Rare Diseases

Treatment with tocilizumab (Actemra) could stabilize or improve lung function in people with early interstitial lung disease associated with systemic sclerosis (SSc-ILD), a new study has found.

goa_novi/ThinkStock

A paper published online Feb. 3 in Arthritis & Rheumatology presents the results of a post hoc analysis of data from a phase 3, placebo-controlled, double-blind trial of subcutaneous tocilizumab in patients with SSc and progressive skin disease, which included high-resolution chest CT to assess lung involvement and fibrosis.

Tocilizumab is a monoclonal antibody that targets interleukin-6 and is currently approved for the treatment of immune-mediated diseases such as rheumatoid arthritis, giant cell arteritis, cytokine release syndrome, and systemic and polyarticular course juvenile idiopathic arthritis.

Two previous studies of tocilizumab in patients with early, diffuse cutaneous SSc had also found that the treatment was associated with preservation of lung function but did not characterize that effect using radiography.

Of the 210 participants in the trial, called focuSSced, 136 were found to have interstitial lung disease at baseline and were randomized to 162 mg tocilizumab weekly or placebo for 48 weeks.

At baseline, around three-quarters of those with interstitial lung disease had moderate to severe lung involvement, defined as ground glass opacities, honeycombing, and fibrotic reticulation across at least 20% of the whole lung.

Those in the tocilizumab group showed a 0.1% mean decline in forced vital capacity (FVC) over the 48-week study, while those in the placebo group had a mean decline of 6.3%.

When stratified by severity of lung involvement, those with mild lung disease group treated with tocilizumab had a 4.1% decline in FVC, compared with a 10% decline in the placebo group; those with moderate disease in the treatment group had an 0.7% mean increase in FVC, compared with a 5.7% decrease in the placebo group, and those with severe lung involvement in the treatment arm had a 2.1% increase in FVC, compared with a 6.7% decrease in the placebo arm.

Those treated with tocilizumab also showed a statistically significant 1.8% improvement in the amount of lung involvement, which was largely seen in those with more extensive lung involvement at baseline. Those with more than 20% of the lung affected had a significant 4.9% reduction in lung area affected, while those in the placebo arm showed a significant increase in fibrosis.

First author David Roofeh, MD, of the University of Michigan Scleroderma Program, and colleagues wrote that most patients with SSc will develop interstitial lung disease – particularly those with early, diffuse cutaneous SSc and elevated markers such as C-reactive protein.

“Patients with these high-risk features, especially those with disease in the initial phase of development, represent an important target for early intervention as ILD is largely irreversible in SSc,” the authors wrote.

Findings from a specific patient population may not be generalizable

Commenting on the findings, Lorinda Chung, MD, of Stanford (Calif.) University, said in an interview that the study demonstrated that tocilizumab could prevent radiographic progression of ILD in early diffuse SSc patients with mild to severe lung disease and evidence of active skin disease, as well as elevated inflammatory markers.

“This was a very specific patient population who was studied in the focuSSced clinical trial, and this paper only evaluated a subset of these patients,” Dr. Chung said. “The results may not be generalizable to all SSc-ILD patients and further studies are needed.”

The authors suggested that the patients with progressive skin disease and elevated acute phase reactants may represent a group in the immunoinflammatory phase of the disease rather than the advanced fibrotic stage, and that this might be a “window of therapeutic opportunity to preserve lung function.”

Dr. Chung noted that the radiographic improvement induced by tocilizumab treatment was greatest in those with the most radiographic disease at baseline.

“This may reflect tocilizumab’s impact on decreasing inflammation, but we are not provided the data on the effects of tocilizumab on the individual components of the QILD [quantitative ILD: summation of ground glass opacities, honeycombing, and fibrotic reticulation],” she said.

The study’s authors also made a point about the utility of screening patients with high-resolution chest CT to detect early signs of ILD.

“Our data demonstrate the value of obtaining HRCT at the time of diagnosis: PFTs [pulmonary function tests] are not sensitive enough to accurately assess the presence of ILD and delays in treatment initiation may lead to irreversible disease,” they wrote.

Describing the results as ‘hypothesis-generating’ owing to the post hoc nature of the analysis, the authors said that FVC was an indirect measure of the flow-resistive properties of the lung, and that other aspects of SSc – such as hide-bound chest thickness – could cause thoracic restriction.

Two authors were funded by the National Institutes of Health. Six authors declared grants, funding, and other support from the pharmaceutical sector, including Roche, which sponsored the original focuSSced trial.

Treatment with tocilizumab (Actemra) could stabilize or improve lung function in people with early interstitial lung disease associated with systemic sclerosis (SSc-ILD), a new study has found.

goa_novi/ThinkStock

A paper published online Feb. 3 in Arthritis & Rheumatology presents the results of a post hoc analysis of data from a phase 3, placebo-controlled, double-blind trial of subcutaneous tocilizumab in patients with SSc and progressive skin disease, which included high-resolution chest CT to assess lung involvement and fibrosis.

Tocilizumab is a monoclonal antibody that targets interleukin-6 and is currently approved for the treatment of immune-mediated diseases such as rheumatoid arthritis, giant cell arteritis, cytokine release syndrome, and systemic and polyarticular course juvenile idiopathic arthritis.

Two previous studies of tocilizumab in patients with early, diffuse cutaneous SSc had also found that the treatment was associated with preservation of lung function but did not characterize that effect using radiography.

Of the 210 participants in the trial, called focuSSced, 136 were found to have interstitial lung disease at baseline and were randomized to 162 mg tocilizumab weekly or placebo for 48 weeks.

At baseline, around three-quarters of those with interstitial lung disease had moderate to severe lung involvement, defined as ground glass opacities, honeycombing, and fibrotic reticulation across at least 20% of the whole lung.

Those in the tocilizumab group showed a 0.1% mean decline in forced vital capacity (FVC) over the 48-week study, while those in the placebo group had a mean decline of 6.3%.

When stratified by severity of lung involvement, those with mild lung disease group treated with tocilizumab had a 4.1% decline in FVC, compared with a 10% decline in the placebo group; those with moderate disease in the treatment group had an 0.7% mean increase in FVC, compared with a 5.7% decrease in the placebo group, and those with severe lung involvement in the treatment arm had a 2.1% increase in FVC, compared with a 6.7% decrease in the placebo arm.

Those treated with tocilizumab also showed a statistically significant 1.8% improvement in the amount of lung involvement, which was largely seen in those with more extensive lung involvement at baseline. Those with more than 20% of the lung affected had a significant 4.9% reduction in lung area affected, while those in the placebo arm showed a significant increase in fibrosis.

First author David Roofeh, MD, of the University of Michigan Scleroderma Program, and colleagues wrote that most patients with SSc will develop interstitial lung disease – particularly those with early, diffuse cutaneous SSc and elevated markers such as C-reactive protein.

“Patients with these high-risk features, especially those with disease in the initial phase of development, represent an important target for early intervention as ILD is largely irreversible in SSc,” the authors wrote.

Findings from a specific patient population may not be generalizable

Commenting on the findings, Lorinda Chung, MD, of Stanford (Calif.) University, said in an interview that the study demonstrated that tocilizumab could prevent radiographic progression of ILD in early diffuse SSc patients with mild to severe lung disease and evidence of active skin disease, as well as elevated inflammatory markers.

“This was a very specific patient population who was studied in the focuSSced clinical trial, and this paper only evaluated a subset of these patients,” Dr. Chung said. “The results may not be generalizable to all SSc-ILD patients and further studies are needed.”

The authors suggested that the patients with progressive skin disease and elevated acute phase reactants may represent a group in the immunoinflammatory phase of the disease rather than the advanced fibrotic stage, and that this might be a “window of therapeutic opportunity to preserve lung function.”

Dr. Chung noted that the radiographic improvement induced by tocilizumab treatment was greatest in those with the most radiographic disease at baseline.

“This may reflect tocilizumab’s impact on decreasing inflammation, but we are not provided the data on the effects of tocilizumab on the individual components of the QILD [quantitative ILD: summation of ground glass opacities, honeycombing, and fibrotic reticulation],” she said.

The study’s authors also made a point about the utility of screening patients with high-resolution chest CT to detect early signs of ILD.

“Our data demonstrate the value of obtaining HRCT at the time of diagnosis: PFTs [pulmonary function tests] are not sensitive enough to accurately assess the presence of ILD and delays in treatment initiation may lead to irreversible disease,” they wrote.

Describing the results as ‘hypothesis-generating’ owing to the post hoc nature of the analysis, the authors said that FVC was an indirect measure of the flow-resistive properties of the lung, and that other aspects of SSc – such as hide-bound chest thickness – could cause thoracic restriction.

Two authors were funded by the National Institutes of Health. Six authors declared grants, funding, and other support from the pharmaceutical sector, including Roche, which sponsored the original focuSSced trial.

Treatment with tocilizumab (Actemra) could stabilize or improve lung function in people with early interstitial lung disease associated with systemic sclerosis (SSc-ILD), a new study has found.

goa_novi/ThinkStock

A paper published online Feb. 3 in Arthritis & Rheumatology presents the results of a post hoc analysis of data from a phase 3, placebo-controlled, double-blind trial of subcutaneous tocilizumab in patients with SSc and progressive skin disease, which included high-resolution chest CT to assess lung involvement and fibrosis.

Tocilizumab is a monoclonal antibody that targets interleukin-6 and is currently approved for the treatment of immune-mediated diseases such as rheumatoid arthritis, giant cell arteritis, cytokine release syndrome, and systemic and polyarticular course juvenile idiopathic arthritis.

Two previous studies of tocilizumab in patients with early, diffuse cutaneous SSc had also found that the treatment was associated with preservation of lung function but did not characterize that effect using radiography.

Of the 210 participants in the trial, called focuSSced, 136 were found to have interstitial lung disease at baseline and were randomized to 162 mg tocilizumab weekly or placebo for 48 weeks.

At baseline, around three-quarters of those with interstitial lung disease had moderate to severe lung involvement, defined as ground glass opacities, honeycombing, and fibrotic reticulation across at least 20% of the whole lung.

Those in the tocilizumab group showed a 0.1% mean decline in forced vital capacity (FVC) over the 48-week study, while those in the placebo group had a mean decline of 6.3%.

When stratified by severity of lung involvement, those with mild lung disease group treated with tocilizumab had a 4.1% decline in FVC, compared with a 10% decline in the placebo group; those with moderate disease in the treatment group had an 0.7% mean increase in FVC, compared with a 5.7% decrease in the placebo group, and those with severe lung involvement in the treatment arm had a 2.1% increase in FVC, compared with a 6.7% decrease in the placebo arm.

Those treated with tocilizumab also showed a statistically significant 1.8% improvement in the amount of lung involvement, which was largely seen in those with more extensive lung involvement at baseline. Those with more than 20% of the lung affected had a significant 4.9% reduction in lung area affected, while those in the placebo arm showed a significant increase in fibrosis.

First author David Roofeh, MD, of the University of Michigan Scleroderma Program, and colleagues wrote that most patients with SSc will develop interstitial lung disease – particularly those with early, diffuse cutaneous SSc and elevated markers such as C-reactive protein.

“Patients with these high-risk features, especially those with disease in the initial phase of development, represent an important target for early intervention as ILD is largely irreversible in SSc,” the authors wrote.

Findings from a specific patient population may not be generalizable

Commenting on the findings, Lorinda Chung, MD, of Stanford (Calif.) University, said in an interview that the study demonstrated that tocilizumab could prevent radiographic progression of ILD in early diffuse SSc patients with mild to severe lung disease and evidence of active skin disease, as well as elevated inflammatory markers.

“This was a very specific patient population who was studied in the focuSSced clinical trial, and this paper only evaluated a subset of these patients,” Dr. Chung said. “The results may not be generalizable to all SSc-ILD patients and further studies are needed.”

The authors suggested that the patients with progressive skin disease and elevated acute phase reactants may represent a group in the immunoinflammatory phase of the disease rather than the advanced fibrotic stage, and that this might be a “window of therapeutic opportunity to preserve lung function.”

Dr. Chung noted that the radiographic improvement induced by tocilizumab treatment was greatest in those with the most radiographic disease at baseline.

“This may reflect tocilizumab’s impact on decreasing inflammation, but we are not provided the data on the effects of tocilizumab on the individual components of the QILD [quantitative ILD: summation of ground glass opacities, honeycombing, and fibrotic reticulation],” she said.

The study’s authors also made a point about the utility of screening patients with high-resolution chest CT to detect early signs of ILD.

“Our data demonstrate the value of obtaining HRCT at the time of diagnosis: PFTs [pulmonary function tests] are not sensitive enough to accurately assess the presence of ILD and delays in treatment initiation may lead to irreversible disease,” they wrote.

Describing the results as ‘hypothesis-generating’ owing to the post hoc nature of the analysis, the authors said that FVC was an indirect measure of the flow-resistive properties of the lung, and that other aspects of SSc – such as hide-bound chest thickness – could cause thoracic restriction.

Two authors were funded by the National Institutes of Health. Six authors declared grants, funding, and other support from the pharmaceutical sector, including Roche, which sponsored the original focuSSced trial.

Tuberous sclerosis (TS), also known as Bourneville’s syndrome or epiloia (epi: epilepsy, loi: low intelligence, a: adenoma sebaceum), is a genetic disease inherited in an autosomal dominant pattern, although up to 75% of cases may be caused by a spontaneous mutation. It is caused by mutations in the TSC1 gene on chromosome 9q34–encoding hamartin or the TSC2 gene on chromosome I6pl3–encoding tuberin. Patients present at birth and males and females are affected equally.

There are multiple skin findings in TS that may herald the diagnosis. The earliest findings are hypopigmented macules, found in 85% of patients. They may be in an ash-leaf shape or confetti pattern. Adenoma sebaceum, or angiofibromas, are present on the forehead, nose, and cheeks, and often present in childhood. Periungual angiofibromas called Koenen tumors tend to occur at puberty. Connective-tissue nevi called Shagreen plaques, or collagenomas, may be present, which is what our patient exhibits on his back. The lumbosacral region is the most common area for these to appear in the first decade of life.

TS can affect other organ systems in the body. Seizures, neuropsychiatric diseases, and mental deficiency are common. Cortical tumors, gliomas, and astrocytomas may develop in the brain. Congenital retinal hamartomas (phakomas) occur. Renal cysts and angiomyolipomas may occur in the kidneys. In the lungs, patients may develop lymphangiomyomatosis. Rhabdomyomas can occur in the heart in infancy and may regress spontaneously over time. Bony changes such as cysts and sclerosis may occur.

Treatment and monitoring of TS requires a multidisciplinary approach with neurology, pulmonology, cardiology, ophthalmology, orthopedics, and dermatology. Cosmetic treatment for angiofibromas includes CO₂ laser, shaving, and dermabrasion. Topical rapamycin use has been described in the literature to improve the appearance of angiofibromas. Our patient has been using rapamycin 1% cream for more than 5 years and has had a substantial reduction in the size and number of angiofibromas.

This case and photo were submitted by Dr. Bilu Martin.
 

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References:

Spitz J. Genodermatoses. A Clinical Guide to Genetic Skin Disorders. Philadelphia: Lippincott Williams & Wilkins, 2005.

James W et al. Andrews’ Diseases of the Skin. Philadelphia: Saunders, 2006.

Bolognia JL et al. Dermatology. London: Mosby Elsevier, 2008.

Tuberous sclerosis (TS), also known as Bourneville’s syndrome or epiloia (epi: epilepsy, loi: low intelligence, a: adenoma sebaceum), is a genetic disease inherited in an autosomal dominant pattern, although up to 75% of cases may be caused by a spontaneous mutation. It is caused by mutations in the TSC1 gene on chromosome 9q34–encoding hamartin or the TSC2 gene on chromosome I6pl3–encoding tuberin. Patients present at birth and males and females are affected equally.

There are multiple skin findings in TS that may herald the diagnosis. The earliest findings are hypopigmented macules, found in 85% of patients. They may be in an ash-leaf shape or confetti pattern. Adenoma sebaceum, or angiofibromas, are present on the forehead, nose, and cheeks, and often present in childhood. Periungual angiofibromas called Koenen tumors tend to occur at puberty. Connective-tissue nevi called Shagreen plaques, or collagenomas, may be present, which is what our patient exhibits on his back. The lumbosacral region is the most common area for these to appear in the first decade of life.

TS can affect other organ systems in the body. Seizures, neuropsychiatric diseases, and mental deficiency are common. Cortical tumors, gliomas, and astrocytomas may develop in the brain. Congenital retinal hamartomas (phakomas) occur. Renal cysts and angiomyolipomas may occur in the kidneys. In the lungs, patients may develop lymphangiomyomatosis. Rhabdomyomas can occur in the heart in infancy and may regress spontaneously over time. Bony changes such as cysts and sclerosis may occur.

Treatment and monitoring of TS requires a multidisciplinary approach with neurology, pulmonology, cardiology, ophthalmology, orthopedics, and dermatology. Cosmetic treatment for angiofibromas includes CO₂ laser, shaving, and dermabrasion. Topical rapamycin use has been described in the literature to improve the appearance of angiofibromas. Our patient has been using rapamycin 1% cream for more than 5 years and has had a substantial reduction in the size and number of angiofibromas.

