September is PAD month. Did you know that the SVS Foundation offers free patient education fliers that you can easily customize with your own office name and contact information? We have one on PAD, one on Smoking and Vascular Disease, and seven others on various vascular-related topics. All are free and available for download in English and Spanish. Visit this page to view and celebrate PAD month with some patient education.

September is PAD month. Did you know that the SVS Foundation offers free patient education fliers that you can easily customize with your own office name and contact information? We have one on PAD, one on Smoking and Vascular Disease, and seven others on various vascular-related topics. All are free and available for download in English and Spanish. Visit this page to view and celebrate PAD month with some patient education.

September is PAD month. Did you know that the SVS Foundation offers free patient education fliers that you can easily customize with your own office name and contact information? We have one on PAD, one on Smoking and Vascular Disease, and seven others on various vascular-related topics. All are free and available for download in English and Spanish. Visit this page to view and celebrate PAD month with some patient education.

To the Editor:

A 75-year-old woman with a history of hypertension, gout, and adult-onset diabetes mellitus was started on dapagliflozin (5 mg) for glycemic control (hemoglobin A_1c, 7.9 [reference range, 4–7]). Within 1 week of starting the medication, she developed a fine papular eruption in a photodistributed area on the neck and chest with associated malaise. The rash progressed over the next 2 weeks, evolving into edematous papules and plaques, some with vesicles involving the neck, chest, postauricular areas, and nose. Approximately 3 weeks after starting dapagliflozin, the patient also developed bilateral painful, hemorrhagic, bullous plaques (10×3 cm overall) without satellite lesions on the dorsal aspects of the hands. The borders of the bullae had rapidly expanding geographic margins and were extremely painful. The patient’s primary care physician advised to discontinue dapagliflozin, as this medication was thought to be triggering the eruption. She was administered triamcinolone (40 mg intramuscularly) and advised to take ibuprofen as needed. She had malaise and reported that she felt hot but had no known fever. No laboratory tests were ordered. 

The lesions on the neck and chest began to fade within 1 week of stopping the medication and administering corticosteroids; however, the hand lesions continued to progress and began to involve the base of the digits (Figure 1). The patient was then seen by a dermatologist who biopsied the hand lesions. Histopathology was characteristic of Sweet syndrome, also known as acute febrile neutrophilic dermatosis and Gomm-Button disease. Notably, there was a dense nodular infiltrate of neutrophils, papillary dermal edema, and leukocytoclastic debris without leukocytoclastic vasculitis (Figure 2).

Because of the presence of lesions on the dorsal aspects of the hands in our patient, the differential diagnosis included the localized variant of Sweet syndrome known as neutrophilic dermatosis of the dorsal hands, but a diagnosis of classic Sweet syndrome was favored due to the lack of intense papillary dermal edema and vasculitis.^1,2 Although the hand lesions appeared after the neck and chest lesions, the temporal relationship of their appearance with medication usage and clearing once the medication was stopped favored these lesions as part of the same drug-induced response.

Dapagliflozin is a member of a new class of medications (gliflozins) used for the treatment of type 2 diabetes mellitus.^3,4 The medication lowers blood glucose by inhibiting the sodium-glucose cotransport protein 2, thus lowering the blood glucose levels by increasing urinary excretion of glucose. Because many patients with type 2 diabetes mellitus are overweight, these medications are poised to gain popularity for weight loss and decreased blood pressure side effects. Three other medications in this class also have been approved by US Food and Drug Administration: empagliflozin, canagliflozin, and ertugliflozin.

Sweet syndrome consists of 4 cardinal features that were first described in 1964: fever, leukocytosis, tender red plaques, and a dermal neutrophilic infiltrate.⁵ Since then, Su and Liu⁶ proposed guidelines consisting of major and minor criteria. In 1996, Walker and Cohen⁷ suggested a set of diagnostic criteria specifically for drug-induced Sweet syndrome, including painful erythematous plaques, histopathologic neutrophilic infiltrate, and fever. Additional criteria included a temporal relationship between drug ingestion and clinical presentation as well as resolution of lesions after drug withdrawal or treatment with systemic corticosteroids.⁷ The lesions of drug-induced Sweet syndrome often are described as painful red papules that can form plaques, may appear vesicular, and are more common in women. These lesions classically appear on the upper extremities, as well as the head, neck, trunk, and back.⁸ Clinically, symptoms most commonly include fever and musculoskeletal involvement, both of which were experienced by the patient who described herself as feeling feverish when the lesions first appeared and reported malaise. Our patient experienced all of these features, and although a fever was not measured in the acute stage of presentation, she reported feeling hot. Other symptoms that may occur include arthralgia, headache, and myalgia.⁹ Microscopically, there is a nodular infiltrate of neutrophils, papillary dermal edema, and leukocytoclastic debris. The pathogenesis of Sweet syndrome remains unclear but can be associated with malignancy, pregnancy, autoimmune disorders, and drug reactions.¹⁰ Many different classes of medications have been reported to cause drug-induced Sweet syndrome and are listed in the Table.^1,8,11 The recommended treatment of Sweet syndrome is systemic corticosteroids.¹²

To the Editor:

A 75-year-old woman with a history of hypertension, gout, and adult-onset diabetes mellitus was started on dapagliflozin (5 mg) for glycemic control (hemoglobin A_1c, 7.9 [reference range, 4–7]). Within 1 week of starting the medication, she developed a fine papular eruption in a photodistributed area on the neck and chest with associated malaise. The rash progressed over the next 2 weeks, evolving into edematous papules and plaques, some with vesicles involving the neck, chest, postauricular areas, and nose. Approximately 3 weeks after starting dapagliflozin, the patient also developed bilateral painful, hemorrhagic, bullous plaques (10×3 cm overall) without satellite lesions on the dorsal aspects of the hands. The borders of the bullae had rapidly expanding geographic margins and were extremely painful. The patient’s primary care physician advised to discontinue dapagliflozin, as this medication was thought to be triggering the eruption. She was administered triamcinolone (40 mg intramuscularly) and advised to take ibuprofen as needed. She had malaise and reported that she felt hot but had no known fever. No laboratory tests were ordered. 

The lesions on the neck and chest began to fade within 1 week of stopping the medication and administering corticosteroids; however, the hand lesions continued to progress and began to involve the base of the digits (Figure 1). The patient was then seen by a dermatologist who biopsied the hand lesions. Histopathology was characteristic of Sweet syndrome, also known as acute febrile neutrophilic dermatosis and Gomm-Button disease. Notably, there was a dense nodular infiltrate of neutrophils, papillary dermal edema, and leukocytoclastic debris without leukocytoclastic vasculitis (Figure 2).

Because of the presence of lesions on the dorsal aspects of the hands in our patient, the differential diagnosis included the localized variant of Sweet syndrome known as neutrophilic dermatosis of the dorsal hands, but a diagnosis of classic Sweet syndrome was favored due to the lack of intense papillary dermal edema and vasculitis.^1,2 Although the hand lesions appeared after the neck and chest lesions, the temporal relationship of their appearance with medication usage and clearing once the medication was stopped favored these lesions as part of the same drug-induced response.

Dapagliflozin is a member of a new class of medications (gliflozins) used for the treatment of type 2 diabetes mellitus.^3,4 The medication lowers blood glucose by inhibiting the sodium-glucose cotransport protein 2, thus lowering the blood glucose levels by increasing urinary excretion of glucose. Because many patients with type 2 diabetes mellitus are overweight, these medications are poised to gain popularity for weight loss and decreased blood pressure side effects. Three other medications in this class also have been approved by US Food and Drug Administration: empagliflozin, canagliflozin, and ertugliflozin.

Sweet syndrome consists of 4 cardinal features that were first described in 1964: fever, leukocytosis, tender red plaques, and a dermal neutrophilic infiltrate.⁵ Since then, Su and Liu⁶ proposed guidelines consisting of major and minor criteria. In 1996, Walker and Cohen⁷ suggested a set of diagnostic criteria specifically for drug-induced Sweet syndrome, including painful erythematous plaques, histopathologic neutrophilic infiltrate, and fever. Additional criteria included a temporal relationship between drug ingestion and clinical presentation as well as resolution of lesions after drug withdrawal or treatment with systemic corticosteroids.⁷ The lesions of drug-induced Sweet syndrome often are described as painful red papules that can form plaques, may appear vesicular, and are more common in women. These lesions classically appear on the upper extremities, as well as the head, neck, trunk, and back.⁸ Clinically, symptoms most commonly include fever and musculoskeletal involvement, both of which were experienced by the patient who described herself as feeling feverish when the lesions first appeared and reported malaise. Our patient experienced all of these features, and although a fever was not measured in the acute stage of presentation, she reported feeling hot. Other symptoms that may occur include arthralgia, headache, and myalgia.⁹ Microscopically, there is a nodular infiltrate of neutrophils, papillary dermal edema, and leukocytoclastic debris. The pathogenesis of Sweet syndrome remains unclear but can be associated with malignancy, pregnancy, autoimmune disorders, and drug reactions.¹⁰ Many different classes of medications have been reported to cause drug-induced Sweet syndrome and are listed in the Table.^1,8,11 The recommended treatment of Sweet syndrome is systemic corticosteroids.¹²

To the Editor:

A 75-year-old woman with a history of hypertension, gout, and adult-onset diabetes mellitus was started on dapagliflozin (5 mg) for glycemic control (hemoglobin A_1c, 7.9 [reference range, 4–7]). Within 1 week of starting the medication, she developed a fine papular eruption in a photodistributed area on the neck and chest with associated malaise. The rash progressed over the next 2 weeks, evolving into edematous papules and plaques, some with vesicles involving the neck, chest, postauricular areas, and nose. Approximately 3 weeks after starting dapagliflozin, the patient also developed bilateral painful, hemorrhagic, bullous plaques (10×3 cm overall) without satellite lesions on the dorsal aspects of the hands. The borders of the bullae had rapidly expanding geographic margins and were extremely painful. The patient’s primary care physician advised to discontinue dapagliflozin, as this medication was thought to be triggering the eruption. She was administered triamcinolone (40 mg intramuscularly) and advised to take ibuprofen as needed. She had malaise and reported that she felt hot but had no known fever. No laboratory tests were ordered. 

