinical Features

Calciphylaxis is most commonly seen on the legs, abdomen, and buttocks.² Patients with ESRD commonly develop proximal lesions affecting adipose-rich sites and have a poor prognosis. Distal lesions are more common in patients with nonuremic calciphylaxis, and mortality rates are lower in this population.²

Early lesions present as painful skin nodules or indurated plaques that often are rock-hard or firm to palpation with overlying mottling or a livedoid pattern (Figure, A). Early lesions progress from livedo reticularis to livedo racemosa and then to retiform purpura (Figure, B). Purpuric lesions later evolve into black eschars (Figure, C), then to necrotic, ulcerated, malodorous plaques or nodules in later stages of the disease (Figure, D). Lesions also may develop a gangrenous sclerotic appearance.^2,5

Although most patients with calciphylaxis have ESRD, nonuremic patients also can develop the disease. Those with calciphylaxis who do not have renal dysfunction frequently have other risk factors for the disease and often report another notable health problem in the weeks or months prior to presentation.⁴ More than half of patients with calciphylaxis become bedridden or require use of a wheelchair.¹⁷ Pain is characteristically severe throughout the course of the disease; it may even precede the appearance of the skin lesions.¹⁸ Because the pain is associated with ischemia, it tends to be relatively refractory to treatment with opioids. Rare extracutaneous vascular calcifications may lead to visual impairment, gastrointestinal tract bleeding, and myopathy.^5,9,19,20

Diagnosis

Considering the high morbidity and mortality associated with calciphylaxis, it is important to provide accurate and timely diagnosis; however, there currently are no validated diagnostic criteria for calciphylaxis. Careful correlation of clinical and histologic findings is required. Calciphylaxis biopsies have demonstrated medial calcification and proliferation of the intima of small- to medium-sized arteries.²¹ Lobular and septal panniculitis and extravascular soft-tissue calcification, particularly stippled calcification of the eccrine sweat glands, also has been seen.^2,22 Special calcium stains (eg, von Kossa, Alizarin red) increase the sensitivity of biopsy by highlighting subtle areas of intravascular and extravascular calcification.^5,23 Sufficient sampling of subcutaneous tissue and specimen evaluation by an experienced dermatopathologist are necessary to ensure proper interpretation of the histologic findings.

Despite these measures, skin biopsies may be nondiagnostic or falsely negative; therefore, when there is high clinical suspicion, it may be appropriate to move forward with a presumptive diagnosis of calciphylaxis even if the histologic findings are nondiagnostic.^1,9,24 It also is worth noting that localized progression and ulceration may occur following skin biopsy, such that biopsy may even be contraindicated in certain cases (eg, penile calciphylaxis).

Standard laboratory workup for calciphylaxis includes evaluation for associated risk factors as well as exclusion of other conditions in the differential diagnosis (Table 2). Blood tests to evaluate for risk factors include liver and renal function tests, a complete metabolic panel, parathyroid hormone level, and serum albumin level.⁵ Elevated calcium and phosphate levels may signal disturbed calcium and phosphate homeostasis but are neither sensitive nor specific for the diagnosis.²⁵ Complete blood cell count, blood cultures, thorough hypercoagulability workup (including but not limited to antiphospholipid antibodies, proteins C and S, factor V Leiden, antithrombin III, homocysteine, methylenetetrahydrofolate reductase mutation, and cryoglobulins), rheumatoid factor, antineutrophil cytoplasmic antibodies, and antinuclear antibody testing may be relevant to help identify contributing factors or mimickers of calciphylaxis.⁵ Various imaging modalities also have been used to evaluate for the presence of soft-tissue calcification in areas of suspected calciphylaxis, including radiography, mammography, computed tomography, ultrasonography, nuclear bone scintigraphy, and spectroscopy.^2,26,27 Unfortunately, there currently is no standardized reproducible imaging modality for reliable diagnosis of calciphylaxis. Ultimately, histologic and radiographic findings should always be interpreted in the context of relevant clinical findings.^2,9

Prevention

Reduction of the net calcium phosphorus product may help reduce the risk of calciphylaxis in ESRD patients, which can be accomplished by using non–calcium-phosphate binders, adequate dialysis, and restricting use of vitamin D and vitamin K antagonists.^2,5 There are limited data regarding the benefits of using bisphosphonates and cinacalcet in ESRD patients on dialysis to prevent calciphylaxis.^28,29