This case and photo were submitted by Dr. Bilu Martin.
 

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References:

Spitz J. Genodermatoses. A Clinical Guide to Genetic Skin Disorders. Philadelphia: Lippincott Williams & Wilkins, 2005.

James W et al. Andrews’ Diseases of the Skin. Philadelphia: Saunders, 2006.

Bolognia JL et al. Dermatology. London: Mosby Elsevier, 2008.

Tuberous sclerosis (TS), also known as Bourneville’s syndrome or epiloia (epi: epilepsy, loi: low intelligence, a: adenoma sebaceum), is a genetic disease inherited in an autosomal dominant pattern, although up to 75% of cases may be caused by a spontaneous mutation. It is caused by mutations in the TSC1 gene on chromosome 9q34–encoding hamartin or the TSC2 gene on chromosome I6pl3–encoding tuberin. Patients present at birth and males and females are affected equally.

There are multiple skin findings in TS that may herald the diagnosis. The earliest findings are hypopigmented macules, found in 85% of patients. They may be in an ash-leaf shape or confetti pattern. Adenoma sebaceum, or angiofibromas, are present on the forehead, nose, and cheeks, and often present in childhood. Periungual angiofibromas called Koenen tumors tend to occur at puberty. Connective-tissue nevi called Shagreen plaques, or collagenomas, may be present, which is what our patient exhibits on his back. The lumbosacral region is the most common area for these to appear in the first decade of life.

TS can affect other organ systems in the body. Seizures, neuropsychiatric diseases, and mental deficiency are common. Cortical tumors, gliomas, and astrocytomas may develop in the brain. Congenital retinal hamartomas (phakomas) occur. Renal cysts and angiomyolipomas may occur in the kidneys. In the lungs, patients may develop lymphangiomyomatosis. Rhabdomyomas can occur in the heart in infancy and may regress spontaneously over time. Bony changes such as cysts and sclerosis may occur.

Treatment and monitoring of TS requires a multidisciplinary approach with neurology, pulmonology, cardiology, ophthalmology, orthopedics, and dermatology. Cosmetic treatment for angiofibromas includes CO₂ laser, shaving, and dermabrasion. Topical rapamycin use has been described in the literature to improve the appearance of angiofibromas. Our patient has been using rapamycin 1% cream for more than 5 years and has had a substantial reduction in the size and number of angiofibromas.

This case and photo were submitted by Dr. Bilu Martin.
 

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References:

Spitz J. Genodermatoses. A Clinical Guide to Genetic Skin Disorders. Philadelphia: Lippincott Williams & Wilkins, 2005.

James W et al. Andrews’ Diseases of the Skin. Philadelphia: Saunders, 2006.

Bolognia JL et al. Dermatology. London: Mosby Elsevier, 2008.

The Royal Swedish Academy of Sciences and the Crafoord Foundation in Lund has awarded Daniel Kastner, MD, PhD, its 2021 Crafoord Prize in Polyarthritis, “for establishing the concept of autoinflammatory diseases.” The prize, named after the donor Holger Crafoord because of his bout with severe rheumatoid arthritis toward the end of his life, is for 6 million Swedish kronor (approximately USD $700,000).

Dr. Kastner, scientific director at the U.S. National Human Genome Research Institute’s division of intramural research, received the award for identifying the mechanisms responsible for familial Mediterranean fever, tumor necrosis factor receptor–associated periodic syndrome, and other diagnoses within the group of autoinflammatory diseases.

“Dan Kastner is often called the father of autoinflammatory diseases, a title that he thoroughly deserves. His discoveries have taught us a great deal about the immune system and its functions, contributing to effective treatments that reduce the symptoms of diseases from which patients previously suffered enormously, sometimes leading to premature death,” Olle Kämpe, chair of the prize committee, said in a press announcement.

While the Crafoord Prize normally is awarded on a 3-year rotating basis for achievements in mathematics and astronomy, geosciences, and biosciences, the prize in polyarthritis is “only awarded when there has been scientific progress that motivates a prize,” according to the press release.

[email protected]

The Royal Swedish Academy of Sciences and the Crafoord Foundation in Lund has awarded Daniel Kastner, MD, PhD, its 2021 Crafoord Prize in Polyarthritis, “for establishing the concept of autoinflammatory diseases.” The prize, named after the donor Holger Crafoord because of his bout with severe rheumatoid arthritis toward the end of his life, is for 6 million Swedish kronor (approximately USD $700,000).

Dr. Kastner, scientific director at the U.S. National Human Genome Research Institute’s division of intramural research, received the award for identifying the mechanisms responsible for familial Mediterranean fever, tumor necrosis factor receptor–associated periodic syndrome, and other diagnoses within the group of autoinflammatory diseases.

“Dan Kastner is often called the father of autoinflammatory diseases, a title that he thoroughly deserves. His discoveries have taught us a great deal about the immune system and its functions, contributing to effective treatments that reduce the symptoms of diseases from which patients previously suffered enormously, sometimes leading to premature death,” Olle Kämpe, chair of the prize committee, said in a press announcement.

While the Crafoord Prize normally is awarded on a 3-year rotating basis for achievements in mathematics and astronomy, geosciences, and biosciences, the prize in polyarthritis is “only awarded when there has been scientific progress that motivates a prize,” according to the press release.

[email protected]

The Royal Swedish Academy of Sciences and the Crafoord Foundation in Lund has awarded Daniel Kastner, MD, PhD, its 2021 Crafoord Prize in Polyarthritis, “for establishing the concept of autoinflammatory diseases.” The prize, named after the donor Holger Crafoord because of his bout with severe rheumatoid arthritis toward the end of his life, is for 6 million Swedish kronor (approximately USD $700,000).

Dr. Kastner, scientific director at the U.S. National Human Genome Research Institute’s division of intramural research, received the award for identifying the mechanisms responsible for familial Mediterranean fever, tumor necrosis factor receptor–associated periodic syndrome, and other diagnoses within the group of autoinflammatory diseases.

“Dan Kastner is often called the father of autoinflammatory diseases, a title that he thoroughly deserves. His discoveries have taught us a great deal about the immune system and its functions, contributing to effective treatments that reduce the symptoms of diseases from which patients previously suffered enormously, sometimes leading to premature death,” Olle Kämpe, chair of the prize committee, said in a press announcement.

While the Crafoord Prize normally is awarded on a 3-year rotating basis for achievements in mathematics and astronomy, geosciences, and biosciences, the prize in polyarthritis is “only awarded when there has been scientific progress that motivates a prize,” according to the press release.

[email protected]

Clinicians using systemic retinoids for treating ichthyosis and other disorders of cornification (DOC) in children and adolescents should aim for the lowest dose possible to balance therapeutic goals with acceptable toxicity levels, advised the authors of a new consensus statement.

In the statement, published in Pediatric Dermatology, they also addressed the effects of topical and systemic retinoid use on bone, eye, cardiovascular, and mental health, and the risks some retinoids pose to reproductive health.

Many patients with these chronic conditions, driven by multiple genetic mutations, respond to topical and/or systemic retinoids. However, to date, no specific guidance has addressed the safety, efficacy, or overall precautions for their use in the pediatric population, one of the statement authors, Moise L. Levy, MD, professor of pediatrics and medicine at the University of Texas at Austin, said in an interview.

Dr. Levy was one of the physicians on the multidisciplinary panel, The Pediatric Dermatology Research Alliance Use of Retinoids in Ichthyosis Work Group, formed to devise best practice recommendations on the use of retinoids in the management of ichthyoses and other cornification disorders in children and adolescents. The panel conducted an extensive evidence-based literature review and met in person to arrive at their conclusions. Representation from the Foundation for Ichthyosis and Related Skin Types (FIRST) was also key to this work. “Additionally, the teratogenic effects of retinoids prompted examination of gynecologic considerations and the role of the iPLEDGE program in the United States on patient access to isotretinoin,” the authors wrote.


 

Retinoid effects, dosing

“Both topical and systemic retinoids can improve scaling in patients with select forms of ichthyosis,” and some subtypes of disease respond better to treatment than others, they noted. Oral or topical retinoids are known to improve cases of congenital ichthyosiform erythroderma (select genotypes), Sjögren-Larsson syndrome, ichthyosis follicularis–alopecia-photophobia syndromes and keratitis-ichthyosis-deafness syndrome, erythrokeratodermia variabilis, harlequin ichthyosis, ichthyosis with confetti, and other subtypes.

Comparatively, they added, there are no data on the use of retinoids, or data showing no improvement with retinoids for several ichthyosis subtypes, including congenital hemidysplasia with ichthyosiform erythroderma and limb defects, CHIME syndrome, Conradi-Hünermann-Happle syndrome, ichthyosis-hypotrichosis syndrome, ichthyosis-hypotrichosis-sclerosing cholangitis, ichthyosis prematurity syndrome, MEDNIK syndrome, peeling skin disease, Refsum syndrome, and trichothiodystrophy though the response to such cases may vary.

Retinoids may worsen conditions that lead to peeling or skin fragility, atopic diathesis, or excessive desquamation, “and should be used with caution,” the authors advised.

Pediatric and adult patients with moderate to severe disease and significant functional or psychological impairment “should be offered the opportunity to make a benefit/risk assessment of treatment” with a systemic retinoid, they added, noting that topical retinoids have a lower risk profile and may be a better choice for milder disease.

Clinicians should aim for the lowest dose possible “that will achieve and maintain the desired therapeutic effect with acceptable mucocutaneous and systemic toxicities,” the panel recommended. Lower doses work especially well in patients with epidermolytic ichthyoses and erythrokeratodermia variabilis.

“Given the cutaneous and extracutaneous toxicities of oral retinoids, lower doses were found to achieve the most acceptable risk-benefit result. Few individuals now receive more than 1 mg/kg per day of isotretinoin or 0.5 mg/kg per day of acitretin,” according to the panel.

Dosing decisions call for a group conversation between physicians, patients and caregivers, addressing skin care, comfort and appearance issues, risk of adverse effects, and tolerance of the therapy.
 

Retinoid effects on organs

The impact of retinoids on the body varies by organ system, type of therapy and dosage. Dose and duration of therapy, for example, help determine the toxic effects of retinoids on bone. “Long-term use of systemic retinoids in ichthyosis/DOC is associated with skeletal concerns,” noted the authors, adding that clinicians should still consider this therapeutic approach if there is a strong clinical case for using it in a patient.

Children on long-term systemic therapy should undergo a series of tests and evaluations for bone monitoring, including an annual growth assessment. The group also recommended a baseline skeletal radiographic survey when children are on long-term systemic retinoid therapy, repeated after 3-5 years or when symptoms are present. Clinicians should also inquire about diet and discuss with patients factors that impact susceptibility to retinoid bone toxicity, such as genetic risk, diet and physical activity.

They also recommended monitoring patients taking systemic retinoids for psychiatric symptoms.

Adolescents of childbearing potential using systemic retinoids, who are sexually active, should receive counseling about contraceptive options, and should use two forms of contraception, including one highly effective method, the statement advises.

In the United States, all patients and prescribers of isotretinoin must comply with iPLEDGE guidelines; the statement addresses the issue that iPLEDGE was not designed for long-term use of isotretinoin in patients with ichthyosis, and “imposes a significant burden” in this group.

Other practice gaps and unmet needs in this area of study were discussed, calling for a closer examination of optimal timing of therapy initiation, and the adverse effects of long-term retinoid treatment. “The work, as a whole, is a starting point for these important management issues,” said Dr. Levy.

Unrestricted educational grants from Sun Pharmaceuticals and FIRST funded this effort. Dr. Levy’s disclosed serving on the advisory board and as a consultant for Cassiopea, Regeneron, and UCB, and an investigator for Fibrocell, Galderma, Janssen, and Pfizer. The other authors disclosed serving as investigators, advisers, consultants, and/or other relationships with various pharmaceutical companies.

Clinicians using systemic retinoids for treating ichthyosis and other disorders of cornification (DOC) in children and adolescents should aim for the lowest dose possible to balance therapeutic goals with acceptable toxicity levels, advised the authors of a new consensus statement.

In the statement, published in Pediatric Dermatology, they also addressed the effects of topical and systemic retinoid use on bone, eye, cardiovascular, and mental health, and the risks some retinoids pose to reproductive health.

Many patients with these chronic conditions, driven by multiple genetic mutations, respond to topical and/or systemic retinoids. However, to date, no specific guidance has addressed the safety, efficacy, or overall precautions for their use in the pediatric population, one of the statement authors, Moise L. Levy, MD, professor of pediatrics and medicine at the University of Texas at Austin, said in an interview.

Dr. Levy was one of the physicians on the multidisciplinary panel, The Pediatric Dermatology Research Alliance Use of Retinoids in Ichthyosis Work Group, formed to devise best practice recommendations on the use of retinoids in the management of ichthyoses and other cornification disorders in children and adolescents. The panel conducted an extensive evidence-based literature review and met in person to arrive at their conclusions. Representation from the Foundation for Ichthyosis and Related Skin Types (FIRST) was also key to this work. “Additionally, the teratogenic effects of retinoids prompted examination of gynecologic considerations and the role of the iPLEDGE program in the United States on patient access to isotretinoin,” the authors wrote.


 

Retinoid effects, dosing

“Both topical and systemic retinoids can improve scaling in patients with select forms of ichthyosis,” and some subtypes of disease respond better to treatment than others, they noted. Oral or topical retinoids are known to improve cases of congenital ichthyosiform erythroderma (select genotypes), Sjögren-Larsson syndrome, ichthyosis follicularis–alopecia-photophobia syndromes and keratitis-ichthyosis-deafness syndrome, erythrokeratodermia variabilis, harlequin ichthyosis, ichthyosis with confetti, and other subtypes.

Comparatively, they added, there are no data on the use of retinoids, or data showing no improvement with retinoids for several ichthyosis subtypes, including congenital hemidysplasia with ichthyosiform erythroderma and limb defects, CHIME syndrome, Conradi-Hünermann-Happle syndrome, ichthyosis-hypotrichosis syndrome, ichthyosis-hypotrichosis-sclerosing cholangitis, ichthyosis prematurity syndrome, MEDNIK syndrome, peeling skin disease, Refsum syndrome, and trichothiodystrophy though the response to such cases may vary.

Retinoids may worsen conditions that lead to peeling or skin fragility, atopic diathesis, or excessive desquamation, “and should be used with caution,” the authors advised.

Pediatric and adult patients with moderate to severe disease and significant functional or psychological impairment “should be offered the opportunity to make a benefit/risk assessment of treatment” with a systemic retinoid, they added, noting that topical retinoids have a lower risk profile and may be a better choice for milder disease.

Clinicians should aim for the lowest dose possible “that will achieve and maintain the desired therapeutic effect with acceptable mucocutaneous and systemic toxicities,” the panel recommended. Lower doses work especially well in patients with epidermolytic ichthyoses and erythrokeratodermia variabilis.

“Given the cutaneous and extracutaneous toxicities of oral retinoids, lower doses were found to achieve the most acceptable risk-benefit result. Few individuals now receive more than 1 mg/kg per day of isotretinoin or 0.5 mg/kg per day of acitretin,” according to the panel.

Dosing decisions call for a group conversation between physicians, patients and caregivers, addressing skin care, comfort and appearance issues, risk of adverse effects, and tolerance of the therapy.
 

Retinoid effects on organs

The impact of retinoids on the body varies by organ system, type of therapy and dosage. Dose and duration of therapy, for example, help determine the toxic effects of retinoids on bone. “Long-term use of systemic retinoids in ichthyosis/DOC is associated with skeletal concerns,” noted the authors, adding that clinicians should still consider this therapeutic approach if there is a strong clinical case for using it in a patient.

Children on long-term systemic therapy should undergo a series of tests and evaluations for bone monitoring, including an annual growth assessment. The group also recommended a baseline skeletal radiographic survey when children are on long-term systemic retinoid therapy, repeated after 3-5 years or when symptoms are present. Clinicians should also inquire about diet and discuss with patients factors that impact susceptibility to retinoid bone toxicity, such as genetic risk, diet and physical activity.

They also recommended monitoring patients taking systemic retinoids for psychiatric symptoms.

Adolescents of childbearing potential using systemic retinoids, who are sexually active, should receive counseling about contraceptive options, and should use two forms of contraception, including one highly effective method, the statement advises.

In the United States, all patients and prescribers of isotretinoin must comply with iPLEDGE guidelines; the statement addresses the issue that iPLEDGE was not designed for long-term use of isotretinoin in patients with ichthyosis, and “imposes a significant burden” in this group.

Other practice gaps and unmet needs in this area of study were discussed, calling for a closer examination of optimal timing of therapy initiation, and the adverse effects of long-term retinoid treatment. “The work, as a whole, is a starting point for these important management issues,” said Dr. Levy.

Unrestricted educational grants from Sun Pharmaceuticals and FIRST funded this effort. Dr. Levy’s disclosed serving on the advisory board and as a consultant for Cassiopea, Regeneron, and UCB, and an investigator for Fibrocell, Galderma, Janssen, and Pfizer. The other authors disclosed serving as investigators, advisers, consultants, and/or other relationships with various pharmaceutical companies.