The lesions on the neck and chest began to fade within 1 week of stopping the medication and administering corticosteroids; however, the hand lesions continued to progress and began to involve the base of the digits (Figure 1). The patient was then seen by a dermatologist who biopsied the hand lesions. Histopathology was characteristic of Sweet syndrome, also known as acute febrile neutrophilic dermatosis and Gomm-Button disease. Notably, there was a dense nodular infiltrate of neutrophils, papillary dermal edema, and leukocytoclastic debris without leukocytoclastic vasculitis (Figure 2).

Because of the presence of lesions on the dorsal aspects of the hands in our patient, the differential diagnosis included the localized variant of Sweet syndrome known as neutrophilic dermatosis of the dorsal hands, but a diagnosis of classic Sweet syndrome was favored due to the lack of intense papillary dermal edema and vasculitis.^1,2 Although the hand lesions appeared after the neck and chest lesions, the temporal relationship of their appearance with medication usage and clearing once the medication was stopped favored these lesions as part of the same drug-induced response.

Dapagliflozin is a member of a new class of medications (gliflozins) used for the treatment of type 2 diabetes mellitus.^3,4 The medication lowers blood glucose by inhibiting the sodium-glucose cotransport protein 2, thus lowering the blood glucose levels by increasing urinary excretion of glucose. Because many patients with type 2 diabetes mellitus are overweight, these medications are poised to gain popularity for weight loss and decreased blood pressure side effects. Three other medications in this class also have been approved by US Food and Drug Administration: empagliflozin, canagliflozin, and ertugliflozin.

Sweet syndrome consists of 4 cardinal features that were first described in 1964: fever, leukocytosis, tender red plaques, and a dermal neutrophilic infiltrate.⁵ Since then, Su and Liu⁶ proposed guidelines consisting of major and minor criteria. In 1996, Walker and Cohen⁷ suggested a set of diagnostic criteria specifically for drug-induced Sweet syndrome, including painful erythematous plaques, histopathologic neutrophilic infiltrate, and fever. Additional criteria included a temporal relationship between drug ingestion and clinical presentation as well as resolution of lesions after drug withdrawal or treatment with systemic corticosteroids.⁷ The lesions of drug-induced Sweet syndrome often are described as painful red papules that can form plaques, may appear vesicular, and are more common in women. These lesions classically appear on the upper extremities, as well as the head, neck, trunk, and back.⁸ Clinically, symptoms most commonly include fever and musculoskeletal involvement, both of which were experienced by the patient who described herself as feeling feverish when the lesions first appeared and reported malaise. Our patient experienced all of these features, and although a fever was not measured in the acute stage of presentation, she reported feeling hot. Other symptoms that may occur include arthralgia, headache, and myalgia.⁹ Microscopically, there is a nodular infiltrate of neutrophils, papillary dermal edema, and leukocytoclastic debris. The pathogenesis of Sweet syndrome remains unclear but can be associated with malignancy, pregnancy, autoimmune disorders, and drug reactions.¹⁰ Many different classes of medications have been reported to cause drug-induced Sweet syndrome and are listed in the Table.^1,8,11 The recommended treatment of Sweet syndrome is systemic corticosteroids.¹²

The Food and Drug Administration has granted breakthrough therapy designation to acalabrutinib (Calquence) as a monotherapy for adults with chronic lymphocytic leukemia (CLL).

The Bruton tyrosine kinase inhibitor is already approved for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy, and multiple trials are underway to evaluate the drug’s use in a variety of B-cell malignancies, according to the drug’s sponsor, AstraZeneca.

The current designation was based on preliminary results from two phase 3 trials – ELEVATE-TN and ASCEND. In the three-arm ELEVATE-TN trial, researchers evaluated acalabrutinib alone or in combination with obinutuzumab versus chlorambucil plus obinutuzumab in previously untreated patients with CLL. In the two-arm ASCEND trial, previously treated patients with CLL were randomized to receive acalabrutinib monotherapy or the physician’s choice of either rituximab plus idelalisib or rituximab plus bendamustine.

Interim analyses of the two trials showed that acalabrutinib alone, or in combination, significantly improved progression-free survival without raising safety concerns.

Breakthrough therapy designation allows for an expedited review by the FDA for treatments aimed at treating serious conditions where there is preliminary clinical evidence showing a substantial improvement over an available therapy or a clinically significant endpoint.

mschneider@mdedge.com

The Food and Drug Administration has granted breakthrough therapy designation to acalabrutinib (Calquence) as a monotherapy for adults with chronic lymphocytic leukemia (CLL).

The Bruton tyrosine kinase inhibitor is already approved for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy, and multiple trials are underway to evaluate the drug’s use in a variety of B-cell malignancies, according to the drug’s sponsor, AstraZeneca.

The current designation was based on preliminary results from two phase 3 trials – ELEVATE-TN and ASCEND. In the three-arm ELEVATE-TN trial, researchers evaluated acalabrutinib alone or in combination with obinutuzumab versus chlorambucil plus obinutuzumab in previously untreated patients with CLL. In the two-arm ASCEND trial, previously treated patients with CLL were randomized to receive acalabrutinib monotherapy or the physician’s choice of either rituximab plus idelalisib or rituximab plus bendamustine.

Interim analyses of the two trials showed that acalabrutinib alone, or in combination, significantly improved progression-free survival without raising safety concerns.

Breakthrough therapy designation allows for an expedited review by the FDA for treatments aimed at treating serious conditions where there is preliminary clinical evidence showing a substantial improvement over an available therapy or a clinically significant endpoint.

mschneider@mdedge.com

The Food and Drug Administration has granted breakthrough therapy designation to acalabrutinib (Calquence) as a monotherapy for adults with chronic lymphocytic leukemia (CLL).

The Bruton tyrosine kinase inhibitor is already approved for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy, and multiple trials are underway to evaluate the drug’s use in a variety of B-cell malignancies, according to the drug’s sponsor, AstraZeneca.

The current designation was based on preliminary results from two phase 3 trials – ELEVATE-TN and ASCEND. In the three-arm ELEVATE-TN trial, researchers evaluated acalabrutinib alone or in combination with obinutuzumab versus chlorambucil plus obinutuzumab in previously untreated patients with CLL. In the two-arm ASCEND trial, previously treated patients with CLL were randomized to receive acalabrutinib monotherapy or the physician’s choice of either rituximab plus idelalisib or rituximab plus bendamustine.

Interim analyses of the two trials showed that acalabrutinib alone, or in combination, significantly improved progression-free survival without raising safety concerns.

Breakthrough therapy designation allows for an expedited review by the FDA for treatments aimed at treating serious conditions where there is preliminary clinical evidence showing a substantial improvement over an available therapy or a clinically significant endpoint.

mschneider@mdedge.com

To the Editor:

Evidence-based recommendations for optimal medical management of patients with immunobullous diseases prior to elective surgery are sparse.^1,2 There is an uncertain balance between the use of immunomodulators and immunosuppressants, and implementation of these agents is heavily weighted against an increased infection risk from both active disease with denuded skin and suboptimal wound healing due to iatrogenic immunosuppression.^1-5 Historically, clinical management of epidermolysis bullosa acquisita (EBA) seldomly has resulted in substantial disease resolution.^1,3,4 Herein, we describe a case of recalcitrant EBA that was treated with a combination of intravenous immunoglobulin (IVIG) and dapsone, which resulted in a favorable clinical response and successful hip arthroplasty without cutaneous complications.

A 66-year-old man presented to an outside clinic with nonhealing ulcers on the oral mucosa, hands, groin, and feet. He was treated with systemic steroids after a histologic examination suggested bullous pemphigoid, but the lesions did not exhibit any appreciable improvement after several months of treatment. Despite the lack of improvement, the patient was continued on systemic steroids with a waxing and waning disease course.

Within a year, the patient presented to an orthopedist at our institution with severe left hip pain that had been limiting his mobility and had become unresponsive to conservative therapy. Radiologic investigations suggested advanced osteoarthritis and avascular necrosis of the left hip. Surgical intervention was delayed, as his orthopedist expressed concern that the extent of the body surface area affected by cutaneous denudation placed him at an unacceptable risk for infection. The orthopedic surgeon then referred the patient to our clinic for evaluation of the lesions. Physical examination revealed numerous crusted erosions in various stages of healing on the oral mucosa, palms, groin, and soles. Repeat biopsy of a denuded ulcer on the patient’s arm was obtained by our providers (nearly 1 year after the first biopsy by the outside physician). Histologic examination showed a pauci-immune subepidermal blister without acantholysis, which in combination with the clinical presentation of tense bullae on trauma-prone surfaces led to a favored diagnosis of EBA.

The patient began trials of several immunomodulatory and immunosuppressive agents, both in isolation and in combination, including systemic steroids, mycophenolate mofetil, four 1000-mg infusions of rituximab, and dapsone. Although results were suboptimal, dapsone 150 mg once daily for 3 months yielded the greatest clinical improvement with subsequent granulation and/or re-epithelialization of the chronic ulcers. After discussion during our department’s Grand Rounds, it was determined that the patient should undergo a trial of IVIG infusions, which were initiated with a loading dose of 2000 mg/kg over 5 consecutive days, followed by once-monthly maintenance infusion doses of 1200 mg/kg for 4 consecutive months. While receiving IVIG, he was maintained on a once-daily dose of dapsone 150 mg. This dual approach was designed to suppress both the humoral and cellular-mediated disease mechanisms so that his treatment would obviate the need for systemic corticosteroids.

Following this treatment regimen, he was noted to have marked improvement with only few scattered healing erosions. Upon completion of his last IVIG infusion, his cutaneous and mucosal manifestations of EBA were greatly minimized, demonstrating the best level of control that had been achieved during the disease course (Figure 1). This therapy completely cleared the cutaneous and mucosal ulcerations, thus permitting the patient to undergo a total left hip arthroplasty without complications (Figure 2).

Our report is novel in that it supports a combination of IVIG and dapsone as a viable presurgical therapy for patients with EBA, and this treatment also may be applicable for other primary immunobullous disorders.^2,5 Our case was particularly challenging in that the severity of the patient’s bullous disease precluded him from an elective orthopedic joint replacement due to the risk for wound dehiscence and surgical site infection.² We determined that IVIG and dapsone would be the most optimal combination therapy to facilitate superior disease control and concurrently allow for appropriate wound healing without impairing the host immune response. This report is unique from a clinical perspective in that a balance was successfully achieved between immune suppression, with avoidance of associated side effects, and disease activity.