Management

Management of calciphylaxis is multifactorial. Besides dermatology and nephrology, specialists in pain management, wound care, plastic surgery, and nutrition are critical partners in management.^1,5,9,30 Nephrologists can help optimize calcium and phosphate balance and ensure adequate dialysis. Pain specialists can aid in creating aggressive multiagent pain regimens that target the neuropathic/ischemic and physical aspects of calciphylaxis pain. When appropriate, nutrition specialists can help establish high-protein, low-phosphorus diets, and wound specialists can provide access to advanced wound dressings and adjunctive hyperbaric oxygen therapy. Plastic surgeons can provide conservative debridement procedures in a subset of patients, usually those with distal stable disease.

The limited understanding of the etiopathogenesis of calciphylaxis and the lack of data on its management are reflected in the limited treatment options for the disease (Table 3).^2,5,9 There are no formal algorithms for the treatment of calciphylaxis. Therapeutic trials are scarce, and most of the current treatment recommendations are based on small retrospective reports or case series. Sodium thiosulfate has been the most widely used treatment option since 2004, when its use in calciphylaxis was first reported.³¹ Sodium thiosulfate chelates calcium and is thought to have antioxidant and vasodilatory properties.³² There are a few promising clinical trials and large-scale studies (Table 4) that aim to evaluate the efficacy of existing treatments (eg, sodium thiosulfate) as well as novel treatment options such as lanthanum carbonate, SNF472 (hexasodium phytate), and vitamin K.^33-36

Prognosis

Calciphylaxis is a potentially fatal condition with a poor prognosis and a median survival rate of approximately 1 year following the appearance of skin lesions.^37-39 Patients with proximal lesions and those on peritoneal dialysis (as opposed to hemodialysis) have a worse prognosis.⁴⁰ Mortality rates are estimated to be 30% at 6 months, 50% at 12 months, and 80% at 2 years, with sepsis secondary to infection of cutaneous ulcers being the leading cause of death.^37-39 The impact of calciphylaxis on patient quality of life and activities of daily living is severe.^8,17

Future Directions

Multi-institution cohort studies and collaborative registries are needed to provide updated information related to the epidemiology, diagnosis, treatment, morbidity, and mortality associated with calciphylaxis and to help formulate evidence-based diagnostic criteria. Radiographic and histologic studies, as well as other tools for early and accurate diagnosis of calciphylaxis, should be studied for feasibility, accuracy, and reproducibility. The incidence of nonuremic calciphylaxis points toward pathogenic pathways besides those based on the bone-mineral axis. Basic science research directed at improving understanding of the pathophysiology of calciphylaxis would be helpful in devising new treatment strategies targeting these pathways. Establishment of a collaborative, multi-institutional calciphylaxis working group would enable experts to formulate therapeutic guidelines based on current evidence. Such a group could facilitate initiation of large prospective studies to establish the efficacy of existing and new treatment modalities for calciphylaxis. A working group within the Society for Dermatology Hospitalists has been tasked with addressing these issues and is currently establishing a multicenter calciphylaxis database.

Calciphylaxis, also known as calcific uremic arteriolopathy, is a painful skin condition classically seen in patients with end-stage renal disease (ESRD), particularly those on chronic dialysis.^1,2 It also has increasingly been reported in patients with normal renal function and calcium and phosphate homeostasis.^3,4 Effective diagnosis and management of calciphylaxis remains challenging for physicians.^2,5 The condition is characterized by tissue ischemia caused by calcification of cutaneous arteriolar vessels. As a result, calciphylaxis is associated with high mortality rates, ranging from 60% to 80%.^5,6 Excruciating pain and nonhealing ulcers often lead to recurrent hospitalizations and infectious complications,⁷ and poor nutritional status, chronic pain, depression, and insomnia can further complicate recovery and lead to poor quality of life.⁸

We provide an update on calciphylaxis etiopathogenesis, diagnosis, and management. We also highlight some challenges faced in managing this potentially fatal condition.