Clinicians using systemic retinoids for treating ichthyosis and other disorders of cornification (DOC) in children and adolescents should aim for the lowest dose possible to balance therapeutic goals with acceptable toxicity levels, advised the authors of a new consensus statement.

In the statement, published in Pediatric Dermatology, they also addressed the effects of topical and systemic retinoid use on bone, eye, cardiovascular, and mental health, and the risks some retinoids pose to reproductive health.

Many patients with these chronic conditions, driven by multiple genetic mutations, respond to topical and/or systemic retinoids. However, to date, no specific guidance has addressed the safety, efficacy, or overall precautions for their use in the pediatric population, one of the statement authors, Moise L. Levy, MD, professor of pediatrics and medicine at the University of Texas at Austin, said in an interview.

Dr. Levy was one of the physicians on the multidisciplinary panel, The Pediatric Dermatology Research Alliance Use of Retinoids in Ichthyosis Work Group, formed to devise best practice recommendations on the use of retinoids in the management of ichthyoses and other cornification disorders in children and adolescents. The panel conducted an extensive evidence-based literature review and met in person to arrive at their conclusions. Representation from the Foundation for Ichthyosis and Related Skin Types (FIRST) was also key to this work. “Additionally, the teratogenic effects of retinoids prompted examination of gynecologic considerations and the role of the iPLEDGE program in the United States on patient access to isotretinoin,” the authors wrote.


 

Retinoid effects, dosing

“Both topical and systemic retinoids can improve scaling in patients with select forms of ichthyosis,” and some subtypes of disease respond better to treatment than others, they noted. Oral or topical retinoids are known to improve cases of congenital ichthyosiform erythroderma (select genotypes), Sjögren-Larsson syndrome, ichthyosis follicularis–alopecia-photophobia syndromes and keratitis-ichthyosis-deafness syndrome, erythrokeratodermia variabilis, harlequin ichthyosis, ichthyosis with confetti, and other subtypes.

Comparatively, they added, there are no data on the use of retinoids, or data showing no improvement with retinoids for several ichthyosis subtypes, including congenital hemidysplasia with ichthyosiform erythroderma and limb defects, CHIME syndrome, Conradi-Hünermann-Happle syndrome, ichthyosis-hypotrichosis syndrome, ichthyosis-hypotrichosis-sclerosing cholangitis, ichthyosis prematurity syndrome, MEDNIK syndrome, peeling skin disease, Refsum syndrome, and trichothiodystrophy though the response to such cases may vary.

Retinoids may worsen conditions that lead to peeling or skin fragility, atopic diathesis, or excessive desquamation, “and should be used with caution,” the authors advised.

Pediatric and adult patients with moderate to severe disease and significant functional or psychological impairment “should be offered the opportunity to make a benefit/risk assessment of treatment” with a systemic retinoid, they added, noting that topical retinoids have a lower risk profile and may be a better choice for milder disease.

Clinicians should aim for the lowest dose possible “that will achieve and maintain the desired therapeutic effect with acceptable mucocutaneous and systemic toxicities,” the panel recommended. Lower doses work especially well in patients with epidermolytic ichthyoses and erythrokeratodermia variabilis.

“Given the cutaneous and extracutaneous toxicities of oral retinoids, lower doses were found to achieve the most acceptable risk-benefit result. Few individuals now receive more than 1 mg/kg per day of isotretinoin or 0.5 mg/kg per day of acitretin,” according to the panel.

Dosing decisions call for a group conversation between physicians, patients and caregivers, addressing skin care, comfort and appearance issues, risk of adverse effects, and tolerance of the therapy.
 

Retinoid effects on organs

The impact of retinoids on the body varies by organ system, type of therapy and dosage. Dose and duration of therapy, for example, help determine the toxic effects of retinoids on bone. “Long-term use of systemic retinoids in ichthyosis/DOC is associated with skeletal concerns,” noted the authors, adding that clinicians should still consider this therapeutic approach if there is a strong clinical case for using it in a patient.

Children on long-term systemic therapy should undergo a series of tests and evaluations for bone monitoring, including an annual growth assessment. The group also recommended a baseline skeletal radiographic survey when children are on long-term systemic retinoid therapy, repeated after 3-5 years or when symptoms are present. Clinicians should also inquire about diet and discuss with patients factors that impact susceptibility to retinoid bone toxicity, such as genetic risk, diet and physical activity.

They also recommended monitoring patients taking systemic retinoids for psychiatric symptoms.

Adolescents of childbearing potential using systemic retinoids, who are sexually active, should receive counseling about contraceptive options, and should use two forms of contraception, including one highly effective method, the statement advises.

In the United States, all patients and prescribers of isotretinoin must comply with iPLEDGE guidelines; the statement addresses the issue that iPLEDGE was not designed for long-term use of isotretinoin in patients with ichthyosis, and “imposes a significant burden” in this group.

Other practice gaps and unmet needs in this area of study were discussed, calling for a closer examination of optimal timing of therapy initiation, and the adverse effects of long-term retinoid treatment. “The work, as a whole, is a starting point for these important management issues,” said Dr. Levy.

Unrestricted educational grants from Sun Pharmaceuticals and FIRST funded this effort. Dr. Levy’s disclosed serving on the advisory board and as a consultant for Cassiopea, Regeneron, and UCB, and an investigator for Fibrocell, Galderma, Janssen, and Pfizer. The other authors disclosed serving as investigators, advisers, consultants, and/or other relationships with various pharmaceutical companies.

Amyloidosis consists of approximately 30 protein-folding disorders sharing the common feature of abnormal extracellular amyloid deposition. In each condition, a specific soluble precursor protein aggregates to form the insoluble fibrils of amyloid, characterized by the beta-pleated sheet structure.¹ Amyloidosis occurs as either a systemic or localized process. Insulin-derived (AIns) amyloidosis, a localized process occurring at insulin injection sites, was first reported in 1983.² There were fewer than 20 reported cases until 2014, when 57 additional cases were reported by just 2 institutions,^3,4 indicating that AIns amyloidosis may be more common than previously thought.^3,5

Despite the increasing prevalence of diabetes mellitus and insulin use, there is a paucity of published cases of AIns amyloidosis. The lack of awareness of this condition among both dermatologists and general practitioners may be in part due to its variable clinical manifestations. We describe 2 patients with unique presentations of localized amyloidosis at repeated insulin injection sites.

Case Reports

Patient 1
A 39-year-old man with a history of type 1 diabetes mellitus presented with 4 asymptomatic nodules on the lateral thighs in areas of previous insulin injection. He first noticed the lesions 9 months prior to presentation and subsequently switched the injection site to the abdomen without development of new nodules. Despite being compliant with his insulin regimen, he had a long history of irregular glucose control, including frequent hypoglycemic episodes. The patient was using regular and neutral protamine hagedorn insulin.

On physical examination, 2 soft, nontender, exophytic nodules were noted on each upper thigh with surrounding hyperpigmented and hyperkeratotic collarettes (Figure 1). The nodules ranged in size from 2 to 3.5 cm in diameter.

Patient 2
A 53-year-old woman with a history of type 2 diabetes mellitus presented with painful subcutaneous nodules on the lower abdomen at sites of previous insulin injections. The nodules developed approximately 1 month after she started treatment with neutral protamine hagedorn insulin and had been slowly enlarging over the past year. She tried switching injection sites after noticing the lesions, but the nodules persisted. The patient had a long history of poor glucose control with chronically elevated glycohemoglobin and blood glucose levels.

On physical examination, 2 hyperpigmented, exophytic, smooth nodules were noted on the right and left lower abdomen, ranging in size from 2.5 to 5.5 cm in diameter (Figure 4).

Comment

Insulin is the suspected precursor protein in AIns amyloidosis, but the exact pathogenesis is unknown. The protein that is derived from insulin in these tumors is now identified as AIns amyloidosis.^5,6 It is hypothesized that insulin accumulates locally and is converted to amyloid by an unknown mechanism.⁷ Other potential contributory factors include chronic inflammation and foreign body reactions developing around amyloid deposits, as well as repeated trauma from injections into a single site.^4,5 It appears that lesions may derive from a wide range of insulin types and occur after variable time periods.

A majority of cases of iatrogenic amyloid have been described as single, firm, subcutaneous masses at an injection site that commonly are misdiagnosed as lipomas or lipohypertrophy.^7-11 To our knowledge, none of the reported cases resembled the multiple, discrete, exophytic nodules seen in our patients.^3,4 The surrounding hyperkeratosis noted in patient 1 is another uncommon feature of AIns amyloidosis (Figures 1 and 2). Only 3 AIns amyloidosis cases described lesions with acanthosis nigricans–like changes, only 1 of which provided a clinical image.^6,7,12The mechanism for the acanthosis nigricans–like changes may have been due to the high levels of insulin at the injection site. It has been suggested that the activation of insulinlike growth factor receptor by insulin leads to the proliferation of keratinocytes and fibroblasts.⁶ Histologic examination of AIns amyloidosis lesions generally demonstrates deposition of homogenous eosinophilic material consistent with amyloid, as well as positive Congo red staining with green birefringence by polarization. Immunohistologic staining with insulin antibody with or without proteomic analysis of the amyloid deposits can confirm the diagnosis. In both of our patients’ specimens, liquid chromatography–tandem mass spectrometry was performed for proteomic analysis, and results were consistent with AIns amyloidosis.

Reports in the literature have suggested that the deposition of amyloid at insulin injection sites has the potential to interfere with insulin absorption, leading to poor glucose control.^4,11,13 Hence, injection site rotation is a crucial aspect of treatment and prevention of AIns amyloidosis. In their study of 4 patients, Nagase et al⁴ compared serum insulin levels after insulin injection into amyloid nodules vs insulin levels after injection into normal skin. Insulin absorption at the amyloid sites was 34% of that at normal sites. Given these results, patients should be instructed to inject away from the amyloid deposit once it is identified.⁶ Glucose levels should be monitored closely when patients first inject away from the amyloid mass, as injection of the same dosage to an area of normal skin can lead to increased insulin absorption and hypoglycemia.^4,6 It is possible that the frequent hypoglycemic episodes noted in patient 1 were due to increased insulin sensitivity after switching to injection sites away from amyloid lesions.

Conclusion

Our patients demonstrate unique presentations of localized cutaneous amyloidosis at repeated insulin injection sites. We report these cases to complement the current data of iatrogenic amyloidosis and provide insight into this likely underreported phenomenon.

Amyloidosis consists of approximately 30 protein-folding disorders sharing the common feature of abnormal extracellular amyloid deposition. In each condition, a specific soluble precursor protein aggregates to form the insoluble fibrils of amyloid, characterized by the beta-pleated sheet structure.¹ Amyloidosis occurs as either a systemic or localized process. Insulin-derived (AIns) amyloidosis, a localized process occurring at insulin injection sites, was first reported in 1983.² There were fewer than 20 reported cases until 2014, when 57 additional cases were reported by just 2 institutions,^3,4 indicating that AIns amyloidosis may be more common than previously thought.^3,5

Despite the increasing prevalence of diabetes mellitus and insulin use, there is a paucity of published cases of AIns amyloidosis. The lack of awareness of this condition among both dermatologists and general practitioners may be in part due to its variable clinical manifestations. We describe 2 patients with unique presentations of localized amyloidosis at repeated insulin injection sites.

Case Reports

Patient 1
A 39-year-old man with a history of type 1 diabetes mellitus presented with 4 asymptomatic nodules on the lateral thighs in areas of previous insulin injection. He first noticed the lesions 9 months prior to presentation and subsequently switched the injection site to the abdomen without development of new nodules. Despite being compliant with his insulin regimen, he had a long history of irregular glucose control, including frequent hypoglycemic episodes. The patient was using regular and neutral protamine hagedorn insulin.

On physical examination, 2 soft, nontender, exophytic nodules were noted on each upper thigh with surrounding hyperpigmented and hyperkeratotic collarettes (Figure 1). The nodules ranged in size from 2 to 3.5 cm in diameter.

Patient 2
A 53-year-old woman with a history of type 2 diabetes mellitus presented with painful subcutaneous nodules on the lower abdomen at sites of previous insulin injections. The nodules developed approximately 1 month after she started treatment with neutral protamine hagedorn insulin and had been slowly enlarging over the past year. She tried switching injection sites after noticing the lesions, but the nodules persisted. The patient had a long history of poor glucose control with chronically elevated glycohemoglobin and blood glucose levels.

On physical examination, 2 hyperpigmented, exophytic, smooth nodules were noted on the right and left lower abdomen, ranging in size from 2.5 to 5.5 cm in diameter (Figure 4).

Comment

Insulin is the suspected precursor protein in AIns amyloidosis, but the exact pathogenesis is unknown. The protein that is derived from insulin in these tumors is now identified as AIns amyloidosis.^5,6 It is hypothesized that insulin accumulates locally and is converted to amyloid by an unknown mechanism.⁷ Other potential contributory factors include chronic inflammation and foreign body reactions developing around amyloid deposits, as well as repeated trauma from injections into a single site.^4,5 It appears that lesions may derive from a wide range of insulin types and occur after variable time periods.

A majority of cases of iatrogenic amyloid have been described as single, firm, subcutaneous masses at an injection site that commonly are misdiagnosed as lipomas or lipohypertrophy.^7-11 To our knowledge, none of the reported cases resembled the multiple, discrete, exophytic nodules seen in our patients.^3,4 The surrounding hyperkeratosis noted in patient 1 is another uncommon feature of AIns amyloidosis (Figures 1 and 2). Only 3 AIns amyloidosis cases described lesions with acanthosis nigricans–like changes, only 1 of which provided a clinical image.^6,7,12The mechanism for the acanthosis nigricans–like changes may have been due to the high levels of insulin at the injection site. It has been suggested that the activation of insulinlike growth factor receptor by insulin leads to the proliferation of keratinocytes and fibroblasts.⁶ Histologic examination of AIns amyloidosis lesions generally demonstrates deposition of homogenous eosinophilic material consistent with amyloid, as well as positive Congo red staining with green birefringence by polarization. Immunohistologic staining with insulin antibody with or without proteomic analysis of the amyloid deposits can confirm the diagnosis. In both of our patients’ specimens, liquid chromatography–tandem mass spectrometry was performed for proteomic analysis, and results were consistent with AIns amyloidosis.

Reports in the literature have suggested that the deposition of amyloid at insulin injection sites has the potential to interfere with insulin absorption, leading to poor glucose control.^4,11,13 Hence, injection site rotation is a crucial aspect of treatment and prevention of AIns amyloidosis. In their study of 4 patients, Nagase et al⁴ compared serum insulin levels after insulin injection into amyloid nodules vs insulin levels after injection into normal skin. Insulin absorption at the amyloid sites was 34% of that at normal sites. Given these results, patients should be instructed to inject away from the amyloid deposit once it is identified.⁶ Glucose levels should be monitored closely when patients first inject away from the amyloid mass, as injection of the same dosage to an area of normal skin can lead to increased insulin absorption and hypoglycemia.^4,6 It is possible that the frequent hypoglycemic episodes noted in patient 1 were due to increased insulin sensitivity after switching to injection sites away from amyloid lesions.

Conclusion

Our patients demonstrate unique presentations of localized cutaneous amyloidosis at repeated insulin injection sites. We report these cases to complement the current data of iatrogenic amyloidosis and provide insight into this likely underreported phenomenon.

Amyloidosis consists of approximately 30 protein-folding disorders sharing the common feature of abnormal extracellular amyloid deposition. In each condition, a specific soluble precursor protein aggregates to form the insoluble fibrils of amyloid, characterized by the beta-pleated sheet structure.¹ Amyloidosis occurs as either a systemic or localized process. Insulin-derived (AIns) amyloidosis, a localized process occurring at insulin injection sites, was first reported in 1983.² There were fewer than 20 reported cases until 2014, when 57 additional cases were reported by just 2 institutions,^3,4 indicating that AIns amyloidosis may be more common than previously thought.^3,5

Despite the increasing prevalence of diabetes mellitus and insulin use, there is a paucity of published cases of AIns amyloidosis. The lack of awareness of this condition among both dermatologists and general practitioners may be in part due to its variable clinical manifestations. We describe 2 patients with unique presentations of localized amyloidosis at repeated insulin injection sites.

Case Reports

Patient 1
A 39-year-old man with a history of type 1 diabetes mellitus presented with 4 asymptomatic nodules on the lateral thighs in areas of previous insulin injection. He first noticed the lesions 9 months prior to presentation and subsequently switched the injection site to the abdomen without development of new nodules. Despite being compliant with his insulin regimen, he had a long history of irregular glucose control, including frequent hypoglycemic episodes. The patient was using regular and neutral protamine hagedorn insulin.

On physical examination, 2 soft, nontender, exophytic nodules were noted on each upper thigh with surrounding hyperpigmented and hyperkeratotic collarettes (Figure 1). The nodules ranged in size from 2 to 3.5 cm in diameter.

Patient 2
A 53-year-old woman with a history of type 2 diabetes mellitus presented with painful subcutaneous nodules on the lower abdomen at sites of previous insulin injections. The nodules developed approximately 1 month after she started treatment with neutral protamine hagedorn insulin and had been slowly enlarging over the past year. She tried switching injection sites after noticing the lesions, but the nodules persisted. The patient had a long history of poor glucose control with chronically elevated glycohemoglobin and blood glucose levels.