To the Editor:

Evidence-based recommendations for optimal medical management of patients with immunobullous diseases prior to elective surgery are sparse.^1,2 There is an uncertain balance between the use of immunomodulators and immunosuppressants, and implementation of these agents is heavily weighted against an increased infection risk from both active disease with denuded skin and suboptimal wound healing due to iatrogenic immunosuppression.^1-5 Historically, clinical management of epidermolysis bullosa acquisita (EBA) seldomly has resulted in substantial disease resolution.^1,3,4 Herein, we describe a case of recalcitrant EBA that was treated with a combination of intravenous immunoglobulin (IVIG) and dapsone, which resulted in a favorable clinical response and successful hip arthroplasty without cutaneous complications.

A 66-year-old man presented to an outside clinic with nonhealing ulcers on the oral mucosa, hands, groin, and feet. He was treated with systemic steroids after a histologic examination suggested bullous pemphigoid, but the lesions did not exhibit any appreciable improvement after several months of treatment. Despite the lack of improvement, the patient was continued on systemic steroids with a waxing and waning disease course.

Within a year, the patient presented to an orthopedist at our institution with severe left hip pain that had been limiting his mobility and had become unresponsive to conservative therapy. Radiologic investigations suggested advanced osteoarthritis and avascular necrosis of the left hip. Surgical intervention was delayed, as his orthopedist expressed concern that the extent of the body surface area affected by cutaneous denudation placed him at an unacceptable risk for infection. The orthopedic surgeon then referred the patient to our clinic for evaluation of the lesions. Physical examination revealed numerous crusted erosions in various stages of healing on the oral mucosa, palms, groin, and soles. Repeat biopsy of a denuded ulcer on the patient’s arm was obtained by our providers (nearly 1 year after the first biopsy by the outside physician). Histologic examination showed a pauci-immune subepidermal blister without acantholysis, which in combination with the clinical presentation of tense bullae on trauma-prone surfaces led to a favored diagnosis of EBA.

The patient began trials of several immunomodulatory and immunosuppressive agents, both in isolation and in combination, including systemic steroids, mycophenolate mofetil, four 1000-mg infusions of rituximab, and dapsone. Although results were suboptimal, dapsone 150 mg once daily for 3 months yielded the greatest clinical improvement with subsequent granulation and/or re-epithelialization of the chronic ulcers. After discussion during our department’s Grand Rounds, it was determined that the patient should undergo a trial of IVIG infusions, which were initiated with a loading dose of 2000 mg/kg over 5 consecutive days, followed by once-monthly maintenance infusion doses of 1200 mg/kg for 4 consecutive months. While receiving IVIG, he was maintained on a once-daily dose of dapsone 150 mg. This dual approach was designed to suppress both the humoral and cellular-mediated disease mechanisms so that his treatment would obviate the need for systemic corticosteroids.

Following this treatment regimen, he was noted to have marked improvement with only few scattered healing erosions. Upon completion of his last IVIG infusion, his cutaneous and mucosal manifestations of EBA were greatly minimized, demonstrating the best level of control that had been achieved during the disease course (Figure 1). This therapy completely cleared the cutaneous and mucosal ulcerations, thus permitting the patient to undergo a total left hip arthroplasty without complications (Figure 2).

Our report is novel in that it supports a combination of IVIG and dapsone as a viable presurgical therapy for patients with EBA, and this treatment also may be applicable for other primary immunobullous disorders.^2,5 Our case was particularly challenging in that the severity of the patient’s bullous disease precluded him from an elective orthopedic joint replacement due to the risk for wound dehiscence and surgical site infection.² We determined that IVIG and dapsone would be the most optimal combination therapy to facilitate superior disease control and concurrently allow for appropriate wound healing without impairing the host immune response. This report is unique from a clinical perspective in that a balance was successfully achieved between immune suppression, with avoidance of associated side effects, and disease activity.

To the Editor:

Evidence-based recommendations for optimal medical management of patients with immunobullous diseases prior to elective surgery are sparse.^1,2 There is an uncertain balance between the use of immunomodulators and immunosuppressants, and implementation of these agents is heavily weighted against an increased infection risk from both active disease with denuded skin and suboptimal wound healing due to iatrogenic immunosuppression.^1-5 Historically, clinical management of epidermolysis bullosa acquisita (EBA) seldomly has resulted in substantial disease resolution.^1,3,4 Herein, we describe a case of recalcitrant EBA that was treated with a combination of intravenous immunoglobulin (IVIG) and dapsone, which resulted in a favorable clinical response and successful hip arthroplasty without cutaneous complications.

A 66-year-old man presented to an outside clinic with nonhealing ulcers on the oral mucosa, hands, groin, and feet. He was treated with systemic steroids after a histologic examination suggested bullous pemphigoid, but the lesions did not exhibit any appreciable improvement after several months of treatment. Despite the lack of improvement, the patient was continued on systemic steroids with a waxing and waning disease course.

Within a year, the patient presented to an orthopedist at our institution with severe left hip pain that had been limiting his mobility and had become unresponsive to conservative therapy. Radiologic investigations suggested advanced osteoarthritis and avascular necrosis of the left hip. Surgical intervention was delayed, as his orthopedist expressed concern that the extent of the body surface area affected by cutaneous denudation placed him at an unacceptable risk for infection. The orthopedic surgeon then referred the patient to our clinic for evaluation of the lesions. Physical examination revealed numerous crusted erosions in various stages of healing on the oral mucosa, palms, groin, and soles. Repeat biopsy of a denuded ulcer on the patient’s arm was obtained by our providers (nearly 1 year after the first biopsy by the outside physician). Histologic examination showed a pauci-immune subepidermal blister without acantholysis, which in combination with the clinical presentation of tense bullae on trauma-prone surfaces led to a favored diagnosis of EBA.

The patient began trials of several immunomodulatory and immunosuppressive agents, both in isolation and in combination, including systemic steroids, mycophenolate mofetil, four 1000-mg infusions of rituximab, and dapsone. Although results were suboptimal, dapsone 150 mg once daily for 3 months yielded the greatest clinical improvement with subsequent granulation and/or re-epithelialization of the chronic ulcers. After discussion during our department’s Grand Rounds, it was determined that the patient should undergo a trial of IVIG infusions, which were initiated with a loading dose of 2000 mg/kg over 5 consecutive days, followed by once-monthly maintenance infusion doses of 1200 mg/kg for 4 consecutive months. While receiving IVIG, he was maintained on a once-daily dose of dapsone 150 mg. This dual approach was designed to suppress both the humoral and cellular-mediated disease mechanisms so that his treatment would obviate the need for systemic corticosteroids.

Following this treatment regimen, he was noted to have marked improvement with only few scattered healing erosions. Upon completion of his last IVIG infusion, his cutaneous and mucosal manifestations of EBA were greatly minimized, demonstrating the best level of control that had been achieved during the disease course (Figure 1). This therapy completely cleared the cutaneous and mucosal ulcerations, thus permitting the patient to undergo a total left hip arthroplasty without complications (Figure 2).

Our report is novel in that it supports a combination of IVIG and dapsone as a viable presurgical therapy for patients with EBA, and this treatment also may be applicable for other primary immunobullous disorders.^2,5 Our case was particularly challenging in that the severity of the patient’s bullous disease precluded him from an elective orthopedic joint replacement due to the risk for wound dehiscence and surgical site infection.² We determined that IVIG and dapsone would be the most optimal combination therapy to facilitate superior disease control and concurrently allow for appropriate wound healing without impairing the host immune response. This report is unique from a clinical perspective in that a balance was successfully achieved between immune suppression, with avoidance of associated side effects, and disease activity.

In trauma patients with normal mental status, two blood biomarkers incrementally increase across three injury types, according to a study of more than 700 adult and pediatric patients. Levels of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) are lowest in patients with nonconcussive body trauma, higher in patients with nonconcussive head trauma, and highest in patients with concussion, researchers reported Aug. 26 in BMJ Paediatrics Open.

Orlando Health

“GFAP outperformed UCH-L1 in detecting concussion in both children and adults within 4 hours of injury,” reported lead author Linda Papa, MD, and collaborators. Dr. Papa is an emergency medicine doctor at Orlando Health. “UCH-L1 was expressed at much higher levels than GFAP in those with nonconcussive trauma, particularly in children. Elevations of these biomarkers in nonconcussive head trauma suggest possible subconcussive brain injury. GFAP could be potentially useful to detect concussion for up to a week post injury.”

In 2018 the Food and Drug Administration approved the use of these biomarkers to guide CT scan ordering in adults with mild to moderate traumatic brain injury, but investigators have not established their ability to detect concussion in children or adults. Clinicians lack an objective measure to diagnose concussion acutely.

To assess the ability of GFAP and UCH-L1 to detect concussion, Dr. Papa and colleagues conducted a prospective cohort study. The researchers enrolled trauma patients of all ages at three level I trauma centers in the United States. They included patients with and without head trauma who had a Glasgow Coma Scale score of 15 and who presented within 4 hours of injury. Investigators screened for concussion symptoms, obtained biomarker data from 712 trauma patients, and conducted repeated blood sampling in adults.

They grouped patients by those with concussion (n = 371), those with head trauma without overt signs of concussion (n = 149), and those with peripheral trauma without head trauma or concussion (n = 192). The study included 175 children. Injury mechanisms included car crashes, falls, bicycle accidents, and sports injuries.

Patients with concussion had significantly higher GFAP concentrations, compared with patients with body trauma and patients with nonconcussive head trauma. UCH-L1 levels did not significantly differ between patients with concussion and head trauma controls, however.

“Based on these results, the potential utility of GFAP to distinguish concussion from body trauma controls over 7 days postinjury was fair to excellent,” with area under the receiver operating characteristics curves (AUCs) of 0.75-0.89, the researchers said. “UCH-L1’s ability was guarded and variable with AUCs from poor to good depending on timing of samples.” UCH-L1 demonstrated AUCs that ranged from 0.54 to 0.78; earlier samples performed better.