Epidemiology

Calciphylaxis is considered a rare dermatosis with an estimated annual incidence of 1% to 4% in ESRD patients on dialysis. Recent data suggest that incidence of calciphylaxis is rising,^5,7,9 which may stem from an increased use of calcium-based phosphate binders, an actual rise in disease incidence, and/or increased recognition of the disease.⁵ It is difficult to estimate the exact disease burden of calciphylaxis because the diagnostic criteria are not well defined, often leading to missed or delayed diagnosis.^3,10 Furthermore, there is no centralized registry for calciphylaxis cases.³

Etiology and Pathogenesis

Calciphylaxis is thought to have a multifactorial etiology with the exact cause or trigger unknown.⁷ A long list of risk factors and triggers is associated with the condition (Table 1). Calciphylaxis primarily affects small arteries (40–600 μm in diameter) that become calcified due to an imbalance between inhibitors and promoters of calcification.^2,11 Fetuin-A and matrix Gla protein inhibit vascular calcification and are downregulated in calciphylaxis.^12,13 Dysfunctional calcium, phosphate, and parathyroid hormone regulatory pathways provide an increased substrate for the process of calcification, which causes endothelial damage and microthrombosis, resulting in tissue ischemia and infarction.^14,15 Notably, there is growing interest in the role of vitamin K in the pathogenesis of calciphylaxis. Vitamin K inhibits vascular calcification, possibly by increasing the circulating levels of carboxylated matrix Gla protein.¹⁶

Clinical Features

Calciphylaxis is most commonly seen on the legs, abdomen, and buttocks.² Patients with ESRD commonly develop proximal lesions affecting adipose-rich sites and have a poor prognosis. Distal lesions are more common in patients with nonuremic calciphylaxis, and mortality rates are lower in this population.²

Early lesions present as painful skin nodules or indurated plaques that often are rock-hard or firm to palpation with overlying mottling or a livedoid pattern (Figure, A). Early lesions progress from livedo reticularis to livedo racemosa and then to retiform purpura (Figure, B). Purpuric lesions later evolve into black eschars (Figure, C), then to necrotic, ulcerated, malodorous plaques or nodules in later stages of the disease (Figure, D). Lesions also may develop a gangrenous sclerotic appearance.^2,5

Although most patients with calciphylaxis have ESRD, nonuremic patients also can develop the disease. Those with calciphylaxis who do not have renal dysfunction frequently have other risk factors for the disease and often report another notable health problem in the weeks or months prior to presentation.⁴ More than half of patients with calciphylaxis become bedridden or require use of a wheelchair.¹⁷ Pain is characteristically severe throughout the course of the disease; it may even precede the appearance of the skin lesions.¹⁸ Because the pain is associated with ischemia, it tends to be relatively refractory to treatment with opioids. Rare extracutaneous vascular calcifications may lead to visual impairment, gastrointestinal tract bleeding, and myopathy.^5,9,19,20

Diagnosis

Considering the high morbidity and mortality associated with calciphylaxis, it is important to provide accurate and timely diagnosis; however, there currently are no validated diagnostic criteria for calciphylaxis. Careful correlation of clinical and histologic findings is required. Calciphylaxis biopsies have demonstrated medial calcification and proliferation of the intima of small- to medium-sized arteries.²¹ Lobular and septal panniculitis and extravascular soft-tissue calcification, particularly stippled calcification of the eccrine sweat glands, also has been seen.^2,22 Special calcium stains (eg, von Kossa, Alizarin red) increase the sensitivity of biopsy by highlighting subtle areas of intravascular and extravascular calcification.^5,23 Sufficient sampling of subcutaneous tissue and specimen evaluation by an experienced dermatopathologist are necessary to ensure proper interpretation of the histologic findings.

Despite these measures, skin biopsies may be nondiagnostic or falsely negative; therefore, when there is high clinical suspicion, it may be appropriate to move forward with a presumptive diagnosis of calciphylaxis even if the histologic findings are nondiagnostic.^1,9,24 It also is worth noting that localized progression and ulceration may occur following skin biopsy, such that biopsy may even be contraindicated in certain cases (eg, penile calciphylaxis).