On physical examination, 2 hyperpigmented, exophytic, smooth nodules were noted on the right and left lower abdomen, ranging in size from 2.5 to 5.5 cm in diameter (Figure 4).

Comment

Insulin is the suspected precursor protein in AIns amyloidosis, but the exact pathogenesis is unknown. The protein that is derived from insulin in these tumors is now identified as AIns amyloidosis.^5,6 It is hypothesized that insulin accumulates locally and is converted to amyloid by an unknown mechanism.⁷ Other potential contributory factors include chronic inflammation and foreign body reactions developing around amyloid deposits, as well as repeated trauma from injections into a single site.^4,5 It appears that lesions may derive from a wide range of insulin types and occur after variable time periods.

A majority of cases of iatrogenic amyloid have been described as single, firm, subcutaneous masses at an injection site that commonly are misdiagnosed as lipomas or lipohypertrophy.^7-11 To our knowledge, none of the reported cases resembled the multiple, discrete, exophytic nodules seen in our patients.^3,4 The surrounding hyperkeratosis noted in patient 1 is another uncommon feature of AIns amyloidosis (Figures 1 and 2). Only 3 AIns amyloidosis cases described lesions with acanthosis nigricans–like changes, only 1 of which provided a clinical image.^6,7,12The mechanism for the acanthosis nigricans–like changes may have been due to the high levels of insulin at the injection site. It has been suggested that the activation of insulinlike growth factor receptor by insulin leads to the proliferation of keratinocytes and fibroblasts.⁶ Histologic examination of AIns amyloidosis lesions generally demonstrates deposition of homogenous eosinophilic material consistent with amyloid, as well as positive Congo red staining with green birefringence by polarization. Immunohistologic staining with insulin antibody with or without proteomic analysis of the amyloid deposits can confirm the diagnosis. In both of our patients’ specimens, liquid chromatography–tandem mass spectrometry was performed for proteomic analysis, and results were consistent with AIns amyloidosis.

Reports in the literature have suggested that the deposition of amyloid at insulin injection sites has the potential to interfere with insulin absorption, leading to poor glucose control.^4,11,13 Hence, injection site rotation is a crucial aspect of treatment and prevention of AIns amyloidosis. In their study of 4 patients, Nagase et al⁴ compared serum insulin levels after insulin injection into amyloid nodules vs insulin levels after injection into normal skin. Insulin absorption at the amyloid sites was 34% of that at normal sites. Given these results, patients should be instructed to inject away from the amyloid deposit once it is identified.⁶ Glucose levels should be monitored closely when patients first inject away from the amyloid mass, as injection of the same dosage to an area of normal skin can lead to increased insulin absorption and hypoglycemia.^4,6 It is possible that the frequent hypoglycemic episodes noted in patient 1 were due to increased insulin sensitivity after switching to injection sites away from amyloid lesions.

Conclusion

Our patients demonstrate unique presentations of localized cutaneous amyloidosis at repeated insulin injection sites. We report these cases to complement the current data of iatrogenic amyloidosis and provide insight into this likely underreported phenomenon.

Children with enthesitis-related arthritis often have a high burden of disease and could benefit from medications currently approved for adults with spondyloarthritis, according to a review published in Arthritis Care & Research.

“Enthesitis-related arthritis (ERA) was the JIA [juvenile idiopathic arthritis] category applied to children with spondyloarthritis (SpA), recognizing enthesitis as a defining characteristic,” wrote Pamela F. Weiss, MD, of Children’s Hospital of Philadelphia, and colleagues.

The ERA criteria include “arthritis plus enthesitis; or arthritis or enthesitis plus at least two of the following: sacroiliac tenderness or inflammatory back pain, HLA-B27 positivity, first-degree relative with HLA-B27–associated disease, acute anterior uveitis, and arthritis in a male older than 6 years,” the review authors noted.

“None of the [Food and Drug Administration]–approved therapies for peripheral SpA or nonradiographic axial SpA” have been studied or approved for use in children with ERA, but data support biologic similarity to SpA in adults; notably, studies of the HLA-B27 allele have identified it as a risk factor for both SpA and ERA, they said.
 

Common factors in adult and childhood conditions

“The principal commonalities of children with ERA and axial arthritis, and adults with nonradiographic axial SpA, include enthesitis, arthritis, inflammatory back pain, anterior uveitis, HLA-B27 positivity, and family history of HLA-B27–associated disease,” the review authors wrote.

The first-line treatment for both ERA with axial arthritis and nonradiographic axial SpA is NSAIDs, followed by tumor necrosis factor (TNF) inhibitors if needed, they said. However, conventional disease-modifying antirheumatic drugs (cDMARDs) may be used in cases of peripheral disease affecting five or more joints. Studies of treatment response show similarities between ERA in children and SpA in adults, the authors added, with nearly half of adults with axial disease unable to achieve remission and approximately one-third of children with ERA failing to respond to therapy.

Clinical trials could improve options and outcomes for those with ERA who need advanced therapy and such trials should evaluate response of axial and peripheral disease separately, the review authors emphasized. For example, “Eligibility criteria for children with ERA and axial features could include the presence of some of the following disease features: active inflammatory sacroiliitis based on typical MRI changes according to ASAS/OMERACT [Assessment of SpondyloArthritis international Society/Outcome Measures in Rheumatology Clinical Trials] criteria; elevated CRP [C-reactive protein]; and inadequate response or intolerance to NSAIDs,” they noted. “Considering the similarities between adult spondyloarthritis and ERA in terms of etiology, genetics, pathogenesis, and clinical manifestations, it is evident that medications approved for axial or peripheral SpA should be studied in children with ERA involving axial or peripheral joints, respectively, with the intent to achieve labeling for use in children,” they concluded.

New data highlight ERA disease burden

The need for additional therapies for ERA patients gained more support from a recent study in which a majority of children with ERA or juvenile psoriatic arthritis (jPsA) used biologics, but those with sacroiliitis in particular showed a significant disease burden despite high biologic use.

The International Leagues Against Rheumatism criteria include seven categories of juvenile idiopathic arthritis, of which ERA and jPsA are the most common; however, characteristics of these children have not been well described, wrote Dax G. Rumsey, MD, of the University of Alberta, Edmonton, and colleagues.

“Children with ERA are more likely to have a clinical picture with predominantly peripheral arthritis, typically described as an oligoarthritis involving the lower limbs with high risk of axial disease, relative to the other categories of JIA,” and report more intense pain and worse health status, compared with children in other categories, the researchers wrote.

To more completely characterize children with ERA and jPsA, the researchers assessed 522 children with ERA and 380 with jPsA. The children were enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. The findings were published in a brief report in Arthritis Care & Research.

Overall, 69% of the children took at least one biologic, including 72% with ERA and 64% with jPsA. Biologic use was even higher (81%) among the 28% of patients with sacroiliitis (40% of ERA patients and 12% of jPsA patients). Approximately 36% of the patients with sacroiliitis were positive for HLA-B27. In addition, Physician Global Assessment scores and clinical Juvenile Arthritis Disease Activity Score-10 (cJADAS10) scores were significantly higher at the first clinical visit with sacroiliitis, compared with the first visit without, which confirms “the clinical impression that active sacroiliitis significantly impacts children and their families,” the researchers said.

The average age at diagnosis was 10.8 years for ERA and 8.2 years for jPsA, and significantly more ERA patients were male (56% vs. 38%). However, more of the patients with sacroiliitis (54%) were female. More than half of the patients reported polyarticular involvement.

The study findings were limited by several factors, including the classification of ERA or jPsA and the reliance on physician diagnoses, as well as the variation in identifying sacroiliitis, the researchers said. However, the results increase understanding of the pathophysiology of ERA and jPsA to help determine optimal treatment, they concluded.
 

Data highlight research and treatment gaps

“Recent research demonstrates a large, unmet medical need in the treatment of JIA with 52%-65% of all JIA patients, including those with ERA and jPsA, having been treated with at least one biologic DMARD and 15%-19% having been treated with an FDA-unapproved biologic. In those with ERA or jPsA, 72%-79% of the children had been treated with a biologic DMARD, although no biologic DMARD has ever been FDA approved for these JIA categories,” Daniel J. Lovell, MD, and Hermine I. Brunner, MD, both with Cincinnati Children’s Hospital Medical Center, wrote in an editorial that accompanied the new study. Dr. Lovell and Dr. Brunner also were coauthors of the review article.

The new study supports findings from other recent publications, the editorialists noted. The new results showed “a significant proportion of the JIA population with active sacroiliitis with high disease burden despite very frequent (over 80% of the population) [treatment] with unstudied and unapproved biologic DMARDs,” they said. “These children with sacroiliitis had significantly greater disease burden with higher physician assessment of disease activity, higher parent assessment of disease impact, and higher disease activity as measured by the Juvenile Idiopathic Arthritis Disease Activity Score, compared to the children with ERA or jPsA without sacroiliitis,” they noted.

Jeff Craven/MDedge News

Previously, “the FDA granted pharmaceutical companies studying new treatments in adult SpA automatic full waivers from doing studies in children for new medications for ‘axial spondyloarthropathies including ankylosing spondylitis’ up until July 2020,” the editorialists said. However, “It is now time now for the pharmaceutical industry to perform FDA-monitored clinical trials of children and adolescents with SpA,” they emphasized. “This will allow for the scientific assessment of proper dosing, efficacy, and safety of the increasing number of new medications that are being licensed by the FDA for the treatment of SpA, such as the anti-TNF, anti–IL[interleukin]-17, and anti–IL-23 biologics, and perhaps JAK [Janus kinase] agents, to address this unmet medical need in these patients with juvenile SpA,” they concluded.

Dr. Weiss disclosed grant support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and financial relationships with Eli Lilly and Pfizer. Dr. Lovell disclosed relationships with companies including Abbott, AbbVie Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Novartis, Pfizer, Takeda, UCB, and Wyeth, as well as serving on the data and safety monitoring board for Forest Research and NIAMS. Dr. Brunner disclosed relationships with companies including Ablynx, AbbVie, AstraZeneca-MedImmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, EMD Serono, F. Hoffmann-La Roche, Genzyme, GlaxoSmithKline, Merck, Novartis, R-Pharm, and Sanofi. The study by Dr. Rumsey and colleagues was supported by Amgen. Dr. Rumsey and colleagues had no relevant financial conflicts to disclose.

SOURCES: Weiss PF et al. Arthritis Care Res. 2020 Dec 5. doi: 10.1002/acr.24529; Rumsey DG et al. Arthritis Care Res. 2020 Dec. 16. doi: 10.1002/acr.24537; Lovell DJ and Brunner HI. Arthritis Care Res. 2020 Dec 16. doi: 10.1002/acr.24536.

Children with enthesitis-related arthritis often have a high burden of disease and could benefit from medications currently approved for adults with spondyloarthritis, according to a review published in Arthritis Care & Research.

“Enthesitis-related arthritis (ERA) was the JIA [juvenile idiopathic arthritis] category applied to children with spondyloarthritis (SpA), recognizing enthesitis as a defining characteristic,” wrote Pamela F. Weiss, MD, of Children’s Hospital of Philadelphia, and colleagues.

The ERA criteria include “arthritis plus enthesitis; or arthritis or enthesitis plus at least two of the following: sacroiliac tenderness or inflammatory back pain, HLA-B27 positivity, first-degree relative with HLA-B27–associated disease, acute anterior uveitis, and arthritis in a male older than 6 years,” the review authors noted.

“None of the [Food and Drug Administration]–approved therapies for peripheral SpA or nonradiographic axial SpA” have been studied or approved for use in children with ERA, but data support biologic similarity to SpA in adults; notably, studies of the HLA-B27 allele have identified it as a risk factor for both SpA and ERA, they said.
 

Common factors in adult and childhood conditions

“The principal commonalities of children with ERA and axial arthritis, and adults with nonradiographic axial SpA, include enthesitis, arthritis, inflammatory back pain, anterior uveitis, HLA-B27 positivity, and family history of HLA-B27–associated disease,” the review authors wrote.

The first-line treatment for both ERA with axial arthritis and nonradiographic axial SpA is NSAIDs, followed by tumor necrosis factor (TNF) inhibitors if needed, they said. However, conventional disease-modifying antirheumatic drugs (cDMARDs) may be used in cases of peripheral disease affecting five or more joints. Studies of treatment response show similarities between ERA in children and SpA in adults, the authors added, with nearly half of adults with axial disease unable to achieve remission and approximately one-third of children with ERA failing to respond to therapy.

Clinical trials could improve options and outcomes for those with ERA who need advanced therapy and such trials should evaluate response of axial and peripheral disease separately, the review authors emphasized. For example, “Eligibility criteria for children with ERA and axial features could include the presence of some of the following disease features: active inflammatory sacroiliitis based on typical MRI changes according to ASAS/OMERACT [Assessment of SpondyloArthritis international Society/Outcome Measures in Rheumatology Clinical Trials] criteria; elevated CRP [C-reactive protein]; and inadequate response or intolerance to NSAIDs,” they noted. “Considering the similarities between adult spondyloarthritis and ERA in terms of etiology, genetics, pathogenesis, and clinical manifestations, it is evident that medications approved for axial or peripheral SpA should be studied in children with ERA involving axial or peripheral joints, respectively, with the intent to achieve labeling for use in children,” they concluded.

New data highlight ERA disease burden

The need for additional therapies for ERA patients gained more support from a recent study in which a majority of children with ERA or juvenile psoriatic arthritis (jPsA) used biologics, but those with sacroiliitis in particular showed a significant disease burden despite high biologic use.

The International Leagues Against Rheumatism criteria include seven categories of juvenile idiopathic arthritis, of which ERA and jPsA are the most common; however, characteristics of these children have not been well described, wrote Dax G. Rumsey, MD, of the University of Alberta, Edmonton, and colleagues.

“Children with ERA are more likely to have a clinical picture with predominantly peripheral arthritis, typically described as an oligoarthritis involving the lower limbs with high risk of axial disease, relative to the other categories of JIA,” and report more intense pain and worse health status, compared with children in other categories, the researchers wrote.

To more completely characterize children with ERA and jPsA, the researchers assessed 522 children with ERA and 380 with jPsA. The children were enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. The findings were published in a brief report in Arthritis Care & Research.

Overall, 69% of the children took at least one biologic, including 72% with ERA and 64% with jPsA. Biologic use was even higher (81%) among the 28% of patients with sacroiliitis (40% of ERA patients and 12% of jPsA patients). Approximately 36% of the patients with sacroiliitis were positive for HLA-B27. In addition, Physician Global Assessment scores and clinical Juvenile Arthritis Disease Activity Score-10 (cJADAS10) scores were significantly higher at the first clinical visit with sacroiliitis, compared with the first visit without, which confirms “the clinical impression that active sacroiliitis significantly impacts children and their families,” the researchers said.

The average age at diagnosis was 10.8 years for ERA and 8.2 years for jPsA, and significantly more ERA patients were male (56% vs. 38%). However, more of the patients with sacroiliitis (54%) were female. More than half of the patients reported polyarticular involvement.

The study findings were limited by several factors, including the classification of ERA or jPsA and the reliance on physician diagnoses, as well as the variation in identifying sacroiliitis, the researchers said. However, the results increase understanding of the pathophysiology of ERA and jPsA to help determine optimal treatment, they concluded.
 

Data highlight research and treatment gaps

“Recent research demonstrates a large, unmet medical need in the treatment of JIA with 52%-65% of all JIA patients, including those with ERA and jPsA, having been treated with at least one biologic DMARD and 15%-19% having been treated with an FDA-unapproved biologic. In those with ERA or jPsA, 72%-79% of the children had been treated with a biologic DMARD, although no biologic DMARD has ever been FDA approved for these JIA categories,” Daniel J. Lovell, MD, and Hermine I. Brunner, MD, both with Cincinnati Children’s Hospital Medical Center, wrote in an editorial that accompanied the new study. Dr. Lovell and Dr. Brunner also were coauthors of the review article.

The new study supports findings from other recent publications, the editorialists noted. The new results showed “a significant proportion of the JIA population with active sacroiliitis with high disease burden despite very frequent (over 80% of the population) [treatment] with unstudied and unapproved biologic DMARDs,” they said. “These children with sacroiliitis had significantly greater disease burden with higher physician assessment of disease activity, higher parent assessment of disease impact, and higher disease activity as measured by the Juvenile Idiopathic Arthritis Disease Activity Score, compared to the children with ERA or jPsA without sacroiliitis,” they noted.

Jeff Craven/MDedge News

Previously, “the FDA granted pharmaceutical companies studying new treatments in adult SpA automatic full waivers from doing studies in children for new medications for ‘axial spondyloarthropathies including ankylosing spondylitis’ up until July 2020,” the editorialists said. However, “It is now time now for the pharmaceutical industry to perform FDA-monitored clinical trials of children and adolescents with SpA,” they emphasized. “This will allow for the scientific assessment of proper dosing, efficacy, and safety of the increasing number of new medications that are being licensed by the FDA for the treatment of SpA, such as the anti-TNF, anti–IL[interleukin]-17, and anti–IL-23 biologics, and perhaps JAK [Janus kinase] agents, to address this unmet medical need in these patients with juvenile SpA,” they concluded.