GFAP elevations in head trauma controls “may represent milder forms of concussion that do not elicit typical signs or symptoms associated with concussion,” the authors wrote. “These injuries may be irrelevant, or they may represent important trauma that is just below the level of clinical detection and referred to as subconcussive trauma. ... Biomarkers (such as GFAP and UCH-L1) could provide a more objective measure of injury and potentially identify those at risk for neurocognitive problems.”

The study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Papa is an unpaid scientific consultant for Banyan Biomarkers, which developed kits to measure the biomarkers, and coauthors receive contract research funding from Banyan Biomarkers.
 

jremaly@mdedge.com

SOURCE: Papa L et al. BMJ Paediatr Open. 2019 Aug 26. doi: 10.1136/bmjpo-2019-000473.

In trauma patients with normal mental status, two blood biomarkers incrementally increase across three injury types, according to a study of more than 700 adult and pediatric patients. Levels of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) are lowest in patients with nonconcussive body trauma, higher in patients with nonconcussive head trauma, and highest in patients with concussion, researchers reported Aug. 26 in BMJ Paediatrics Open.

Orlando Health

“GFAP outperformed UCH-L1 in detecting concussion in both children and adults within 4 hours of injury,” reported lead author Linda Papa, MD, and collaborators. Dr. Papa is an emergency medicine doctor at Orlando Health. “UCH-L1 was expressed at much higher levels than GFAP in those with nonconcussive trauma, particularly in children. Elevations of these biomarkers in nonconcussive head trauma suggest possible subconcussive brain injury. GFAP could be potentially useful to detect concussion for up to a week post injury.”

In 2018 the Food and Drug Administration approved the use of these biomarkers to guide CT scan ordering in adults with mild to moderate traumatic brain injury, but investigators have not established their ability to detect concussion in children or adults. Clinicians lack an objective measure to diagnose concussion acutely.

To assess the ability of GFAP and UCH-L1 to detect concussion, Dr. Papa and colleagues conducted a prospective cohort study. The researchers enrolled trauma patients of all ages at three level I trauma centers in the United States. They included patients with and without head trauma who had a Glasgow Coma Scale score of 15 and who presented within 4 hours of injury. Investigators screened for concussion symptoms, obtained biomarker data from 712 trauma patients, and conducted repeated blood sampling in adults.

They grouped patients by those with concussion (n = 371), those with head trauma without overt signs of concussion (n = 149), and those with peripheral trauma without head trauma or concussion (n = 192). The study included 175 children. Injury mechanisms included car crashes, falls, bicycle accidents, and sports injuries.

Patients with concussion had significantly higher GFAP concentrations, compared with patients with body trauma and patients with nonconcussive head trauma. UCH-L1 levels did not significantly differ between patients with concussion and head trauma controls, however.

“Based on these results, the potential utility of GFAP to distinguish concussion from body trauma controls over 7 days postinjury was fair to excellent,” with area under the receiver operating characteristics curves (AUCs) of 0.75-0.89, the researchers said. “UCH-L1’s ability was guarded and variable with AUCs from poor to good depending on timing of samples.” UCH-L1 demonstrated AUCs that ranged from 0.54 to 0.78; earlier samples performed better.

GFAP elevations in head trauma controls “may represent milder forms of concussion that do not elicit typical signs or symptoms associated with concussion,” the authors wrote. “These injuries may be irrelevant, or they may represent important trauma that is just below the level of clinical detection and referred to as subconcussive trauma. ... Biomarkers (such as GFAP and UCH-L1) could provide a more objective measure of injury and potentially identify those at risk for neurocognitive problems.”

The study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Papa is an unpaid scientific consultant for Banyan Biomarkers, which developed kits to measure the biomarkers, and coauthors receive contract research funding from Banyan Biomarkers.
 

jremaly@mdedge.com

SOURCE: Papa L et al. BMJ Paediatr Open. 2019 Aug 26. doi: 10.1136/bmjpo-2019-000473.

In trauma patients with normal mental status, two blood biomarkers incrementally increase across three injury types, according to a study of more than 700 adult and pediatric patients. Levels of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) are lowest in patients with nonconcussive body trauma, higher in patients with nonconcussive head trauma, and highest in patients with concussion, researchers reported Aug. 26 in BMJ Paediatrics Open.

Orlando Health

“GFAP outperformed UCH-L1 in detecting concussion in both children and adults within 4 hours of injury,” reported lead author Linda Papa, MD, and collaborators. Dr. Papa is an emergency medicine doctor at Orlando Health. “UCH-L1 was expressed at much higher levels than GFAP in those with nonconcussive trauma, particularly in children. Elevations of these biomarkers in nonconcussive head trauma suggest possible subconcussive brain injury. GFAP could be potentially useful to detect concussion for up to a week post injury.”

In 2018 the Food and Drug Administration approved the use of these biomarkers to guide CT scan ordering in adults with mild to moderate traumatic brain injury, but investigators have not established their ability to detect concussion in children or adults. Clinicians lack an objective measure to diagnose concussion acutely.

To assess the ability of GFAP and UCH-L1 to detect concussion, Dr. Papa and colleagues conducted a prospective cohort study. The researchers enrolled trauma patients of all ages at three level I trauma centers in the United States. They included patients with and without head trauma who had a Glasgow Coma Scale score of 15 and who presented within 4 hours of injury. Investigators screened for concussion symptoms, obtained biomarker data from 712 trauma patients, and conducted repeated blood sampling in adults.

They grouped patients by those with concussion (n = 371), those with head trauma without overt signs of concussion (n = 149), and those with peripheral trauma without head trauma or concussion (n = 192). The study included 175 children. Injury mechanisms included car crashes, falls, bicycle accidents, and sports injuries.

Patients with concussion had significantly higher GFAP concentrations, compared with patients with body trauma and patients with nonconcussive head trauma. UCH-L1 levels did not significantly differ between patients with concussion and head trauma controls, however.

“Based on these results, the potential utility of GFAP to distinguish concussion from body trauma controls over 7 days postinjury was fair to excellent,” with area under the receiver operating characteristics curves (AUCs) of 0.75-0.89, the researchers said. “UCH-L1’s ability was guarded and variable with AUCs from poor to good depending on timing of samples.” UCH-L1 demonstrated AUCs that ranged from 0.54 to 0.78; earlier samples performed better.

GFAP elevations in head trauma controls “may represent milder forms of concussion that do not elicit typical signs or symptoms associated with concussion,” the authors wrote. “These injuries may be irrelevant, or they may represent important trauma that is just below the level of clinical detection and referred to as subconcussive trauma. ... Biomarkers (such as GFAP and UCH-L1) could provide a more objective measure of injury and potentially identify those at risk for neurocognitive problems.”

The study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Papa is an unpaid scientific consultant for Banyan Biomarkers, which developed kits to measure the biomarkers, and coauthors receive contract research funding from Banyan Biomarkers.
 

jremaly@mdedge.com

SOURCE: Papa L et al. BMJ Paediatr Open. 2019 Aug 26. doi: 10.1136/bmjpo-2019-000473.

Perceived everyday discrimination was associated with an extended duration between symptom onset and cancer diagnosis (prolonged symptom duration) in black women with ovarian cancer, according to results from a case-control analysis.

In contrast, another interpersonal factor, trust in physicians, was not associated with prolonged symptom duration.

“We [examined] the association of everyday discrimination and trust in physicians with a prolonged interval between symptom onset and ovarian cancer diagnosis,” wrote Megan A. Mullins, MPH, of the University of Michigan, Ann Arbor, and colleagues. The findings were published in Cancer.

The analysis included 486 cases of black women with newly diagnosed epithelial ovarian cancer, 302 of whom had prolonged symptom duration. Study cases were obtained from the African American Cancer Epidemiology Study that took place from December 2010 to December 2015. Perceived discrimination was evaluated with the five-question version of the Williams Everyday Discrimination Scale.

In the model, adjustments were made for various demographic characteristics, including marital status, body mass index, and age at diagnosis, among other parameters.

After analysis, the researchers found that every 1-unit rise in the frequency of everyday discrimination was associated with a higher likelihood of prolonged symptom duration (odds ratio, 1.74; 95% confidence interval, 1.22-2.49).

No association was found between trust in physicians and prolonged symptom duration (odds ratio, 0.86; 95% CI, 0.66-1.11).

“These results point to the social context in daily life playing a role in receiving optimal ovarian cancer care,” the researchers wrote.

One key limitation of the study was that the data was obtained in a cross-sectional manner, which could introduce bias because of reverse causality.

“This work is a novel first step in understanding the relationship between interpersonal exposures and racial disparities in ovarian cancer care. More equitable access to ovarian cancer care necessitates that women feel comfortable about advocating for their needs and trust their self-assessment of their symptoms,” they concluded.

The study was funded by the National Cancer Institute, the Metropolitan Detroit Cancer Surveillance System, and the Epidemiology Research Core. The authors reported no conflicts of interest.
 

SOURCE: Mullins MA et al. Cancer. 2019 Aug 15. doi: 10.1002/cncr.32451.

Perceived everyday discrimination was associated with an extended duration between symptom onset and cancer diagnosis (prolonged symptom duration) in black women with ovarian cancer, according to results from a case-control analysis.

In contrast, another interpersonal factor, trust in physicians, was not associated with prolonged symptom duration.

“We [examined] the association of everyday discrimination and trust in physicians with a prolonged interval between symptom onset and ovarian cancer diagnosis,” wrote Megan A. Mullins, MPH, of the University of Michigan, Ann Arbor, and colleagues. The findings were published in Cancer.

The analysis included 486 cases of black women with newly diagnosed epithelial ovarian cancer, 302 of whom had prolonged symptom duration. Study cases were obtained from the African American Cancer Epidemiology Study that took place from December 2010 to December 2015. Perceived discrimination was evaluated with the five-question version of the Williams Everyday Discrimination Scale.

In the model, adjustments were made for various demographic characteristics, including marital status, body mass index, and age at diagnosis, among other parameters.

After analysis, the researchers found that every 1-unit rise in the frequency of everyday discrimination was associated with a higher likelihood of prolonged symptom duration (odds ratio, 1.74; 95% confidence interval, 1.22-2.49).