Standard laboratory workup for calciphylaxis includes evaluation for associated risk factors as well as exclusion of other conditions in the differential diagnosis (Table 2). Blood tests to evaluate for risk factors include liver and renal function tests, a complete metabolic panel, parathyroid hormone level, and serum albumin level.⁵ Elevated calcium and phosphate levels may signal disturbed calcium and phosphate homeostasis but are neither sensitive nor specific for the diagnosis.²⁵ Complete blood cell count, blood cultures, thorough hypercoagulability workup (including but not limited to antiphospholipid antibodies, proteins C and S, factor V Leiden, antithrombin III, homocysteine, methylenetetrahydrofolate reductase mutation, and cryoglobulins), rheumatoid factor, antineutrophil cytoplasmic antibodies, and antinuclear antibody testing may be relevant to help identify contributing factors or mimickers of calciphylaxis.⁵ Various imaging modalities also have been used to evaluate for the presence of soft-tissue calcification in areas of suspected calciphylaxis, including radiography, mammography, computed tomography, ultrasonography, nuclear bone scintigraphy, and spectroscopy.^2,26,27 Unfortunately, there currently is no standardized reproducible imaging modality for reliable diagnosis of calciphylaxis. Ultimately, histologic and radiographic findings should always be interpreted in the context of relevant clinical findings.^2,9

Prevention

Reduction of the net calcium phosphorus product may help reduce the risk of calciphylaxis in ESRD patients, which can be accomplished by using non–calcium-phosphate binders, adequate dialysis, and restricting use of vitamin D and vitamin K antagonists.^2,5 There are limited data regarding the benefits of using bisphosphonates and cinacalcet in ESRD patients on dialysis to prevent calciphylaxis.^28,29

Management

Management of calciphylaxis is multifactorial. Besides dermatology and nephrology, specialists in pain management, wound care, plastic surgery, and nutrition are critical partners in management.^1,5,9,30 Nephrologists can help optimize calcium and phosphate balance and ensure adequate dialysis. Pain specialists can aid in creating aggressive multiagent pain regimens that target the neuropathic/ischemic and physical aspects of calciphylaxis pain. When appropriate, nutrition specialists can help establish high-protein, low-phosphorus diets, and wound specialists can provide access to advanced wound dressings and adjunctive hyperbaric oxygen therapy. Plastic surgeons can provide conservative debridement procedures in a subset of patients, usually those with distal stable disease.

The limited understanding of the etiopathogenesis of calciphylaxis and the lack of data on its management are reflected in the limited treatment options for the disease (Table 3).^2,5,9 There are no formal algorithms for the treatment of calciphylaxis. Therapeutic trials are scarce, and most of the current treatment recommendations are based on small retrospective reports or case series. Sodium thiosulfate has been the most widely used treatment option since 2004, when its use in calciphylaxis was first reported.³¹ Sodium thiosulfate chelates calcium and is thought to have antioxidant and vasodilatory properties.³² There are a few promising clinical trials and large-scale studies (Table 4) that aim to evaluate the efficacy of existing treatments (eg, sodium thiosulfate) as well as novel treatment options such as lanthanum carbonate, SNF472 (hexasodium phytate), and vitamin K.^33-36

Prognosis

Calciphylaxis is a potentially fatal condition with a poor prognosis and a median survival rate of approximately 1 year following the appearance of skin lesions.^37-39 Patients with proximal lesions and those on peritoneal dialysis (as opposed to hemodialysis) have a worse prognosis.⁴⁰ Mortality rates are estimated to be 30% at 6 months, 50% at 12 months, and 80% at 2 years, with sepsis secondary to infection of cutaneous ulcers being the leading cause of death.^37-39 The impact of calciphylaxis on patient quality of life and activities of daily living is severe.^8,17

Future Directions

Multi-institution cohort studies and collaborative registries are needed to provide updated information related to the epidemiology, diagnosis, treatment, morbidity, and mortality associated with calciphylaxis and to help formulate evidence-based diagnostic criteria. Radiographic and histologic studies, as well as other tools for early and accurate diagnosis of calciphylaxis, should be studied for feasibility, accuracy, and reproducibility. The incidence of nonuremic calciphylaxis points toward pathogenic pathways besides those based on the bone-mineral axis. Basic science research directed at improving understanding of the pathophysiology of calciphylaxis would be helpful in devising new treatment strategies targeting these pathways. Establishment of a collaborative, multi-institutional calciphylaxis working group would enable experts to formulate therapeutic guidelines based on current evidence. Such a group could facilitate initiation of large prospective studies to establish the efficacy of existing and new treatment modalities for calciphylaxis. A working group within the Society for Dermatology Hospitalists has been tasked with addressing these issues and is currently establishing a multicenter calciphylaxis database.