Dr. Weiss disclosed grant support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and financial relationships with Eli Lilly and Pfizer. Dr. Lovell disclosed relationships with companies including Abbott, AbbVie Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Novartis, Pfizer, Takeda, UCB, and Wyeth, as well as serving on the data and safety monitoring board for Forest Research and NIAMS. Dr. Brunner disclosed relationships with companies including Ablynx, AbbVie, AstraZeneca-MedImmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, EMD Serono, F. Hoffmann-La Roche, Genzyme, GlaxoSmithKline, Merck, Novartis, R-Pharm, and Sanofi. The study by Dr. Rumsey and colleagues was supported by Amgen. Dr. Rumsey and colleagues had no relevant financial conflicts to disclose.

SOURCES: Weiss PF et al. Arthritis Care Res. 2020 Dec 5. doi: 10.1002/acr.24529; Rumsey DG et al. Arthritis Care Res. 2020 Dec. 16. doi: 10.1002/acr.24537; Lovell DJ and Brunner HI. Arthritis Care Res. 2020 Dec 16. doi: 10.1002/acr.24536.

Children with enthesitis-related arthritis often have a high burden of disease and could benefit from medications currently approved for adults with spondyloarthritis, according to a review published in Arthritis Care & Research.

“Enthesitis-related arthritis (ERA) was the JIA [juvenile idiopathic arthritis] category applied to children with spondyloarthritis (SpA), recognizing enthesitis as a defining characteristic,” wrote Pamela F. Weiss, MD, of Children’s Hospital of Philadelphia, and colleagues.

The ERA criteria include “arthritis plus enthesitis; or arthritis or enthesitis plus at least two of the following: sacroiliac tenderness or inflammatory back pain, HLA-B27 positivity, first-degree relative with HLA-B27–associated disease, acute anterior uveitis, and arthritis in a male older than 6 years,” the review authors noted.

“None of the [Food and Drug Administration]–approved therapies for peripheral SpA or nonradiographic axial SpA” have been studied or approved for use in children with ERA, but data support biologic similarity to SpA in adults; notably, studies of the HLA-B27 allele have identified it as a risk factor for both SpA and ERA, they said.
 

Common factors in adult and childhood conditions

“The principal commonalities of children with ERA and axial arthritis, and adults with nonradiographic axial SpA, include enthesitis, arthritis, inflammatory back pain, anterior uveitis, HLA-B27 positivity, and family history of HLA-B27–associated disease,” the review authors wrote.

The first-line treatment for both ERA with axial arthritis and nonradiographic axial SpA is NSAIDs, followed by tumor necrosis factor (TNF) inhibitors if needed, they said. However, conventional disease-modifying antirheumatic drugs (cDMARDs) may be used in cases of peripheral disease affecting five or more joints. Studies of treatment response show similarities between ERA in children and SpA in adults, the authors added, with nearly half of adults with axial disease unable to achieve remission and approximately one-third of children with ERA failing to respond to therapy.

Clinical trials could improve options and outcomes for those with ERA who need advanced therapy and such trials should evaluate response of axial and peripheral disease separately, the review authors emphasized. For example, “Eligibility criteria for children with ERA and axial features could include the presence of some of the following disease features: active inflammatory sacroiliitis based on typical MRI changes according to ASAS/OMERACT [Assessment of SpondyloArthritis international Society/Outcome Measures in Rheumatology Clinical Trials] criteria; elevated CRP [C-reactive protein]; and inadequate response or intolerance to NSAIDs,” they noted. “Considering the similarities between adult spondyloarthritis and ERA in terms of etiology, genetics, pathogenesis, and clinical manifestations, it is evident that medications approved for axial or peripheral SpA should be studied in children with ERA involving axial or peripheral joints, respectively, with the intent to achieve labeling for use in children,” they concluded.

New data highlight ERA disease burden

The need for additional therapies for ERA patients gained more support from a recent study in which a majority of children with ERA or juvenile psoriatic arthritis (jPsA) used biologics, but those with sacroiliitis in particular showed a significant disease burden despite high biologic use.

The International Leagues Against Rheumatism criteria include seven categories of juvenile idiopathic arthritis, of which ERA and jPsA are the most common; however, characteristics of these children have not been well described, wrote Dax G. Rumsey, MD, of the University of Alberta, Edmonton, and colleagues.

“Children with ERA are more likely to have a clinical picture with predominantly peripheral arthritis, typically described as an oligoarthritis involving the lower limbs with high risk of axial disease, relative to the other categories of JIA,” and report more intense pain and worse health status, compared with children in other categories, the researchers wrote.

To more completely characterize children with ERA and jPsA, the researchers assessed 522 children with ERA and 380 with jPsA. The children were enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. The findings were published in a brief report in Arthritis Care & Research.

Overall, 69% of the children took at least one biologic, including 72% with ERA and 64% with jPsA. Biologic use was even higher (81%) among the 28% of patients with sacroiliitis (40% of ERA patients and 12% of jPsA patients). Approximately 36% of the patients with sacroiliitis were positive for HLA-B27. In addition, Physician Global Assessment scores and clinical Juvenile Arthritis Disease Activity Score-10 (cJADAS10) scores were significantly higher at the first clinical visit with sacroiliitis, compared with the first visit without, which confirms “the clinical impression that active sacroiliitis significantly impacts children and their families,” the researchers said.

The average age at diagnosis was 10.8 years for ERA and 8.2 years for jPsA, and significantly more ERA patients were male (56% vs. 38%). However, more of the patients with sacroiliitis (54%) were female. More than half of the patients reported polyarticular involvement.

The study findings were limited by several factors, including the classification of ERA or jPsA and the reliance on physician diagnoses, as well as the variation in identifying sacroiliitis, the researchers said. However, the results increase understanding of the pathophysiology of ERA and jPsA to help determine optimal treatment, they concluded.
 

Data highlight research and treatment gaps

“Recent research demonstrates a large, unmet medical need in the treatment of JIA with 52%-65% of all JIA patients, including those with ERA and jPsA, having been treated with at least one biologic DMARD and 15%-19% having been treated with an FDA-unapproved biologic. In those with ERA or jPsA, 72%-79% of the children had been treated with a biologic DMARD, although no biologic DMARD has ever been FDA approved for these JIA categories,” Daniel J. Lovell, MD, and Hermine I. Brunner, MD, both with Cincinnati Children’s Hospital Medical Center, wrote in an editorial that accompanied the new study. Dr. Lovell and Dr. Brunner also were coauthors of the review article.

The new study supports findings from other recent publications, the editorialists noted. The new results showed “a significant proportion of the JIA population with active sacroiliitis with high disease burden despite very frequent (over 80% of the population) [treatment] with unstudied and unapproved biologic DMARDs,” they said. “These children with sacroiliitis had significantly greater disease burden with higher physician assessment of disease activity, higher parent assessment of disease impact, and higher disease activity as measured by the Juvenile Idiopathic Arthritis Disease Activity Score, compared to the children with ERA or jPsA without sacroiliitis,” they noted.

Jeff Craven/MDedge News

Previously, “the FDA granted pharmaceutical companies studying new treatments in adult SpA automatic full waivers from doing studies in children for new medications for ‘axial spondyloarthropathies including ankylosing spondylitis’ up until July 2020,” the editorialists said. However, “It is now time now for the pharmaceutical industry to perform FDA-monitored clinical trials of children and adolescents with SpA,” they emphasized. “This will allow for the scientific assessment of proper dosing, efficacy, and safety of the increasing number of new medications that are being licensed by the FDA for the treatment of SpA, such as the anti-TNF, anti–IL[interleukin]-17, and anti–IL-23 biologics, and perhaps JAK [Janus kinase] agents, to address this unmet medical need in these patients with juvenile SpA,” they concluded.

Dr. Weiss disclosed grant support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and financial relationships with Eli Lilly and Pfizer. Dr. Lovell disclosed relationships with companies including Abbott, AbbVie Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Novartis, Pfizer, Takeda, UCB, and Wyeth, as well as serving on the data and safety monitoring board for Forest Research and NIAMS. Dr. Brunner disclosed relationships with companies including Ablynx, AbbVie, AstraZeneca-MedImmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, EMD Serono, F. Hoffmann-La Roche, Genzyme, GlaxoSmithKline, Merck, Novartis, R-Pharm, and Sanofi. The study by Dr. Rumsey and colleagues was supported by Amgen. Dr. Rumsey and colleagues had no relevant financial conflicts to disclose.

SOURCES: Weiss PF et al. Arthritis Care Res. 2020 Dec 5. doi: 10.1002/acr.24529; Rumsey DG et al. Arthritis Care Res. 2020 Dec. 16. doi: 10.1002/acr.24537; Lovell DJ and Brunner HI. Arthritis Care Res. 2020 Dec 16. doi: 10.1002/acr.24536.

Mastocytosis is a rare disease that causes allergic and anaphylactic symptoms due to chronic or episodic, excessive mast cell degranulation as well as mast cell infiltration of the skin or other organs.¹ Mast cells aid in innate immunity by generation of a vasodilatory and inflammatory response and are significant contributors to allergic reactions. Cutaneous mastocytosis is defined by isolated skin involvement. Systemic mastocytosis (SM) is characterized by mast cell infiltration of extracutaneous organs, most often bone marrow.²

Background

SM is divided into distinct subtypes (Table 1). Nonadvanced SM subtypes include indolent SM and smoldering SM. These are the most common forms and tend to have more slowly progressing courses without evidence of organ tissue dysfunction, a myelodysplastic syndrome, or of a myeloproliferative disorder.³ Advanced SM is less common and is associated with organ tissue dysfunction. It also may be associated with myeloproliferative, myelodysplastic, or lymphoproliferative hematologic neoplasms, and subtypes include aggressive SM, SM with an associated hematologic neoplasm, and mast cell leukemia (Table 2).⁴

Treatment options approved by the US Food and Drug Administration (FDA) for advanced SM include disease-altering medications, such as tyrosine kinase inhibitors (eg, imatinib), but the approved treatment options for nonadvanced SM are generally aimed at managing only symptoms (Table 3). Although not approved by the FDA for the treatment of SM, omalizumab may aid in the prevention of anaphylaxis, the reduction of disease burden, and the improvement in quality of life for patients with SM.⁵ Omalizumab is a humanized monoclonal antibody against the Fc portion of immunoglobulin E (IgE). It is approved by the FDA for treatment of asthma as well as chronic idiopathic urticaria.⁶

Case Presentation

A 32-year-old female initially presented to Womack Army Medical Center at Fort Bragg, North Carolina, for evaluation due to recurrent episodes of anaphylaxis occurring 1 to 2 times per month as well as chronic skin rashes that progressed over the previous 5 years (Figure). She initially was diagnosed with idiopathic anaphylaxis and subsequently had multiple emergency department (ED) and clinic visits for vasovagal syncope, unexplained allergic reactions, dizziness, giddiness, and shortness of breath. More recently, she was diagnosed with idiopathic urticaria.

The patient reported at least 12 episodes in the previous year involving facial flushing that proceeded inferiorly, chest tightness, shortness of breath, labored breathing, crampy abdominal pain, and nausea without urticaria or significant pruritus. These bouts often were accompanied by mild facial angioedema, acute sinus pressure, vomiting, tachycardia, and lightheadedness. She reported experiencing brief losses of consciousness with at least 4 of these episodes. Home and ED blood pressure measurements revealed hypotension on several occasions with systolic readings in the 80s. She also developed nonpruritic freckles on her upper chest initially with subsequent increase in number and spread to involve her entire trunk, proximal extremities, and eventually distal extremities.

Discussion

Mast cell overactivation and degranulation in mastocytosis is largely driven by the IgE antibody, which plays a significant role in atopic conditions, immediate hypersensitivity reactions, and anaphylaxis, as well as in the immunologic response to parasitic infections. The severity of atopic disease seems to be associated with serum IgE levels in many patients.⁷ IgE binding to surface receptors on mast cells and eosinophils prompts the release of toxic mediators, incites inflammation, and induces allergic symptoms.⁸ Activation of mast cells is classically elicited by IgE binding to the high-affinity Fcε RI receptor, the expression of which correlates with IgE levels.⁹

The anti-IgE, recombinant, humanized immunoglobulin G monoclonal antibody, omalizumab, decreases mastocytic and eosinophilic symptoms by binding and inhibiting IgE. This diminishes free IgE levels, inhibits IgE binding to the Fcε RI receptor, and affects downregulation of this high-affinity receptor on mast cells and basophils.⁶ Omalizumab is currently FDA approved only for the treatment of moderate-to-severe, persistent, allergic asthma that is not controlled by inhaled corticosteroids in patients aged ≥ 6 years, and for chronic idiopathic urticaria not controlled by H1 antihistamine therapy in patients aged ≥ 12 years.¹⁰ However, it stands to reason that this therapy also should be effective in the treatment of other poorly controlled atopic conditions, especially mastocytosis, the symptoms of which are driven by excessive mast cell degranulation and tissue infiltration.

As early as 2007, preliminary data showed that treatment with omalizumab could decrease the frequency of episodes of anaphylaxis.¹¹ A National Institutes of Health case report followed 2 patients, one for 5 months and the other for 24 months. Both patients experienced a decrease in frequency of anaphylaxis following initiation of omalizumab. In 2010, a second case report described the treatment of an Australian patient with recurrent idiopathic anaphylaxis also diagnosed with SM. After initiation of treatment with omalizumab, she, too, experienced decreased frequency of episodes of anaphylaxis over 14 months.¹² A review of patients treated at the Mastocytosis Centre Odense University Hospital in Denmark was published in 2017. Of 13 patients with SM treated with omalizumab, 5 experienced what was considered a complete response to the medication, with 3 each experiencing major and partial responses.⁵ The median treatment time in these patients was 27 months. Each of these cases showed significant promise in the use of omalizumab to treat SM, informing the decision to attempt this treatment in our patient.

The potential positive effects of omalizumab in reducing symptom severity in patients with SM was further supported by a 2017 meta-analysis. This review included several individual case reports noting that omalizumab could decrease frequency of pulmonary and gastrointestinal manifestations of SM.¹³ A small randomized control trial of omalizumab for treatment of mild symptoms of SM found improvement in disease severity, although neither primary nor secondary endpoints reached statistical significance.¹⁴

This case demonstrates a substantial, long-term, clinical benefit and quality of life improvement with omalizumab therapy in a patient with indolent SM that was not adequately controlled by conventional therapies. This is evidenced by an impressive decline in the frequency of mastocytic anaphylactic episodes as well as diminished patient-endorsed cutaneous symptoms.

This case provides further evidence of the efficacy of this therapy in diminishing disease burden for patients with SM who are otherwise limited to treatments aimed at transient symptomatic relief without significant alteration of the underlying cause of symptoms. At the time this article was written, our patient had now 52 months of continuous treatment without any adverse reactions noted, suggesting the treatment's long-term efficacy. It also adds to a small but growing body of literature that supports the use of anti-IgE therapy as a treatment option for improved management of this distressing, life-altering illness. Even in the time that our patient has been receiving omalizumab for SM, another small case series of 2 patients has been published showing sustained treatment effect at 12 years of therapy.¹⁵ This adds further insight that omalizumab can offer long-term, safe treatment for this limiting condition.

Omalizumab therapy is not without risk, but for patients afflicted by unrestrained mastocytic disease, the benefits may outweigh the risks. The most common significant risk with this medication is anaphylaxis, occurring in 1 to 2 per 1,000 patients, usually within 2 hours of an injection.¹⁶ This may correlate to the underlying degree of atopy in patients receiving omalizumab, and the risk of anaphylaxis is relatively low compared with that of many other biologic medications.¹⁷ Additionally, early data from initial phases of clinical trials indicated a potentially elevated malignancy risk with omalizumab. However, subsequent pooled analysis of larger numbers of patients has decreased suspicion that a causal relationship exists.¹⁸

Conclusions

Omalizumab has proven value in the treatment of atopic conditions, such as asthma and idiopathic urticaria, for which it has been approved for use by the FDA. Its effectiveness in significantly decreasing free serum IgE levels, and inhibiting IgE activation of mast cells makes it a possible treatment option for patients with SM who are not sufficiently controlled with conventional therapy. The findings in this case suggest that omalizumab may be effective in the prevention of anaphylaxis and in the reduction of disease burden associated with SM. Further studies and formal clinical trials are needed to confirm these findings. Patients should be counseled appropriately concerning the risks, benefits, and off-label status of this treatment option.