No association was found between trust in physicians and prolonged symptom duration (odds ratio, 0.86; 95% CI, 0.66-1.11).

“These results point to the social context in daily life playing a role in receiving optimal ovarian cancer care,” the researchers wrote.

One key limitation of the study was that the data was obtained in a cross-sectional manner, which could introduce bias because of reverse causality.

“This work is a novel first step in understanding the relationship between interpersonal exposures and racial disparities in ovarian cancer care. More equitable access to ovarian cancer care necessitates that women feel comfortable about advocating for their needs and trust their self-assessment of their symptoms,” they concluded.

The study was funded by the National Cancer Institute, the Metropolitan Detroit Cancer Surveillance System, and the Epidemiology Research Core. The authors reported no conflicts of interest.
 

SOURCE: Mullins MA et al. Cancer. 2019 Aug 15. doi: 10.1002/cncr.32451.

Perceived everyday discrimination was associated with an extended duration between symptom onset and cancer diagnosis (prolonged symptom duration) in black women with ovarian cancer, according to results from a case-control analysis.

In contrast, another interpersonal factor, trust in physicians, was not associated with prolonged symptom duration.

“We [examined] the association of everyday discrimination and trust in physicians with a prolonged interval between symptom onset and ovarian cancer diagnosis,” wrote Megan A. Mullins, MPH, of the University of Michigan, Ann Arbor, and colleagues. The findings were published in Cancer.

The analysis included 486 cases of black women with newly diagnosed epithelial ovarian cancer, 302 of whom had prolonged symptom duration. Study cases were obtained from the African American Cancer Epidemiology Study that took place from December 2010 to December 2015. Perceived discrimination was evaluated with the five-question version of the Williams Everyday Discrimination Scale.

In the model, adjustments were made for various demographic characteristics, including marital status, body mass index, and age at diagnosis, among other parameters.

After analysis, the researchers found that every 1-unit rise in the frequency of everyday discrimination was associated with a higher likelihood of prolonged symptom duration (odds ratio, 1.74; 95% confidence interval, 1.22-2.49).

No association was found between trust in physicians and prolonged symptom duration (odds ratio, 0.86; 95% CI, 0.66-1.11).

“These results point to the social context in daily life playing a role in receiving optimal ovarian cancer care,” the researchers wrote.

One key limitation of the study was that the data was obtained in a cross-sectional manner, which could introduce bias because of reverse causality.

“This work is a novel first step in understanding the relationship between interpersonal exposures and racial disparities in ovarian cancer care. More equitable access to ovarian cancer care necessitates that women feel comfortable about advocating for their needs and trust their self-assessment of their symptoms,” they concluded.

The study was funded by the National Cancer Institute, the Metropolitan Detroit Cancer Surveillance System, and the Epidemiology Research Core. The authors reported no conflicts of interest.
 

SOURCE: Mullins MA et al. Cancer. 2019 Aug 15. doi: 10.1002/cncr.32451.

The Diagnosis: Phacomatosis Cesioflammea  

Phacomatosis pigmentovascularis (PPV) encompasses a group of diseases that have a vascular nevus coupled with a pigmented nevus.¹ It is divided into 5 types: Type I is defined by the presence of a vascular malformation and epidermal nevus; type II by a vascular malformation and dermal melanosis with or without nevus anemicus; type III by a vascular malformation and nevus spilus with or without nevus anemicus; type IV by a vascular malformation, dermal melanosis, and nevus spilus with or without nevus anemicus; and type V as cutis marmorata telangiectatica congenita and dermal melanosis.¹  

Happle² proposed a descriptive classification system in 2005 that eliminated type I PPV because neither linear epidermal nevus nor Becker nevus are derived from pigmentary cells. An appended "a" denotes a subtype with isolated cutaneous findings, while "b" is associated with extracutaneous manifestations. Phacomatosis cesioflammea (type IIa/b) refers to blue-hued dermal melanocytosis and nevus flammeus. Phacomatosis spilorosea (type IIIa/b) refers to nevus spilus and rose-colored nevus flammeus. Phacomatosis cesiomarmorata (type Va/b) refers to dermal melanocytosis and cutis marmorata telangiectasia congenita. The last group (type IVa/b) is unclassifiable phacomatosis pigmentovascularis.^2,3  

Phacomatosis pigmentovascularis can be isolated to the skin or have associated extracutaneous findings, including ocular melanocytosis, seizures, or cognitive delay due to intracerebral vascular malformations. Patients also can develop limb and soft-tissue overgrowth.⁴ Phacomatosis pigmentovascularis has been found to be associated with mutations in the GNA11 and GNAQ genes. The theory behind PPV is twin spotting, resulting from a somatic mutation that leads to mosaic proliferation of 2 different cell lines.⁵ Phacomatosis pigmentovascularis can occur in isolation or can demonstrate the phenotype of Sturge-Weber syndrome or Klippel-Trenaunay syndrome. In Sturge-Weber syndrome, capillary malformations involve the face and underlying leptomeninges and cerebral cortex. Glaucoma and epilepsy also may be present. In Klippel-Trenaunay syndrome, capillary malformations involve the extremities (usually the legs) in association with varicose veins, soft-tissue hypertrophy, and skeletal overgrowth.^6-9 Tuberous sclerosis is an autosomal-dominant neurocutaneous disease in which patients develop hamartomas throughout the body, including the brain, skin, eyes, kidneys, heart, and lungs. Cutaneous manifestations include facial angiofibromas, ungual fibromas, hypomelanotic macules (ash leaf spots, confetti-like lesions), shagreen patches or connective tissue hamartomas, and fibrous plaques on the forehead. Tuberous sclerosis does not include vascular malformations.¹⁰  

Our patient was diagnosed with PPV type IIb, or phacomatosis cesioflammea. He had a large port-wine stain involving the right upper arm, back (Figure, A), and chest (Figure, B) with involvement of the bilateral conjunctivae (Figure, C). Our case is unique because our patient did not have dermal melanocytosis, only ocular melanocytosis.  

Once underlying neurologic and vascular anomalies have been ruled out, port-wine stains can be treated cosmetically. Pulsed dye laser is the gold standard therapy for capillary malformations, especially when instituted early. Follow-up with ophthalmology is advised to monitor ocular involvement. Shields et al¹¹ suggested dilated fundoscopy for patients with port-wine stains because choroidal pigmentation often is the only ocular change seen. Ocular melanocytosis can progress to pigmented glaucoma or choroidal melanoma. 

The Diagnosis: Phacomatosis Cesioflammea  

Phacomatosis pigmentovascularis (PPV) encompasses a group of diseases that have a vascular nevus coupled with a pigmented nevus.¹ It is divided into 5 types: Type I is defined by the presence of a vascular malformation and epidermal nevus; type II by a vascular malformation and dermal melanosis with or without nevus anemicus; type III by a vascular malformation and nevus spilus with or without nevus anemicus; type IV by a vascular malformation, dermal melanosis, and nevus spilus with or without nevus anemicus; and type V as cutis marmorata telangiectatica congenita and dermal melanosis.¹  

Happle² proposed a descriptive classification system in 2005 that eliminated type I PPV because neither linear epidermal nevus nor Becker nevus are derived from pigmentary cells. An appended "a" denotes a subtype with isolated cutaneous findings, while "b" is associated with extracutaneous manifestations. Phacomatosis cesioflammea (type IIa/b) refers to blue-hued dermal melanocytosis and nevus flammeus. Phacomatosis spilorosea (type IIIa/b) refers to nevus spilus and rose-colored nevus flammeus. Phacomatosis cesiomarmorata (type Va/b) refers to dermal melanocytosis and cutis marmorata telangiectasia congenita. The last group (type IVa/b) is unclassifiable phacomatosis pigmentovascularis.^2,3  

Phacomatosis pigmentovascularis can be isolated to the skin or have associated extracutaneous findings, including ocular melanocytosis, seizures, or cognitive delay due to intracerebral vascular malformations. Patients also can develop limb and soft-tissue overgrowth.⁴ Phacomatosis pigmentovascularis has been found to be associated with mutations in the GNA11 and GNAQ genes. The theory behind PPV is twin spotting, resulting from a somatic mutation that leads to mosaic proliferation of 2 different cell lines.⁵ Phacomatosis pigmentovascularis can occur in isolation or can demonstrate the phenotype of Sturge-Weber syndrome or Klippel-Trenaunay syndrome. In Sturge-Weber syndrome, capillary malformations involve the face and underlying leptomeninges and cerebral cortex. Glaucoma and epilepsy also may be present. In Klippel-Trenaunay syndrome, capillary malformations involve the extremities (usually the legs) in association with varicose veins, soft-tissue hypertrophy, and skeletal overgrowth.^6-9 Tuberous sclerosis is an autosomal-dominant neurocutaneous disease in which patients develop hamartomas throughout the body, including the brain, skin, eyes, kidneys, heart, and lungs. Cutaneous manifestations include facial angiofibromas, ungual fibromas, hypomelanotic macules (ash leaf spots, confetti-like lesions), shagreen patches or connective tissue hamartomas, and fibrous plaques on the forehead. Tuberous sclerosis does not include vascular malformations.¹⁰  

Our patient was diagnosed with PPV type IIb, or phacomatosis cesioflammea. He had a large port-wine stain involving the right upper arm, back (Figure, A), and chest (Figure, B) with involvement of the bilateral conjunctivae (Figure, C). Our case is unique because our patient did not have dermal melanocytosis, only ocular melanocytosis.  

Once underlying neurologic and vascular anomalies have been ruled out, port-wine stains can be treated cosmetically. Pulsed dye laser is the gold standard therapy for capillary malformations, especially when instituted early. Follow-up with ophthalmology is advised to monitor ocular involvement. Shields et al¹¹ suggested dilated fundoscopy for patients with port-wine stains because choroidal pigmentation often is the only ocular change seen. Ocular melanocytosis can progress to pigmented glaucoma or choroidal melanoma. 