Mastocytosis is a rare disease that causes allergic and anaphylactic symptoms due to chronic or episodic, excessive mast cell degranulation as well as mast cell infiltration of the skin or other organs.¹ Mast cells aid in innate immunity by generation of a vasodilatory and inflammatory response and are significant contributors to allergic reactions. Cutaneous mastocytosis is defined by isolated skin involvement. Systemic mastocytosis (SM) is characterized by mast cell infiltration of extracutaneous organs, most often bone marrow.²

Background

SM is divided into distinct subtypes (Table 1). Nonadvanced SM subtypes include indolent SM and smoldering SM. These are the most common forms and tend to have more slowly progressing courses without evidence of organ tissue dysfunction, a myelodysplastic syndrome, or of a myeloproliferative disorder.³ Advanced SM is less common and is associated with organ tissue dysfunction. It also may be associated with myeloproliferative, myelodysplastic, or lymphoproliferative hematologic neoplasms, and subtypes include aggressive SM, SM with an associated hematologic neoplasm, and mast cell leukemia (Table 2).⁴

Treatment options approved by the US Food and Drug Administration (FDA) for advanced SM include disease-altering medications, such as tyrosine kinase inhibitors (eg, imatinib), but the approved treatment options for nonadvanced SM are generally aimed at managing only symptoms (Table 3). Although not approved by the FDA for the treatment of SM, omalizumab may aid in the prevention of anaphylaxis, the reduction of disease burden, and the improvement in quality of life for patients with SM.⁵ Omalizumab is a humanized monoclonal antibody against the Fc portion of immunoglobulin E (IgE). It is approved by the FDA for treatment of asthma as well as chronic idiopathic urticaria.⁶

Case Presentation

A 32-year-old female initially presented to Womack Army Medical Center at Fort Bragg, North Carolina, for evaluation due to recurrent episodes of anaphylaxis occurring 1 to 2 times per month as well as chronic skin rashes that progressed over the previous 5 years (Figure). She initially was diagnosed with idiopathic anaphylaxis and subsequently had multiple emergency department (ED) and clinic visits for vasovagal syncope, unexplained allergic reactions, dizziness, giddiness, and shortness of breath. More recently, she was diagnosed with idiopathic urticaria.

The patient reported at least 12 episodes in the previous year involving facial flushing that proceeded inferiorly, chest tightness, shortness of breath, labored breathing, crampy abdominal pain, and nausea without urticaria or significant pruritus. These bouts often were accompanied by mild facial angioedema, acute sinus pressure, vomiting, tachycardia, and lightheadedness. She reported experiencing brief losses of consciousness with at least 4 of these episodes. Home and ED blood pressure measurements revealed hypotension on several occasions with systolic readings in the 80s. She also developed nonpruritic freckles on her upper chest initially with subsequent increase in number and spread to involve her entire trunk, proximal extremities, and eventually distal extremities.

Discussion

Mast cell overactivation and degranulation in mastocytosis is largely driven by the IgE antibody, which plays a significant role in atopic conditions, immediate hypersensitivity reactions, and anaphylaxis, as well as in the immunologic response to parasitic infections. The severity of atopic disease seems to be associated with serum IgE levels in many patients.⁷ IgE binding to surface receptors on mast cells and eosinophils prompts the release of toxic mediators, incites inflammation, and induces allergic symptoms.⁸ Activation of mast cells is classically elicited by IgE binding to the high-affinity Fcε RI receptor, the expression of which correlates with IgE levels.⁹

The anti-IgE, recombinant, humanized immunoglobulin G monoclonal antibody, omalizumab, decreases mastocytic and eosinophilic symptoms by binding and inhibiting IgE. This diminishes free IgE levels, inhibits IgE binding to the Fcε RI receptor, and affects downregulation of this high-affinity receptor on mast cells and basophils.⁶ Omalizumab is currently FDA approved only for the treatment of moderate-to-severe, persistent, allergic asthma that is not controlled by inhaled corticosteroids in patients aged ≥ 6 years, and for chronic idiopathic urticaria not controlled by H1 antihistamine therapy in patients aged ≥ 12 years.¹⁰ However, it stands to reason that this therapy also should be effective in the treatment of other poorly controlled atopic conditions, especially mastocytosis, the symptoms of which are driven by excessive mast cell degranulation and tissue infiltration.

As early as 2007, preliminary data showed that treatment with omalizumab could decrease the frequency of episodes of anaphylaxis.¹¹ A National Institutes of Health case report followed 2 patients, one for 5 months and the other for 24 months. Both patients experienced a decrease in frequency of anaphylaxis following initiation of omalizumab. In 2010, a second case report described the treatment of an Australian patient with recurrent idiopathic anaphylaxis also diagnosed with SM. After initiation of treatment with omalizumab, she, too, experienced decreased frequency of episodes of anaphylaxis over 14 months.¹² A review of patients treated at the Mastocytosis Centre Odense University Hospital in Denmark was published in 2017. Of 13 patients with SM treated with omalizumab, 5 experienced what was considered a complete response to the medication, with 3 each experiencing major and partial responses.⁵ The median treatment time in these patients was 27 months. Each of these cases showed significant promise in the use of omalizumab to treat SM, informing the decision to attempt this treatment in our patient.

The potential positive effects of omalizumab in reducing symptom severity in patients with SM was further supported by a 2017 meta-analysis. This review included several individual case reports noting that omalizumab could decrease frequency of pulmonary and gastrointestinal manifestations of SM.¹³ A small randomized control trial of omalizumab for treatment of mild symptoms of SM found improvement in disease severity, although neither primary nor secondary endpoints reached statistical significance.¹⁴

This case demonstrates a substantial, long-term, clinical benefit and quality of life improvement with omalizumab therapy in a patient with indolent SM that was not adequately controlled by conventional therapies. This is evidenced by an impressive decline in the frequency of mastocytic anaphylactic episodes as well as diminished patient-endorsed cutaneous symptoms.

This case provides further evidence of the efficacy of this therapy in diminishing disease burden for patients with SM who are otherwise limited to treatments aimed at transient symptomatic relief without significant alteration of the underlying cause of symptoms. At the time this article was written, our patient had now 52 months of continuous treatment without any adverse reactions noted, suggesting the treatment's long-term efficacy. It also adds to a small but growing body of literature that supports the use of anti-IgE therapy as a treatment option for improved management of this distressing, life-altering illness. Even in the time that our patient has been receiving omalizumab for SM, another small case series of 2 patients has been published showing sustained treatment effect at 12 years of therapy.¹⁵ This adds further insight that omalizumab can offer long-term, safe treatment for this limiting condition.

Omalizumab therapy is not without risk, but for patients afflicted by unrestrained mastocytic disease, the benefits may outweigh the risks. The most common significant risk with this medication is anaphylaxis, occurring in 1 to 2 per 1,000 patients, usually within 2 hours of an injection.¹⁶ This may correlate to the underlying degree of atopy in patients receiving omalizumab, and the risk of anaphylaxis is relatively low compared with that of many other biologic medications.¹⁷ Additionally, early data from initial phases of clinical trials indicated a potentially elevated malignancy risk with omalizumab. However, subsequent pooled analysis of larger numbers of patients has decreased suspicion that a causal relationship exists.¹⁸

Conclusions

Omalizumab has proven value in the treatment of atopic conditions, such as asthma and idiopathic urticaria, for which it has been approved for use by the FDA. Its effectiveness in significantly decreasing free serum IgE levels, and inhibiting IgE activation of mast cells makes it a possible treatment option for patients with SM who are not sufficiently controlled with conventional therapy. The findings in this case suggest that omalizumab may be effective in the prevention of anaphylaxis and in the reduction of disease burden associated with SM. Further studies and formal clinical trials are needed to confirm these findings. Patients should be counseled appropriately concerning the risks, benefits, and off-label status of this treatment option.

Mastocytosis is a rare disease that causes allergic and anaphylactic symptoms due to chronic or episodic, excessive mast cell degranulation as well as mast cell infiltration of the skin or other organs.¹ Mast cells aid in innate immunity by generation of a vasodilatory and inflammatory response and are significant contributors to allergic reactions. Cutaneous mastocytosis is defined by isolated skin involvement. Systemic mastocytosis (SM) is characterized by mast cell infiltration of extracutaneous organs, most often bone marrow.²

Background

SM is divided into distinct subtypes (Table 1). Nonadvanced SM subtypes include indolent SM and smoldering SM. These are the most common forms and tend to have more slowly progressing courses without evidence of organ tissue dysfunction, a myelodysplastic syndrome, or of a myeloproliferative disorder.³ Advanced SM is less common and is associated with organ tissue dysfunction. It also may be associated with myeloproliferative, myelodysplastic, or lymphoproliferative hematologic neoplasms, and subtypes include aggressive SM, SM with an associated hematologic neoplasm, and mast cell leukemia (Table 2).⁴

Treatment options approved by the US Food and Drug Administration (FDA) for advanced SM include disease-altering medications, such as tyrosine kinase inhibitors (eg, imatinib), but the approved treatment options for nonadvanced SM are generally aimed at managing only symptoms (Table 3). Although not approved by the FDA for the treatment of SM, omalizumab may aid in the prevention of anaphylaxis, the reduction of disease burden, and the improvement in quality of life for patients with SM.⁵ Omalizumab is a humanized monoclonal antibody against the Fc portion of immunoglobulin E (IgE). It is approved by the FDA for treatment of asthma as well as chronic idiopathic urticaria.⁶

Case Presentation

A 32-year-old female initially presented to Womack Army Medical Center at Fort Bragg, North Carolina, for evaluation due to recurrent episodes of anaphylaxis occurring 1 to 2 times per month as well as chronic skin rashes that progressed over the previous 5 years (Figure). She initially was diagnosed with idiopathic anaphylaxis and subsequently had multiple emergency department (ED) and clinic visits for vasovagal syncope, unexplained allergic reactions, dizziness, giddiness, and shortness of breath. More recently, she was diagnosed with idiopathic urticaria.

The patient reported at least 12 episodes in the previous year involving facial flushing that proceeded inferiorly, chest tightness, shortness of breath, labored breathing, crampy abdominal pain, and nausea without urticaria or significant pruritus. These bouts often were accompanied by mild facial angioedema, acute sinus pressure, vomiting, tachycardia, and lightheadedness. She reported experiencing brief losses of consciousness with at least 4 of these episodes. Home and ED blood pressure measurements revealed hypotension on several occasions with systolic readings in the 80s. She also developed nonpruritic freckles on her upper chest initially with subsequent increase in number and spread to involve her entire trunk, proximal extremities, and eventually distal extremities.

Discussion

Mast cell overactivation and degranulation in mastocytosis is largely driven by the IgE antibody, which plays a significant role in atopic conditions, immediate hypersensitivity reactions, and anaphylaxis, as well as in the immunologic response to parasitic infections. The severity of atopic disease seems to be associated with serum IgE levels in many patients.⁷ IgE binding to surface receptors on mast cells and eosinophils prompts the release of toxic mediators, incites inflammation, and induces allergic symptoms.⁸ Activation of mast cells is classically elicited by IgE binding to the high-affinity Fcε RI receptor, the expression of which correlates with IgE levels.⁹

The anti-IgE, recombinant, humanized immunoglobulin G monoclonal antibody, omalizumab, decreases mastocytic and eosinophilic symptoms by binding and inhibiting IgE. This diminishes free IgE levels, inhibits IgE binding to the Fcε RI receptor, and affects downregulation of this high-affinity receptor on mast cells and basophils.⁶ Omalizumab is currently FDA approved only for the treatment of moderate-to-severe, persistent, allergic asthma that is not controlled by inhaled corticosteroids in patients aged ≥ 6 years, and for chronic idiopathic urticaria not controlled by H1 antihistamine therapy in patients aged ≥ 12 years.¹⁰ However, it stands to reason that this therapy also should be effective in the treatment of other poorly controlled atopic conditions, especially mastocytosis, the symptoms of which are driven by excessive mast cell degranulation and tissue infiltration.

As early as 2007, preliminary data showed that treatment with omalizumab could decrease the frequency of episodes of anaphylaxis.¹¹ A National Institutes of Health case report followed 2 patients, one for 5 months and the other for 24 months. Both patients experienced a decrease in frequency of anaphylaxis following initiation of omalizumab. In 2010, a second case report described the treatment of an Australian patient with recurrent idiopathic anaphylaxis also diagnosed with SM. After initiation of treatment with omalizumab, she, too, experienced decreased frequency of episodes of anaphylaxis over 14 months.¹² A review of patients treated at the Mastocytosis Centre Odense University Hospital in Denmark was published in 2017. Of 13 patients with SM treated with omalizumab, 5 experienced what was considered a complete response to the medication, with 3 each experiencing major and partial responses.⁵ The median treatment time in these patients was 27 months. Each of these cases showed significant promise in the use of omalizumab to treat SM, informing the decision to attempt this treatment in our patient.

The potential positive effects of omalizumab in reducing symptom severity in patients with SM was further supported by a 2017 meta-analysis. This review included several individual case reports noting that omalizumab could decrease frequency of pulmonary and gastrointestinal manifestations of SM.¹³ A small randomized control trial of omalizumab for treatment of mild symptoms of SM found improvement in disease severity, although neither primary nor secondary endpoints reached statistical significance.¹⁴

This case demonstrates a substantial, long-term, clinical benefit and quality of life improvement with omalizumab therapy in a patient with indolent SM that was not adequately controlled by conventional therapies. This is evidenced by an impressive decline in the frequency of mastocytic anaphylactic episodes as well as diminished patient-endorsed cutaneous symptoms.

This case provides further evidence of the efficacy of this therapy in diminishing disease burden for patients with SM who are otherwise limited to treatments aimed at transient symptomatic relief without significant alteration of the underlying cause of symptoms. At the time this article was written, our patient had now 52 months of continuous treatment without any adverse reactions noted, suggesting the treatment's long-term efficacy. It also adds to a small but growing body of literature that supports the use of anti-IgE therapy as a treatment option for improved management of this distressing, life-altering illness. Even in the time that our patient has been receiving omalizumab for SM, another small case series of 2 patients has been published showing sustained treatment effect at 12 years of therapy.¹⁵ This adds further insight that omalizumab can offer long-term, safe treatment for this limiting condition.

Omalizumab therapy is not without risk, but for patients afflicted by unrestrained mastocytic disease, the benefits may outweigh the risks. The most common significant risk with this medication is anaphylaxis, occurring in 1 to 2 per 1,000 patients, usually within 2 hours of an injection.¹⁶ This may correlate to the underlying degree of atopy in patients receiving omalizumab, and the risk of anaphylaxis is relatively low compared with that of many other biologic medications.¹⁷ Additionally, early data from initial phases of clinical trials indicated a potentially elevated malignancy risk with omalizumab. However, subsequent pooled analysis of larger numbers of patients has decreased suspicion that a causal relationship exists.¹⁸

Conclusions

Omalizumab has proven value in the treatment of atopic conditions, such as asthma and idiopathic urticaria, for which it has been approved for use by the FDA. Its effectiveness in significantly decreasing free serum IgE levels, and inhibiting IgE activation of mast cells makes it a possible treatment option for patients with SM who are not sufficiently controlled with conventional therapy. The findings in this case suggest that omalizumab may be effective in the prevention of anaphylaxis and in the reduction of disease burden associated with SM. Further studies and formal clinical trials are needed to confirm these findings. Patients should be counseled appropriately concerning the risks, benefits, and off-label status of this treatment option.

The Food and Drug Administration has approved the EndoRotor System (Interscope, Inc.) for removal of necrotic tissue in patients with walled-off pancreatic necrosis (WOPN).

“This device has shown its potential to provide a minimally invasive way to remove harmful necrotic pancreatic tissue in patients with walled-off pancreatic necrosis,” Charles Viviano, MD, PhD, acting director, Reproductive, Gastro-Renal, Urological, General Hospital Device and Human Factors Office, FDA Center for Devices and Radiological Health, said in a statement.

“Currently, in order to remove dead tissue from a patient’s necrotic pancreatic cavity, health care providers need to perform an invasive surgery or use other endoscopic tools not specifically indicated to treat this condition. With [this] marketing authorization, patients with walled-off pancreatic necrosis now have a new treatment option,” said Dr. Viviano.

WOPN is a potentially deadly condition that occurs in about 15% of patients with severe pancreatitis. Often, the dead tissue must be removed.

The EndoRotor System is made up of a power console, foot control, specimen trap, and single-use catheter.

The device is used to perform endoscopic necrosectomy. In this procedure, a stent is used to create a portal between the stomach and the necrotic cavity in the pancreas to accommodate a standard endoscope through which the EndoRotor cuts and removes necrotized tissue.

The FDA approved the EndoRotor System on the basis of a clinical trial involving 30 patients with WOPN who underwent a total of 63 direct endoscopic necrosectomies with the EndoRotor System (average, 2.1 procedures per patient).

The effectiveness of the EndoRotor System was determined by how well it cleared pancreatic necrotic tissue measured during CT with contrast before and after the procedure, endoscopy, or MRI 14 to 28 days after the last procedure.

Results showed an average 85% reduction in the amount of necrotic tissue, with half of the patients having 98.5% clearance of necrotic tissue, the FDA said.

Three patients suffered procedure-related serious adverse events (10% complication rate). Two patients experienced gastrointestinal bleeding. One patient had a pneumoperitoneum and later died after suffering from sepsis and multiorgan system failure caused by massive collections of infected pancreatic necrotic tissue.

Other serious adverse events, which were thought to be due to the patient’s underlying condition and not related to the device or procedure, included hematemesis, deep vein thrombosis, and pancreatitis.

The EndoRotor System should not be used for patients with known or suspected pancreatic cancer, and the device will carry a boxed warning stating this.

The FDA said it knows of one patient who died from pancreatic cancer 3 months after having necrotic pancreatic tissue removed with the EndoRotor System.