The Diagnosis: Phacomatosis Cesioflammea  

Phacomatosis pigmentovascularis (PPV) encompasses a group of diseases that have a vascular nevus coupled with a pigmented nevus.¹ It is divided into 5 types: Type I is defined by the presence of a vascular malformation and epidermal nevus; type II by a vascular malformation and dermal melanosis with or without nevus anemicus; type III by a vascular malformation and nevus spilus with or without nevus anemicus; type IV by a vascular malformation, dermal melanosis, and nevus spilus with or without nevus anemicus; and type V as cutis marmorata telangiectatica congenita and dermal melanosis.¹  

Happle² proposed a descriptive classification system in 2005 that eliminated type I PPV because neither linear epidermal nevus nor Becker nevus are derived from pigmentary cells. An appended "a" denotes a subtype with isolated cutaneous findings, while "b" is associated with extracutaneous manifestations. Phacomatosis cesioflammea (type IIa/b) refers to blue-hued dermal melanocytosis and nevus flammeus. Phacomatosis spilorosea (type IIIa/b) refers to nevus spilus and rose-colored nevus flammeus. Phacomatosis cesiomarmorata (type Va/b) refers to dermal melanocytosis and cutis marmorata telangiectasia congenita. The last group (type IVa/b) is unclassifiable phacomatosis pigmentovascularis.^2,3  

Phacomatosis pigmentovascularis can be isolated to the skin or have associated extracutaneous findings, including ocular melanocytosis, seizures, or cognitive delay due to intracerebral vascular malformations. Patients also can develop limb and soft-tissue overgrowth.⁴ Phacomatosis pigmentovascularis has been found to be associated with mutations in the GNA11 and GNAQ genes. The theory behind PPV is twin spotting, resulting from a somatic mutation that leads to mosaic proliferation of 2 different cell lines.⁵ Phacomatosis pigmentovascularis can occur in isolation or can demonstrate the phenotype of Sturge-Weber syndrome or Klippel-Trenaunay syndrome. In Sturge-Weber syndrome, capillary malformations involve the face and underlying leptomeninges and cerebral cortex. Glaucoma and epilepsy also may be present. In Klippel-Trenaunay syndrome, capillary malformations involve the extremities (usually the legs) in association with varicose veins, soft-tissue hypertrophy, and skeletal overgrowth.^6-9 Tuberous sclerosis is an autosomal-dominant neurocutaneous disease in which patients develop hamartomas throughout the body, including the brain, skin, eyes, kidneys, heart, and lungs. Cutaneous manifestations include facial angiofibromas, ungual fibromas, hypomelanotic macules (ash leaf spots, confetti-like lesions), shagreen patches or connective tissue hamartomas, and fibrous plaques on the forehead. Tuberous sclerosis does not include vascular malformations.¹⁰  

Our patient was diagnosed with PPV type IIb, or phacomatosis cesioflammea. He had a large port-wine stain involving the right upper arm, back (Figure, A), and chest (Figure, B) with involvement of the bilateral conjunctivae (Figure, C). Our case is unique because our patient did not have dermal melanocytosis, only ocular melanocytosis.  

Once underlying neurologic and vascular anomalies have been ruled out, port-wine stains can be treated cosmetically. Pulsed dye laser is the gold standard therapy for capillary malformations, especially when instituted early. Follow-up with ophthalmology is advised to monitor ocular involvement. Shields et al¹¹ suggested dilated fundoscopy for patients with port-wine stains because choroidal pigmentation often is the only ocular change seen. Ocular melanocytosis can progress to pigmented glaucoma or choroidal melanoma. 

The U.S. Preventive Services Task Force has issued a draft recommendation statement for screening for hepatitis C virus (HCV) infection in adolescents and adults, and now suggests that all adults aged 18-79 years receive screening.

Wikimedia Commons/BruceBlaus

This proposal represents an update and expansion of its current recommendation for screening for HCV infection. The draft recommendation incorporates new evidence and would replace the recommendation made in 2013, which calls for screening in persons at high risk for infection and one-time screening in adults born between 1945 and 1965 (Grade B).

“Today, more people are infected with hepatitis C than there were a decade ago, but there are now better treatments available. The evidence now shows more people can benefit from screening; therefore, we are recommending to screen all adults ages 18-79 for hepatitis C,” task force chair Douglas K. Owens, MD, MS, said in a bulletin issued by the USPSTF.

To update the previous recommendation, the USPSTF conducted a systematic review that included a total of 97 studies. No direct evidence was found regarding the benefits of HCV screening versus no screening or repeat versus one-time screening, and no new studies analyzed the psychological and social consequences of HCV screening.

Evidence concerning direct-acting antiviral (DAA) treatment was more compelling given that 49 trials found DAA therapy to be associated with pooled sustained virologic response (SVR) rates between 95.5% and 98.9% across genotypes. The rate of serious adverse events caused by DAA treatment was 1.9%, and the discontinuation of treatment because of adverse events was 0.4%. In seven trials involving adolescents, SVR rates after antiviral treatment were similar to those in adults.

Achieving an SVR after DAA treatment was associated with a decreased risk in those treated of all-cause mortality (hazard ratio, 0.40; 95% confidence interval, 0.28-0.56), liver mortality (HR, 0.11; 95% CI, 0.04-0.27), cirrhosis (HR, 0.36; 95% CI, 0.33-0.40), and hepatocellular carcinoma (HR, 0.29; 95% CI, 0.23-0.38), compared with those who did not respond.

Because of the evidence collected, the USPSTF issued a B recommendation for HCV screening in adults and recommended screening for all people aged 18-79 years in the draft recommendation statement. “Clinicians may want to consider screening in adolescents younger than age 18 years and in adults older than age 79 years who are at high risk [for HCV],” the proposal says.

The draft recommendation statement and evidence review is available at www.uspreventiveservicestaskforce.org. The public comment period will last until Sept. 23, 2019.

Help educate your patients about hepatitis C, their risks and treatment options using AGA patient education, which can be found in the GI Patient Center at https://www.gastro.org/practice-guidance/gi-patient-center/topic/hepatitis-c-hcv.

lfranki@mdedge.com

The U.S. Preventive Services Task Force has issued a draft recommendation statement for screening for hepatitis C virus (HCV) infection in adolescents and adults, and now suggests that all adults aged 18-79 years receive screening.

Wikimedia Commons/BruceBlaus

This proposal represents an update and expansion of its current recommendation for screening for HCV infection. The draft recommendation incorporates new evidence and would replace the recommendation made in 2013, which calls for screening in persons at high risk for infection and one-time screening in adults born between 1945 and 1965 (Grade B).

“Today, more people are infected with hepatitis C than there were a decade ago, but there are now better treatments available. The evidence now shows more people can benefit from screening; therefore, we are recommending to screen all adults ages 18-79 for hepatitis C,” task force chair Douglas K. Owens, MD, MS, said in a bulletin issued by the USPSTF.

To update the previous recommendation, the USPSTF conducted a systematic review that included a total of 97 studies. No direct evidence was found regarding the benefits of HCV screening versus no screening or repeat versus one-time screening, and no new studies analyzed the psychological and social consequences of HCV screening.

Evidence concerning direct-acting antiviral (DAA) treatment was more compelling given that 49 trials found DAA therapy to be associated with pooled sustained virologic response (SVR) rates between 95.5% and 98.9% across genotypes. The rate of serious adverse events caused by DAA treatment was 1.9%, and the discontinuation of treatment because of adverse events was 0.4%. In seven trials involving adolescents, SVR rates after antiviral treatment were similar to those in adults.

Achieving an SVR after DAA treatment was associated with a decreased risk in those treated of all-cause mortality (hazard ratio, 0.40; 95% confidence interval, 0.28-0.56), liver mortality (HR, 0.11; 95% CI, 0.04-0.27), cirrhosis (HR, 0.36; 95% CI, 0.33-0.40), and hepatocellular carcinoma (HR, 0.29; 95% CI, 0.23-0.38), compared with those who did not respond.

Because of the evidence collected, the USPSTF issued a B recommendation for HCV screening in adults and recommended screening for all people aged 18-79 years in the draft recommendation statement. “Clinicians may want to consider screening in adolescents younger than age 18 years and in adults older than age 79 years who are at high risk [for HCV],” the proposal says.

The draft recommendation statement and evidence review is available at www.uspreventiveservicestaskforce.org. The public comment period will last until Sept. 23, 2019.

Help educate your patients about hepatitis C, their risks and treatment options using AGA patient education, which can be found in the GI Patient Center at https://www.gastro.org/practice-guidance/gi-patient-center/topic/hepatitis-c-hcv.

lfranki@mdedge.com

The U.S. Preventive Services Task Force has issued a draft recommendation statement for screening for hepatitis C virus (HCV) infection in adolescents and adults, and now suggests that all adults aged 18-79 years receive screening.

Wikimedia Commons/BruceBlaus

This proposal represents an update and expansion of its current recommendation for screening for HCV infection. The draft recommendation incorporates new evidence and would replace the recommendation made in 2013, which calls for screening in persons at high risk for infection and one-time screening in adults born between 1945 and 1965 (Grade B).

“Today, more people are infected with hepatitis C than there were a decade ago, but there are now better treatments available. The evidence now shows more people can benefit from screening; therefore, we are recommending to screen all adults ages 18-79 for hepatitis C,” task force chair Douglas K. Owens, MD, MS, said in a bulletin issued by the USPSTF.

To update the previous recommendation, the USPSTF conducted a systematic review that included a total of 97 studies. No direct evidence was found regarding the benefits of HCV screening versus no screening or repeat versus one-time screening, and no new studies analyzed the psychological and social consequences of HCV screening.

Evidence concerning direct-acting antiviral (DAA) treatment was more compelling given that 49 trials found DAA therapy to be associated with pooled sustained virologic response (SVR) rates between 95.5% and 98.9% across genotypes. The rate of serious adverse events caused by DAA treatment was 1.9%, and the discontinuation of treatment because of adverse events was 0.4%. In seven trials involving adolescents, SVR rates after antiviral treatment were similar to those in adults.

Achieving an SVR after DAA treatment was associated with a decreased risk in those treated of all-cause mortality (hazard ratio, 0.40; 95% confidence interval, 0.28-0.56), liver mortality (HR, 0.11; 95% CI, 0.04-0.27), cirrhosis (HR, 0.36; 95% CI, 0.33-0.40), and hepatocellular carcinoma (HR, 0.29; 95% CI, 0.23-0.38), compared with those who did not respond.

Because of the evidence collected, the USPSTF issued a B recommendation for HCV screening in adults and recommended screening for all people aged 18-79 years in the draft recommendation statement. “Clinicians may want to consider screening in adolescents younger than age 18 years and in adults older than age 79 years who are at high risk [for HCV],” the proposal says.

The draft recommendation statement and evidence review is available at www.uspreventiveservicestaskforce.org. The public comment period will last until Sept. 23, 2019.

Help educate your patients about hepatitis C, their risks and treatment options using AGA patient education, which can be found in the GI Patient Center at https://www.gastro.org/practice-guidance/gi-patient-center/topic/hepatitis-c-hcv.

lfranki@mdedge.com

The U.S. Preventive Services Task Force has issued a draft recommendation statement for screening for hepatitis C virus (HCV) infection in adolescents and adults, and now suggests that all adults aged 18-79 years receive screening.

Wikimedia Commons/BruceBlaus

This proposal represents an update and expansion of its current recommendation for screening for HCV infection. The draft recommendation incorporates new evidence and would replace the recommendation made in 2013, which calls for screening in persons at high risk for infection and one-time screening in adults born between 1945 and 1965 (Grade B).

“Today, more people are infected with hepatitis C than there were a decade ago, but there are now better treatments available. The evidence now shows more people can benefit from screening; therefore, we are recommending to screen all adults ages 18-79 for hepatitis C,” task force chair Douglas K. Owens, MD, MS, said in a bulletin issued by the USPSTF.

To update the previous recommendation, the USPSTF conducted a systematic review that included a total of 97 studies. No direct evidence was found regarding the benefits of HCV screening versus no screening or repeat versus one-time screening, and no new studies analyzed the psychological and social consequences of HCV screening.

Evidence concerning direct-acting antiviral (DAA) treatment was more compelling given that 49 trials found DAA therapy to be associated with pooled sustained virologic response (SVR) rates between 95.5% and 98.9% across genotypes. The rate of serious adverse events caused by DAA treatment was 1.9%, and the discontinuation of treatment because of adverse events was 0.4%. In seven trials involving adolescents, SVR rates after antiviral treatment were similar to those in adults.

Achieving an SVR after DAA treatment was associated with a decreased risk in those treated of all-cause mortality (hazard ratio, 0.40; 95% confidence interval, 0.28-0.56), liver mortality (HR, 0.11; 95% CI, 0.04-0.27), cirrhosis (HR, 0.36; 95% CI, 0.33-0.40), and hepatocellular carcinoma (HR, 0.29; 95% CI, 0.23-0.38), compared with those who did not respond.

Because of the evidence collected, the USPSTF issued a B recommendation for HCV screening in adults and recommended screening for all people aged 18-79 years in the draft recommendation statement. “Clinicians may want to consider screening in adolescents younger than age 18 years and in adults older than age 79 years who are at high risk [for HCV],” the proposal says.

The draft recommendation statement and evidence review is available at www.uspreventiveservicestaskforce.org. The public comment period will last until Sept. 23, 2019.

lfranki@mdedge.com

The U.S. Preventive Services Task Force has issued a draft recommendation statement for screening for hepatitis C virus (HCV) infection in adolescents and adults, and now suggests that all adults aged 18-79 years receive screening.

Wikimedia Commons/BruceBlaus

This proposal represents an update and expansion of its current recommendation for screening for HCV infection. The draft recommendation incorporates new evidence and would replace the recommendation made in 2013, which calls for screening in persons at high risk for infection and one-time screening in adults born between 1945 and 1965 (Grade B).

“Today, more people are infected with hepatitis C than there were a decade ago, but there are now better treatments available. The evidence now shows more people can benefit from screening; therefore, we are recommending to screen all adults ages 18-79 for hepatitis C,” task force chair Douglas K. Owens, MD, MS, said in a bulletin issued by the USPSTF.

To update the previous recommendation, the USPSTF conducted a systematic review that included a total of 97 studies. No direct evidence was found regarding the benefits of HCV screening versus no screening or repeat versus one-time screening, and no new studies analyzed the psychological and social consequences of HCV screening.

Evidence concerning direct-acting antiviral (DAA) treatment was more compelling given that 49 trials found DAA therapy to be associated with pooled sustained virologic response (SVR) rates between 95.5% and 98.9% across genotypes. The rate of serious adverse events caused by DAA treatment was 1.9%, and the discontinuation of treatment because of adverse events was 0.4%. In seven trials involving adolescents, SVR rates after antiviral treatment were similar to those in adults.

Achieving an SVR after DAA treatment was associated with a decreased risk in those treated of all-cause mortality (hazard ratio, 0.40; 95% confidence interval, 0.28-0.56), liver mortality (HR, 0.11; 95% CI, 0.04-0.27), cirrhosis (HR, 0.36; 95% CI, 0.33-0.40), and hepatocellular carcinoma (HR, 0.29; 95% CI, 0.23-0.38), compared with those who did not respond.

Because of the evidence collected, the USPSTF issued a B recommendation for HCV screening in adults and recommended screening for all people aged 18-79 years in the draft recommendation statement. “Clinicians may want to consider screening in adolescents younger than age 18 years and in adults older than age 79 years who are at high risk [for HCV],” the proposal says.

The draft recommendation statement and evidence review is available at www.uspreventiveservicestaskforce.org. The public comment period will last until Sept. 23, 2019.

lfranki@mdedge.com

The U.S. Preventive Services Task Force has issued a draft recommendation statement for screening for hepatitis C virus (HCV) infection in adolescents and adults, and now suggests that all adults aged 18-79 years receive screening.

Wikimedia Commons/BruceBlaus

This proposal represents an update and expansion of its current recommendation for screening for HCV infection. The draft recommendation incorporates new evidence and would replace the recommendation made in 2013, which calls for screening in persons at high risk for infection and one-time screening in adults born between 1945 and 1965 (Grade B).

“Today, more people are infected with hepatitis C than there were a decade ago, but there are now better treatments available. The evidence now shows more people can benefit from screening; therefore, we are recommending to screen all adults ages 18-79 for hepatitis C,” task force chair Douglas K. Owens, MD, MS, said in a bulletin issued by the USPSTF.

To update the previous recommendation, the USPSTF conducted a systematic review that included a total of 97 studies. No direct evidence was found regarding the benefits of HCV screening versus no screening or repeat versus one-time screening, and no new studies analyzed the psychological and social consequences of HCV screening.

Evidence concerning direct-acting antiviral (DAA) treatment was more compelling given that 49 trials found DAA therapy to be associated with pooled sustained virologic response (SVR) rates between 95.5% and 98.9% across genotypes. The rate of serious adverse events caused by DAA treatment was 1.9%, and the discontinuation of treatment because of adverse events was 0.4%. In seven trials involving adolescents, SVR rates after antiviral treatment were similar to those in adults.

Achieving an SVR after DAA treatment was associated with a decreased risk in those treated of all-cause mortality (hazard ratio, 0.40; 95% confidence interval, 0.28-0.56), liver mortality (HR, 0.11; 95% CI, 0.04-0.27), cirrhosis (HR, 0.36; 95% CI, 0.33-0.40), and hepatocellular carcinoma (HR, 0.29; 95% CI, 0.23-0.38), compared with those who did not respond.

Because of the evidence collected, the USPSTF issued a B recommendation for HCV screening in adults and recommended screening for all people aged 18-79 years in the draft recommendation statement. “Clinicians may want to consider screening in adolescents younger than age 18 years and in adults older than age 79 years who are at high risk [for HCV],” the proposal says.

The draft recommendation statement and evidence review is available at www.uspreventiveservicestaskforce.org. The public comment period will last until Sept. 23, 2019.

lfranki@mdedge.com

High-dose vitamin D supplementation provides no benefit for maintaining bone quality in healthy older adults without osteoporosis, findings from a 3-year, randomized clinical trial suggest.

Irina Shisterova/Getty Images

In fact, rather than a hypothesized increase in volumetric bone mineral density (BMD) with doses well above the recommended dietary allowance, a negative dose-response relationship was observed, Lauren A. Burt, PhD, of the McCaig Institute for Bone and Joint Health at the University of Calgary (Alta.) and colleagues found.

The total volumetric radial BMD was significantly lower in 101 and 97 study participants randomized to receive daily vitamin D₃ doses of 10,000 IU or 4,000 IU for 3 years, respectively (–7.5 and –3.9 mg of calcium hydroxyapatite [HA] per cm³), compared with 105 participants randomized to a reference group that received 400 IU (mean percent changes, –3.5%, –2.4%, and –1.2%, respectively). Total volumetric tibial BMD was also significantly lower in the 10,000 IU arm, compared with the reference arm (–4.1 mg HA per cm³; mean percent change –1.7% vs. –0.4%), the investigators reported Aug. 27 in JAMA.

There also were no significant differences seen between the three groups for the coprimary endpoint of bone strength at either the radius or tibia.

Participants in the double-blind trial were community-dwelling healthy men and women aged 55-70 years (mean age, 62.2 years) without osteoporosis and with baseline levels of 25-hydroxyvitamin D (25[OH]D) of 30-125 nmol/L. They were enrolled from a single center between August 2013 and December 2017 and treated with daily oral vitamin D₃ drops at the assigned dosage for 3 years and with calcium supplementation if dietary calcium intake was less than 1,200 mg daily.

Mean supplementation adherence was 99% among the 303 participants who completed the trial (out of 311 enrolled), and adherence was similar across the groups.

Baseline 25(OH)D levels in the 400 IU group were 76.3 nmol/L at baseline, 76.7 nmol/L at 3 months, and 77.4 nmol/L at 3 years. The corresponding measures for the 4,000 IU group were 81.3, 115.3, and 132.2 nmol/L, and for the 10,000 IU group, they were 78.4, 188.0, and 144.4, the investigators said, noting that significant group-by-time interactions were noted for volumetric BMD.

Bone strength decreased over time, but group-by-time interactions for that measure were not statistically significant, they said.

A total of 44 serious adverse events occurred in 38 participants (12.2%), and one death from presumed myocardial infarction occurred in the 400 IU group. Of eight prespecified adverse events, only hypercalcemia and hypercalciuria had significant dose-response effects; all episodes of hypercalcemia were mild and had resolved at follow-up, and the two hypercalcemia events, which occurred in one participant in the 10,000 IU group, were also transient. No significant difference in fall rates was seen in the three groups, they noted.