“This patient did not have a diagnosis of pancreatic cancer prior to treatment, although the patient’s outcome is believed to be unrelated to the device or procedure,” the FDA said.

The EndoRotor System should be used only after patients have undergone other procedures to drain the WOPN.

It is also not appropriate for patients with walled-off necrosis who have a documented pseudoaneurysm greater than 1 cm within the cavity or with intervening gastric varices or unavoidable blood vessels within the access tract.

The EndoRotor System was approved under the de novo premarket review pathway for new low- to moderate-risk devices.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved the EndoRotor System (Interscope, Inc.) for removal of necrotic tissue in patients with walled-off pancreatic necrosis (WOPN).

“This device has shown its potential to provide a minimally invasive way to remove harmful necrotic pancreatic tissue in patients with walled-off pancreatic necrosis,” Charles Viviano, MD, PhD, acting director, Reproductive, Gastro-Renal, Urological, General Hospital Device and Human Factors Office, FDA Center for Devices and Radiological Health, said in a statement.

“Currently, in order to remove dead tissue from a patient’s necrotic pancreatic cavity, health care providers need to perform an invasive surgery or use other endoscopic tools not specifically indicated to treat this condition. With [this] marketing authorization, patients with walled-off pancreatic necrosis now have a new treatment option,” said Dr. Viviano.

WOPN is a potentially deadly condition that occurs in about 15% of patients with severe pancreatitis. Often, the dead tissue must be removed.

The EndoRotor System is made up of a power console, foot control, specimen trap, and single-use catheter.

The device is used to perform endoscopic necrosectomy. In this procedure, a stent is used to create a portal between the stomach and the necrotic cavity in the pancreas to accommodate a standard endoscope through which the EndoRotor cuts and removes necrotized tissue.

The FDA approved the EndoRotor System on the basis of a clinical trial involving 30 patients with WOPN who underwent a total of 63 direct endoscopic necrosectomies with the EndoRotor System (average, 2.1 procedures per patient).

The effectiveness of the EndoRotor System was determined by how well it cleared pancreatic necrotic tissue measured during CT with contrast before and after the procedure, endoscopy, or MRI 14 to 28 days after the last procedure.

Results showed an average 85% reduction in the amount of necrotic tissue, with half of the patients having 98.5% clearance of necrotic tissue, the FDA said.

Three patients suffered procedure-related serious adverse events (10% complication rate). Two patients experienced gastrointestinal bleeding. One patient had a pneumoperitoneum and later died after suffering from sepsis and multiorgan system failure caused by massive collections of infected pancreatic necrotic tissue.

Other serious adverse events, which were thought to be due to the patient’s underlying condition and not related to the device or procedure, included hematemesis, deep vein thrombosis, and pancreatitis.

The EndoRotor System should not be used for patients with known or suspected pancreatic cancer, and the device will carry a boxed warning stating this.

The FDA said it knows of one patient who died from pancreatic cancer 3 months after having necrotic pancreatic tissue removed with the EndoRotor System.

“This patient did not have a diagnosis of pancreatic cancer prior to treatment, although the patient’s outcome is believed to be unrelated to the device or procedure,” the FDA said.

The EndoRotor System should be used only after patients have undergone other procedures to drain the WOPN.

It is also not appropriate for patients with walled-off necrosis who have a documented pseudoaneurysm greater than 1 cm within the cavity or with intervening gastric varices or unavoidable blood vessels within the access tract.

The EndoRotor System was approved under the de novo premarket review pathway for new low- to moderate-risk devices.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved the EndoRotor System (Interscope, Inc.) for removal of necrotic tissue in patients with walled-off pancreatic necrosis (WOPN).

“This device has shown its potential to provide a minimally invasive way to remove harmful necrotic pancreatic tissue in patients with walled-off pancreatic necrosis,” Charles Viviano, MD, PhD, acting director, Reproductive, Gastro-Renal, Urological, General Hospital Device and Human Factors Office, FDA Center for Devices and Radiological Health, said in a statement.

“Currently, in order to remove dead tissue from a patient’s necrotic pancreatic cavity, health care providers need to perform an invasive surgery or use other endoscopic tools not specifically indicated to treat this condition. With [this] marketing authorization, patients with walled-off pancreatic necrosis now have a new treatment option,” said Dr. Viviano.

WOPN is a potentially deadly condition that occurs in about 15% of patients with severe pancreatitis. Often, the dead tissue must be removed.

The EndoRotor System is made up of a power console, foot control, specimen trap, and single-use catheter.

The device is used to perform endoscopic necrosectomy. In this procedure, a stent is used to create a portal between the stomach and the necrotic cavity in the pancreas to accommodate a standard endoscope through which the EndoRotor cuts and removes necrotized tissue.

The FDA approved the EndoRotor System on the basis of a clinical trial involving 30 patients with WOPN who underwent a total of 63 direct endoscopic necrosectomies with the EndoRotor System (average, 2.1 procedures per patient).

The effectiveness of the EndoRotor System was determined by how well it cleared pancreatic necrotic tissue measured during CT with contrast before and after the procedure, endoscopy, or MRI 14 to 28 days after the last procedure.

Results showed an average 85% reduction in the amount of necrotic tissue, with half of the patients having 98.5% clearance of necrotic tissue, the FDA said.

Three patients suffered procedure-related serious adverse events (10% complication rate). Two patients experienced gastrointestinal bleeding. One patient had a pneumoperitoneum and later died after suffering from sepsis and multiorgan system failure caused by massive collections of infected pancreatic necrotic tissue.

Other serious adverse events, which were thought to be due to the patient’s underlying condition and not related to the device or procedure, included hematemesis, deep vein thrombosis, and pancreatitis.

The EndoRotor System should not be used for patients with known or suspected pancreatic cancer, and the device will carry a boxed warning stating this.

The FDA said it knows of one patient who died from pancreatic cancer 3 months after having necrotic pancreatic tissue removed with the EndoRotor System.

“This patient did not have a diagnosis of pancreatic cancer prior to treatment, although the patient’s outcome is believed to be unrelated to the device or procedure,” the FDA said.

The EndoRotor System should be used only after patients have undergone other procedures to drain the WOPN.

It is also not appropriate for patients with walled-off necrosis who have a documented pseudoaneurysm greater than 1 cm within the cavity or with intervening gastric varices or unavoidable blood vessels within the access tract.

The EndoRotor System was approved under the de novo premarket review pathway for new low- to moderate-risk devices.

A version of this article first appeared on Medscape.com.

Wound cultures from patients with the rare disease epidermolysis bullosa (EB) were most frequently positive for Staphylococcus aureus (SA), Pseudomonas aeruginosa (PA), and Streptococcus pyogenes (GAS) – and antibiotic resistance was common – in a retrospective analysis of over 700 wound cultures from 158 patients across the United States and Canada.

The findings from the EB Clinical Characterization and Outcomes Database speak to the value of surveillance cultures with routine testing for microbial resistance – including mupirocin resistance – and to the importance of antibiotic stewardship not only for oral antibiotics but for topicals as well, according to Laura E. Levin, MD, and Kimberly D. Morel, MD, of the departments of dermatology and pediatrics, Columbia University Irving Medical Center, New York, the lead and senior authors, respectively, of the paper recently published in Pediatric Dermatology.

Almost all of the 158 patients with at least one wound culture recorded in the database from the period of 2001-2018 had one or more positive culture results. Of 152 patients with positive cultures, 131 (86%) were positive for SA and 56 (37%) and 34 (22%) were positive for PA and GAS, respectively. Other bacteria isolated included Corynebacterium spp and Proteus spp. Nearly half (47%) of patients with SA-positive cultures had methicillin-resistant SA, and 68% had methicillin-susceptible SA. (Some patients grew both MSSA and MRSA at different points in time.)

Mupirocin-susceptibility testing was performed at only some of the 13 participating centers. Of 15 patients whose cultures had recorded SA mupirocin-susceptibility testing, 11 had cultures positive for mupirocin-susceptible SA and 6 (40%) had mupirocin-resistant SA isolates (2 patients grew both). Of these six patients, half had isolates that were also methicillin-resistant.

Mupirocin, a topical antibiotic, has been a cornerstone of decolonization regimens for MSSA and MRSA, but resistance has been demonstrated in other research as well and is not specific to EB, wrote Dr. Levin, Dr. Morel, and coauthors.

“Pediatric dermatologists often rely on topical antimicrobials in the treatment of patients’ open wounds to both prevent and treat infection, depending on the clinical scenario,” and surveillance cultures with routine testing for mupirocin resistance can help guide antibiotic choice and management strategies, Dr. Levin said in an interview.

More broadly, she added, “it’s helpful to know what bacteria are routinely colonizing wounds, not causing infection, versus those that are more likely to be associated with infection, chronic wounds, or the risk of developing skin cancer ... [to know] which wounds need to be treated more aggressively.”

A subset of patients with EB have been known to be at risk for squamous cell carcinoma, and research is implicating certain bacteria “as contributing to wound inflammation,” Dr. Morel said in an interview.

SCC was reported in 23 out of 717 patients in the database – but fewer than half of the patients with SCC had recorded wound cultures. The small numbers precluded the identification of microbes that may confer significant risk.

Correlating particular microbes with clinical features also will take more research. About half (57%) of the patients with recorded wound cultures had wounds with purulent exudate or other features of clinical infection. However, the presence or absence of clinical signs of infection was not temporally correlated with culture results in the database.

The 158 patients with recorded wound cultures had a mean age of 12.8 years and represented a range of EB subtypes.

PA was present in the wounds of patients as young as 1 month old, the authors noted. Investigators are “looking to further study PA and characterize clinical features ... to understand more about this microbe and its impact on patients with EB,” Dr. Morel said.

In the meantime, the analysis reaffirms the importance of antibiotic stewardship. Mupirocin is labeled to be used three times a day for a short period of time, but “tends to be prescribed and used less judiciously than intended,” Dr. Morel said. “It’s important [not to overuse it]. We have seen that patients’ culture results become sensitive to mupirocin again in the future when they avoid it for a period of time.”

The work was supported by the EB Research Partnership and EB Medical Research Foundation, as well as an NIH/NCATS grant. No investigator disclosures were listed.

SOURCE: Pediatr Dermatol. 2020 Nov 28. doi: 10.1111/pde.14444.

Wound cultures from patients with the rare disease epidermolysis bullosa (EB) were most frequently positive for Staphylococcus aureus (SA), Pseudomonas aeruginosa (PA), and Streptococcus pyogenes (GAS) – and antibiotic resistance was common – in a retrospective analysis of over 700 wound cultures from 158 patients across the United States and Canada.

The findings from the EB Clinical Characterization and Outcomes Database speak to the value of surveillance cultures with routine testing for microbial resistance – including mupirocin resistance – and to the importance of antibiotic stewardship not only for oral antibiotics but for topicals as well, according to Laura E. Levin, MD, and Kimberly D. Morel, MD, of the departments of dermatology and pediatrics, Columbia University Irving Medical Center, New York, the lead and senior authors, respectively, of the paper recently published in Pediatric Dermatology.

Almost all of the 158 patients with at least one wound culture recorded in the database from the period of 2001-2018 had one or more positive culture results. Of 152 patients with positive cultures, 131 (86%) were positive for SA and 56 (37%) and 34 (22%) were positive for PA and GAS, respectively. Other bacteria isolated included Corynebacterium spp and Proteus spp. Nearly half (47%) of patients with SA-positive cultures had methicillin-resistant SA, and 68% had methicillin-susceptible SA. (Some patients grew both MSSA and MRSA at different points in time.)

Mupirocin-susceptibility testing was performed at only some of the 13 participating centers. Of 15 patients whose cultures had recorded SA mupirocin-susceptibility testing, 11 had cultures positive for mupirocin-susceptible SA and 6 (40%) had mupirocin-resistant SA isolates (2 patients grew both). Of these six patients, half had isolates that were also methicillin-resistant.

Mupirocin, a topical antibiotic, has been a cornerstone of decolonization regimens for MSSA and MRSA, but resistance has been demonstrated in other research as well and is not specific to EB, wrote Dr. Levin, Dr. Morel, and coauthors.

“Pediatric dermatologists often rely on topical antimicrobials in the treatment of patients’ open wounds to both prevent and treat infection, depending on the clinical scenario,” and surveillance cultures with routine testing for mupirocin resistance can help guide antibiotic choice and management strategies, Dr. Levin said in an interview.

More broadly, she added, “it’s helpful to know what bacteria are routinely colonizing wounds, not causing infection, versus those that are more likely to be associated with infection, chronic wounds, or the risk of developing skin cancer ... [to know] which wounds need to be treated more aggressively.”

A subset of patients with EB have been known to be at risk for squamous cell carcinoma, and research is implicating certain bacteria “as contributing to wound inflammation,” Dr. Morel said in an interview.

SCC was reported in 23 out of 717 patients in the database – but fewer than half of the patients with SCC had recorded wound cultures. The small numbers precluded the identification of microbes that may confer significant risk.

Correlating particular microbes with clinical features also will take more research. About half (57%) of the patients with recorded wound cultures had wounds with purulent exudate or other features of clinical infection. However, the presence or absence of clinical signs of infection was not temporally correlated with culture results in the database.

The 158 patients with recorded wound cultures had a mean age of 12.8 years and represented a range of EB subtypes.

PA was present in the wounds of patients as young as 1 month old, the authors noted. Investigators are “looking to further study PA and characterize clinical features ... to understand more about this microbe and its impact on patients with EB,” Dr. Morel said.

In the meantime, the analysis reaffirms the importance of antibiotic stewardship. Mupirocin is labeled to be used three times a day for a short period of time, but “tends to be prescribed and used less judiciously than intended,” Dr. Morel said. “It’s important [not to overuse it]. We have seen that patients’ culture results become sensitive to mupirocin again in the future when they avoid it for a period of time.”

The work was supported by the EB Research Partnership and EB Medical Research Foundation, as well as an NIH/NCATS grant. No investigator disclosures were listed.

SOURCE: Pediatr Dermatol. 2020 Nov 28. doi: 10.1111/pde.14444.

Wound cultures from patients with the rare disease epidermolysis bullosa (EB) were most frequently positive for Staphylococcus aureus (SA), Pseudomonas aeruginosa (PA), and Streptococcus pyogenes (GAS) – and antibiotic resistance was common – in a retrospective analysis of over 700 wound cultures from 158 patients across the United States and Canada.

The findings from the EB Clinical Characterization and Outcomes Database speak to the value of surveillance cultures with routine testing for microbial resistance – including mupirocin resistance – and to the importance of antibiotic stewardship not only for oral antibiotics but for topicals as well, according to Laura E. Levin, MD, and Kimberly D. Morel, MD, of the departments of dermatology and pediatrics, Columbia University Irving Medical Center, New York, the lead and senior authors, respectively, of the paper recently published in Pediatric Dermatology.

Almost all of the 158 patients with at least one wound culture recorded in the database from the period of 2001-2018 had one or more positive culture results. Of 152 patients with positive cultures, 131 (86%) were positive for SA and 56 (37%) and 34 (22%) were positive for PA and GAS, respectively. Other bacteria isolated included Corynebacterium spp and Proteus spp. Nearly half (47%) of patients with SA-positive cultures had methicillin-resistant SA, and 68% had methicillin-susceptible SA. (Some patients grew both MSSA and MRSA at different points in time.)

Mupirocin-susceptibility testing was performed at only some of the 13 participating centers. Of 15 patients whose cultures had recorded SA mupirocin-susceptibility testing, 11 had cultures positive for mupirocin-susceptible SA and 6 (40%) had mupirocin-resistant SA isolates (2 patients grew both). Of these six patients, half had isolates that were also methicillin-resistant.

Mupirocin, a topical antibiotic, has been a cornerstone of decolonization regimens for MSSA and MRSA, but resistance has been demonstrated in other research as well and is not specific to EB, wrote Dr. Levin, Dr. Morel, and coauthors.

“Pediatric dermatologists often rely on topical antimicrobials in the treatment of patients’ open wounds to both prevent and treat infection, depending on the clinical scenario,” and surveillance cultures with routine testing for mupirocin resistance can help guide antibiotic choice and management strategies, Dr. Levin said in an interview.

More broadly, she added, “it’s helpful to know what bacteria are routinely colonizing wounds, not causing infection, versus those that are more likely to be associated with infection, chronic wounds, or the risk of developing skin cancer ... [to know] which wounds need to be treated more aggressively.”

A subset of patients with EB have been known to be at risk for squamous cell carcinoma, and research is implicating certain bacteria “as contributing to wound inflammation,” Dr. Morel said in an interview.

SCC was reported in 23 out of 717 patients in the database – but fewer than half of the patients with SCC had recorded wound cultures. The small numbers precluded the identification of microbes that may confer significant risk.

Correlating particular microbes with clinical features also will take more research. About half (57%) of the patients with recorded wound cultures had wounds with purulent exudate or other features of clinical infection. However, the presence or absence of clinical signs of infection was not temporally correlated with culture results in the database.

The 158 patients with recorded wound cultures had a mean age of 12.8 years and represented a range of EB subtypes.

PA was present in the wounds of patients as young as 1 month old, the authors noted. Investigators are “looking to further study PA and characterize clinical features ... to understand more about this microbe and its impact on patients with EB,” Dr. Morel said.