Vitamin D is considered beneficial for preventing and treating osteoporosis, and data support supplementation in individuals with 25(OH)D levels less than 30 nmol/L, but recent meta-analyses did not find a major treatment benefit for osteoporosis or for preventing falls and fractures, the investigators said.

Further, while most supplementation recommendations call for 400-2,000 IU daily, with a tolerable upper intake level of 4,000-10,000 IU, 3% of U.S. adults in 2013-2014 reported intake of at least 4,000 IU per day, but few studies have assessed the effects of doses at or above the upper intake level for 12 months or longer, they noted, adding that this study was “motivated by the prevalence of high-dose vitamin D supplementation among healthy adults.”

“It was hypothesized that a higher dose of vitamin D has a positive effect on high-resolution peripheral quantitative CT measures of volumetric density and strength, perhaps via suppression of parathyroid hormone (PTH)–mediated bone turnover,” they wrote.

However, based on the significantly lower radial BMD seen with both 4,000 and 10,000 IU, compared with 400 IU; the lower tibial BMD with 10,000 IU, compared with 400 IU; and the lack of a difference in bone strength at the radius and tibia, the findings do not support a benefit of high-dose vitamin D supplementation for bone health, they said, noting that additional study is needed to determine whether such doses are harmful.

“Because these results are in the opposite direction of the research hypothesis, this evidence of high-dose vitamin D having a negative effect on bone should be regarded as hypothesis generating, requiring confirmation with further research,” they concluded.

sworcester@mdedge.com

SOURCE: Burt L et al. JAMA. 2019 Aug 27;322(8):736-45.

High-dose vitamin D supplementation provides no benefit for maintaining bone quality in healthy older adults without osteoporosis, findings from a 3-year, randomized clinical trial suggest.

Irina Shisterova/Getty Images

In fact, rather than a hypothesized increase in volumetric bone mineral density (BMD) with doses well above the recommended dietary allowance, a negative dose-response relationship was observed, Lauren A. Burt, PhD, of the McCaig Institute for Bone and Joint Health at the University of Calgary (Alta.) and colleagues found.

The total volumetric radial BMD was significantly lower in 101 and 97 study participants randomized to receive daily vitamin D₃ doses of 10,000 IU or 4,000 IU for 3 years, respectively (–7.5 and –3.9 mg of calcium hydroxyapatite [HA] per cm³), compared with 105 participants randomized to a reference group that received 400 IU (mean percent changes, –3.5%, –2.4%, and –1.2%, respectively). Total volumetric tibial BMD was also significantly lower in the 10,000 IU arm, compared with the reference arm (–4.1 mg HA per cm³; mean percent change –1.7% vs. –0.4%), the investigators reported Aug. 27 in JAMA.

There also were no significant differences seen between the three groups for the coprimary endpoint of bone strength at either the radius or tibia.

Participants in the double-blind trial were community-dwelling healthy men and women aged 55-70 years (mean age, 62.2 years) without osteoporosis and with baseline levels of 25-hydroxyvitamin D (25[OH]D) of 30-125 nmol/L. They were enrolled from a single center between August 2013 and December 2017 and treated with daily oral vitamin D₃ drops at the assigned dosage for 3 years and with calcium supplementation if dietary calcium intake was less than 1,200 mg daily.

Mean supplementation adherence was 99% among the 303 participants who completed the trial (out of 311 enrolled), and adherence was similar across the groups.

Baseline 25(OH)D levels in the 400 IU group were 76.3 nmol/L at baseline, 76.7 nmol/L at 3 months, and 77.4 nmol/L at 3 years. The corresponding measures for the 4,000 IU group were 81.3, 115.3, and 132.2 nmol/L, and for the 10,000 IU group, they were 78.4, 188.0, and 144.4, the investigators said, noting that significant group-by-time interactions were noted for volumetric BMD.

Bone strength decreased over time, but group-by-time interactions for that measure were not statistically significant, they said.

A total of 44 serious adverse events occurred in 38 participants (12.2%), and one death from presumed myocardial infarction occurred in the 400 IU group. Of eight prespecified adverse events, only hypercalcemia and hypercalciuria had significant dose-response effects; all episodes of hypercalcemia were mild and had resolved at follow-up, and the two hypercalcemia events, which occurred in one participant in the 10,000 IU group, were also transient. No significant difference in fall rates was seen in the three groups, they noted.

Vitamin D is considered beneficial for preventing and treating osteoporosis, and data support supplementation in individuals with 25(OH)D levels less than 30 nmol/L, but recent meta-analyses did not find a major treatment benefit for osteoporosis or for preventing falls and fractures, the investigators said.

Further, while most supplementation recommendations call for 400-2,000 IU daily, with a tolerable upper intake level of 4,000-10,000 IU, 3% of U.S. adults in 2013-2014 reported intake of at least 4,000 IU per day, but few studies have assessed the effects of doses at or above the upper intake level for 12 months or longer, they noted, adding that this study was “motivated by the prevalence of high-dose vitamin D supplementation among healthy adults.”

“It was hypothesized that a higher dose of vitamin D has a positive effect on high-resolution peripheral quantitative CT measures of volumetric density and strength, perhaps via suppression of parathyroid hormone (PTH)–mediated bone turnover,” they wrote.

However, based on the significantly lower radial BMD seen with both 4,000 and 10,000 IU, compared with 400 IU; the lower tibial BMD with 10,000 IU, compared with 400 IU; and the lack of a difference in bone strength at the radius and tibia, the findings do not support a benefit of high-dose vitamin D supplementation for bone health, they said, noting that additional study is needed to determine whether such doses are harmful.

“Because these results are in the opposite direction of the research hypothesis, this evidence of high-dose vitamin D having a negative effect on bone should be regarded as hypothesis generating, requiring confirmation with further research,” they concluded.

sworcester@mdedge.com

SOURCE: Burt L et al. JAMA. 2019 Aug 27;322(8):736-45.

High-dose vitamin D supplementation provides no benefit for maintaining bone quality in healthy older adults without osteoporosis, findings from a 3-year, randomized clinical trial suggest.

Irina Shisterova/Getty Images

In fact, rather than a hypothesized increase in volumetric bone mineral density (BMD) with doses well above the recommended dietary allowance, a negative dose-response relationship was observed, Lauren A. Burt, PhD, of the McCaig Institute for Bone and Joint Health at the University of Calgary (Alta.) and colleagues found.

The total volumetric radial BMD was significantly lower in 101 and 97 study participants randomized to receive daily vitamin D₃ doses of 10,000 IU or 4,000 IU for 3 years, respectively (–7.5 and –3.9 mg of calcium hydroxyapatite [HA] per cm³), compared with 105 participants randomized to a reference group that received 400 IU (mean percent changes, –3.5%, –2.4%, and –1.2%, respectively). Total volumetric tibial BMD was also significantly lower in the 10,000 IU arm, compared with the reference arm (–4.1 mg HA per cm³; mean percent change –1.7% vs. –0.4%), the investigators reported Aug. 27 in JAMA.

There also were no significant differences seen between the three groups for the coprimary endpoint of bone strength at either the radius or tibia.

Participants in the double-blind trial were community-dwelling healthy men and women aged 55-70 years (mean age, 62.2 years) without osteoporosis and with baseline levels of 25-hydroxyvitamin D (25[OH]D) of 30-125 nmol/L. They were enrolled from a single center between August 2013 and December 2017 and treated with daily oral vitamin D₃ drops at the assigned dosage for 3 years and with calcium supplementation if dietary calcium intake was less than 1,200 mg daily.

Mean supplementation adherence was 99% among the 303 participants who completed the trial (out of 311 enrolled), and adherence was similar across the groups.

Baseline 25(OH)D levels in the 400 IU group were 76.3 nmol/L at baseline, 76.7 nmol/L at 3 months, and 77.4 nmol/L at 3 years. The corresponding measures for the 4,000 IU group were 81.3, 115.3, and 132.2 nmol/L, and for the 10,000 IU group, they were 78.4, 188.0, and 144.4, the investigators said, noting that significant group-by-time interactions were noted for volumetric BMD.

Bone strength decreased over time, but group-by-time interactions for that measure were not statistically significant, they said.

A total of 44 serious adverse events occurred in 38 participants (12.2%), and one death from presumed myocardial infarction occurred in the 400 IU group. Of eight prespecified adverse events, only hypercalcemia and hypercalciuria had significant dose-response effects; all episodes of hypercalcemia were mild and had resolved at follow-up, and the two hypercalcemia events, which occurred in one participant in the 10,000 IU group, were also transient. No significant difference in fall rates was seen in the three groups, they noted.

Vitamin D is considered beneficial for preventing and treating osteoporosis, and data support supplementation in individuals with 25(OH)D levels less than 30 nmol/L, but recent meta-analyses did not find a major treatment benefit for osteoporosis or for preventing falls and fractures, the investigators said.

Further, while most supplementation recommendations call for 400-2,000 IU daily, with a tolerable upper intake level of 4,000-10,000 IU, 3% of U.S. adults in 2013-2014 reported intake of at least 4,000 IU per day, but few studies have assessed the effects of doses at or above the upper intake level for 12 months or longer, they noted, adding that this study was “motivated by the prevalence of high-dose vitamin D supplementation among healthy adults.”

“It was hypothesized that a higher dose of vitamin D has a positive effect on high-resolution peripheral quantitative CT measures of volumetric density and strength, perhaps via suppression of parathyroid hormone (PTH)–mediated bone turnover,” they wrote.

However, based on the significantly lower radial BMD seen with both 4,000 and 10,000 IU, compared with 400 IU; the lower tibial BMD with 10,000 IU, compared with 400 IU; and the lack of a difference in bone strength at the radius and tibia, the findings do not support a benefit of high-dose vitamin D supplementation for bone health, they said, noting that additional study is needed to determine whether such doses are harmful.

“Because these results are in the opposite direction of the research hypothesis, this evidence of high-dose vitamin D having a negative effect on bone should be regarded as hypothesis generating, requiring confirmation with further research,” they concluded.

sworcester@mdedge.com

SOURCE: Burt L et al. JAMA. 2019 Aug 27;322(8):736-45.