In the meantime, the analysis reaffirms the importance of antibiotic stewardship. Mupirocin is labeled to be used three times a day for a short period of time, but “tends to be prescribed and used less judiciously than intended,” Dr. Morel said. “It’s important [not to overuse it]. We have seen that patients’ culture results become sensitive to mupirocin again in the future when they avoid it for a period of time.”

The work was supported by the EB Research Partnership and EB Medical Research Foundation, as well as an NIH/NCATS grant. No investigator disclosures were listed.

SOURCE: Pediatr Dermatol. 2020 Nov 28. doi: 10.1111/pde.14444.

Rare cancers comprise about 20% of all cancers in the United States and Europe, according to recent estimates, but patients with rare cancers are vastly underrepresented in clinical trials.

Recently, there has been a focus on immune checkpoint blockade (ICB) in common cancer types. Since several rare tumor types share similar biologic features with the more common tumors, there is a need to test ICB in rare tumors, particularly because remissions with ICB can be durable.

Enter the DART trial, a phase 2, single-arm study of combinatorial ICB with ipilimumab plus nivolumab in patients with unresectable or metastatic rare cancers.

Results from DART were recently presented at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting. Michael J. Wagner, MD, of the University of Washington, Seattle, reported results in patients with advanced or unresectable angiosarcoma, one of the rare tumor types included in DART.
 

About angiosarcomas

Angiosarcomas account for less than 3% of all adult soft-tissue sarcomas, according to a review published in The Lancet Oncology. Angiosarcomas may arise in any part of the body, especially the head and neck (27%), breast (19.7%), and extremities (15.3%). These cancers can be primary or secondary (i.e., associated with prior radiation therapy or chronic lymphedema).

Angiosarcomas are aggressive, difficult to treat, and confer high mortality. The tumors are responsive to chemotherapy, but responses are brief. The estimated 5-year survival rate for all patients with angiosarcoma, including those who present with localized disease, is 30%-40%.

According to Dr. Wagner, a subset of angiosarcomas are characterized by high tumor mutational burden (TMB) and COSMIC signature 7, a DNA mutational signature that is consistent with other cancers caused by ultraviolet light exposure.

The high TMB subset of angiosarcomas is comparable with other cancer types that are responsive to ICB. Indeed, patients with angiosarcoma treated with ICB have shown responses, according to research published in the Journal for Immunotherapy of Cancer. However, no prospective studies of ICB in angiosarcoma have been published.
 

About DART

The DART trial includes more than 50 cohorts of rare cancer subtypes. Patients receive IV ipilimumab at 1 mg/kg every 6 weeks and IV nivolumab at 240 mg every 2 weeks.

The primary endpoint is objective response rate, as assessed by RECIST v1.1. Secondary endpoints include progression-free survival, overall survival, stable disease at 6 months, and toxicity.

The trial has a two-stage design. Six patients are enrolled in the first stage, and, if at least one patient responds to treatment, an additional 10 patients are enrolled in the second stage.

If at least two responses are seen among the 16 patients enrolled, further study of ICB is considered warranted.
 

Results in angiosarcoma

Dr. Wagner reported on the 16 angiosarcoma patients enrolled in DART. Nine patients had cutaneous primary tumors, seven had noncutaneous primary tumors, and three patients had radiation-associated angiosarcoma of the breast or chest wall.

Patients had received a median of two (range, zero to five) prior lines of therapy.

Adverse events (AEs) were consistent with prior safety results of the ipilimumab-nivolumab combination. Three-quarters of patients experienced an AE of any grade. The most common AEs were transaminase elevation, anemia, diarrhea, fatigue, hypothyroidism, pneumonitis, pruritus, and rash.

A quarter of patients had a grade 3-4 AE, and 12.5% of AEs led to premature treatment discontinuation. There were no fatal AEs.

The ORR was 25%. Responses occurred in 4 of the 16 patients, including 3 of 5 patients with primary cutaneous tumors of the scalp or face and 1 of 3 patients with radiation-associated breast angiosarcoma.

Two of the four responses and one case of stable disease have persisted for almost a year, and these patients remain on treatment. To put these results into perspective, Dr. Wagner noted that responses to cytotoxic chemotherapy rarely last 6 months.

The 6-month progression-free survival rate was 38%. The median overall survival has not yet been reached.

Dr. Wagner concluded that the combinatorial ICB regimen employed in DART was well tolerated and had an ORR of 25% in angiosarcoma regardless of primary site. Per the criteria of the DART trial, further investigation of ICB in angiosarcoma is warranted.
 

Molecular insights

Although correlative analyses of tumor tissue and peripheral blood are embedded in the DART trial, those analyses have not yet been performed. Eight of the 16 angiosarcoma patients had diagnostic molecular studies performed at their parent institutions, utilizing a variety of commercial platforms.

All eight patients for whom molecular data were available had at least two deleterious genomic alterations detected, but each had a distinct molecular profile.

Seven patients had TMB analyzed, including two partial responders to ICB. One of the seven patients had a high TMB, and this patient was one of the two responders. The other responder had an intermediate TMB.

Three patients had programmed death–ligand 1 staining on their tumors. Two of the three had high expression of PD-L1, including the responder with an intermediate TMB.
 

The real impact of DART

The DART trial is a “basket trial,” employing a similar treatment regimen for multiple tumor types. It provides a uniform framework for studying tumors that have been neglected in clinical trials heretofore.

Although the cohort of angiosarcoma patients is small, central pathology review was not required, and the treatment regimen was not compared directly with other potential therapies, the reported results of the ipilimumab-nivolumab regimen justify further study.

The biospecimens collected in DART will provide a rich source of data to identify common themes among responders and nonresponders, among patients who experience durable remissions and those who do not.

Angiosarcoma is not the only rare cancer for which combinatorial ICB has been valuable under the auspices of the DART trial. In Clinical Cancer Research, investigators reported an ORR of 44% among patients with high-grade neuroendocrine cancers, independent of primary site of origin. Progression-free survival at 6 months was 31%.

The DART trial is available at more than 800 sites, providing access to potentially promising treatment in a rigorous, scientifically valuable study for geographically underserved populations, including patients who live in rural areas.

The key message for practicing oncologists and clinical investigators is that clinical trials in rare tumors are feasible and can yield hope for patients who might lack it otherwise.

DART is funded by the National Cancer Institute and Bristol-Myers Squibb. Dr. Wagner disclosed relationships with Deciphera, Adaptimmune, GlaxoSmithKline, Athenex, and Incyte.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Wagner M et al. SITC 2020, Abstract 795.

Rare cancers comprise about 20% of all cancers in the United States and Europe, according to recent estimates, but patients with rare cancers are vastly underrepresented in clinical trials.

Recently, there has been a focus on immune checkpoint blockade (ICB) in common cancer types. Since several rare tumor types share similar biologic features with the more common tumors, there is a need to test ICB in rare tumors, particularly because remissions with ICB can be durable.

Enter the DART trial, a phase 2, single-arm study of combinatorial ICB with ipilimumab plus nivolumab in patients with unresectable or metastatic rare cancers.

Results from DART were recently presented at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting. Michael J. Wagner, MD, of the University of Washington, Seattle, reported results in patients with advanced or unresectable angiosarcoma, one of the rare tumor types included in DART.
 

About angiosarcomas

Angiosarcomas account for less than 3% of all adult soft-tissue sarcomas, according to a review published in The Lancet Oncology. Angiosarcomas may arise in any part of the body, especially the head and neck (27%), breast (19.7%), and extremities (15.3%). These cancers can be primary or secondary (i.e., associated with prior radiation therapy or chronic lymphedema).

Angiosarcomas are aggressive, difficult to treat, and confer high mortality. The tumors are responsive to chemotherapy, but responses are brief. The estimated 5-year survival rate for all patients with angiosarcoma, including those who present with localized disease, is 30%-40%.

According to Dr. Wagner, a subset of angiosarcomas are characterized by high tumor mutational burden (TMB) and COSMIC signature 7, a DNA mutational signature that is consistent with other cancers caused by ultraviolet light exposure.

The high TMB subset of angiosarcomas is comparable with other cancer types that are responsive to ICB. Indeed, patients with angiosarcoma treated with ICB have shown responses, according to research published in the Journal for Immunotherapy of Cancer. However, no prospective studies of ICB in angiosarcoma have been published.
 

About DART

The DART trial includes more than 50 cohorts of rare cancer subtypes. Patients receive IV ipilimumab at 1 mg/kg every 6 weeks and IV nivolumab at 240 mg every 2 weeks.

The primary endpoint is objective response rate, as assessed by RECIST v1.1. Secondary endpoints include progression-free survival, overall survival, stable disease at 6 months, and toxicity.

The trial has a two-stage design. Six patients are enrolled in the first stage, and, if at least one patient responds to treatment, an additional 10 patients are enrolled in the second stage.

If at least two responses are seen among the 16 patients enrolled, further study of ICB is considered warranted.
 

Results in angiosarcoma

Dr. Wagner reported on the 16 angiosarcoma patients enrolled in DART. Nine patients had cutaneous primary tumors, seven had noncutaneous primary tumors, and three patients had radiation-associated angiosarcoma of the breast or chest wall.

Patients had received a median of two (range, zero to five) prior lines of therapy.

Adverse events (AEs) were consistent with prior safety results of the ipilimumab-nivolumab combination. Three-quarters of patients experienced an AE of any grade. The most common AEs were transaminase elevation, anemia, diarrhea, fatigue, hypothyroidism, pneumonitis, pruritus, and rash.

A quarter of patients had a grade 3-4 AE, and 12.5% of AEs led to premature treatment discontinuation. There were no fatal AEs.

The ORR was 25%. Responses occurred in 4 of the 16 patients, including 3 of 5 patients with primary cutaneous tumors of the scalp or face and 1 of 3 patients with radiation-associated breast angiosarcoma.

Two of the four responses and one case of stable disease have persisted for almost a year, and these patients remain on treatment. To put these results into perspective, Dr. Wagner noted that responses to cytotoxic chemotherapy rarely last 6 months.

The 6-month progression-free survival rate was 38%. The median overall survival has not yet been reached.

Dr. Wagner concluded that the combinatorial ICB regimen employed in DART was well tolerated and had an ORR of 25% in angiosarcoma regardless of primary site. Per the criteria of the DART trial, further investigation of ICB in angiosarcoma is warranted.
 

Molecular insights

Although correlative analyses of tumor tissue and peripheral blood are embedded in the DART trial, those analyses have not yet been performed. Eight of the 16 angiosarcoma patients had diagnostic molecular studies performed at their parent institutions, utilizing a variety of commercial platforms.

All eight patients for whom molecular data were available had at least two deleterious genomic alterations detected, but each had a distinct molecular profile.

Seven patients had TMB analyzed, including two partial responders to ICB. One of the seven patients had a high TMB, and this patient was one of the two responders. The other responder had an intermediate TMB.

Three patients had programmed death–ligand 1 staining on their tumors. Two of the three had high expression of PD-L1, including the responder with an intermediate TMB.
 

The real impact of DART

The DART trial is a “basket trial,” employing a similar treatment regimen for multiple tumor types. It provides a uniform framework for studying tumors that have been neglected in clinical trials heretofore.

Although the cohort of angiosarcoma patients is small, central pathology review was not required, and the treatment regimen was not compared directly with other potential therapies, the reported results of the ipilimumab-nivolumab regimen justify further study.

The biospecimens collected in DART will provide a rich source of data to identify common themes among responders and nonresponders, among patients who experience durable remissions and those who do not.

Angiosarcoma is not the only rare cancer for which combinatorial ICB has been valuable under the auspices of the DART trial. In Clinical Cancer Research, investigators reported an ORR of 44% among patients with high-grade neuroendocrine cancers, independent of primary site of origin. Progression-free survival at 6 months was 31%.

The DART trial is available at more than 800 sites, providing access to potentially promising treatment in a rigorous, scientifically valuable study for geographically underserved populations, including patients who live in rural areas.

The key message for practicing oncologists and clinical investigators is that clinical trials in rare tumors are feasible and can yield hope for patients who might lack it otherwise.

DART is funded by the National Cancer Institute and Bristol-Myers Squibb. Dr. Wagner disclosed relationships with Deciphera, Adaptimmune, GlaxoSmithKline, Athenex, and Incyte.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Wagner M et al. SITC 2020, Abstract 795.

Rare cancers comprise about 20% of all cancers in the United States and Europe, according to recent estimates, but patients with rare cancers are vastly underrepresented in clinical trials.

Recently, there has been a focus on immune checkpoint blockade (ICB) in common cancer types. Since several rare tumor types share similar biologic features with the more common tumors, there is a need to test ICB in rare tumors, particularly because remissions with ICB can be durable.

Enter the DART trial, a phase 2, single-arm study of combinatorial ICB with ipilimumab plus nivolumab in patients with unresectable or metastatic rare cancers.

Results from DART were recently presented at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting. Michael J. Wagner, MD, of the University of Washington, Seattle, reported results in patients with advanced or unresectable angiosarcoma, one of the rare tumor types included in DART.
 

About angiosarcomas

Angiosarcomas account for less than 3% of all adult soft-tissue sarcomas, according to a review published in The Lancet Oncology. Angiosarcomas may arise in any part of the body, especially the head and neck (27%), breast (19.7%), and extremities (15.3%). These cancers can be primary or secondary (i.e., associated with prior radiation therapy or chronic lymphedema).

Angiosarcomas are aggressive, difficult to treat, and confer high mortality. The tumors are responsive to chemotherapy, but responses are brief. The estimated 5-year survival rate for all patients with angiosarcoma, including those who present with localized disease, is 30%-40%.

According to Dr. Wagner, a subset of angiosarcomas are characterized by high tumor mutational burden (TMB) and COSMIC signature 7, a DNA mutational signature that is consistent with other cancers caused by ultraviolet light exposure.

The high TMB subset of angiosarcomas is comparable with other cancer types that are responsive to ICB. Indeed, patients with angiosarcoma treated with ICB have shown responses, according to research published in the Journal for Immunotherapy of Cancer. However, no prospective studies of ICB in angiosarcoma have been published.
 

About DART

The DART trial includes more than 50 cohorts of rare cancer subtypes. Patients receive IV ipilimumab at 1 mg/kg every 6 weeks and IV nivolumab at 240 mg every 2 weeks.

The primary endpoint is objective response rate, as assessed by RECIST v1.1. Secondary endpoints include progression-free survival, overall survival, stable disease at 6 months, and toxicity.

The trial has a two-stage design. Six patients are enrolled in the first stage, and, if at least one patient responds to treatment, an additional 10 patients are enrolled in the second stage.

If at least two responses are seen among the 16 patients enrolled, further study of ICB is considered warranted.
 

Results in angiosarcoma

Dr. Wagner reported on the 16 angiosarcoma patients enrolled in DART. Nine patients had cutaneous primary tumors, seven had noncutaneous primary tumors, and three patients had radiation-associated angiosarcoma of the breast or chest wall.

Patients had received a median of two (range, zero to five) prior lines of therapy.

Adverse events (AEs) were consistent with prior safety results of the ipilimumab-nivolumab combination. Three-quarters of patients experienced an AE of any grade. The most common AEs were transaminase elevation, anemia, diarrhea, fatigue, hypothyroidism, pneumonitis, pruritus, and rash.

A quarter of patients had a grade 3-4 AE, and 12.5% of AEs led to premature treatment discontinuation. There were no fatal AEs.

The ORR was 25%. Responses occurred in 4 of the 16 patients, including 3 of 5 patients with primary cutaneous tumors of the scalp or face and 1 of 3 patients with radiation-associated breast angiosarcoma.

Two of the four responses and one case of stable disease have persisted for almost a year, and these patients remain on treatment. To put these results into perspective, Dr. Wagner noted that responses to cytotoxic chemotherapy rarely last 6 months.

The 6-month progression-free survival rate was 38%. The median overall survival has not yet been reached.

Dr. Wagner concluded that the combinatorial ICB regimen employed in DART was well tolerated and had an ORR of 25% in angiosarcoma regardless of primary site. Per the criteria of the DART trial, further investigation of ICB in angiosarcoma is warranted.
 

Molecular insights

Although correlative analyses of tumor tissue and peripheral blood are embedded in the DART trial, those analyses have not yet been performed. Eight of the 16 angiosarcoma patients had diagnostic molecular studies performed at their parent institutions, utilizing a variety of commercial platforms.

All eight patients for whom molecular data were available had at least two deleterious genomic alterations detected, but each had a distinct molecular profile.

Seven patients had TMB analyzed, including two partial responders to ICB. One of the seven patients had a high TMB, and this patient was one of the two responders. The other responder had an intermediate TMB.

Three patients had programmed death–ligand 1 staining on their tumors. Two of the three had high expression of PD-L1, including the responder with an intermediate TMB.
 

The real impact of DART

The DART trial is a “basket trial,” employing a similar treatment regimen for multiple tumor types. It provides a uniform framework for studying tumors that have been neglected in clinical trials heretofore.

Although the cohort of angiosarcoma patients is small, central pathology review was not required, and the treatment regimen was not compared directly with other potential therapies, the reported results of the ipilimumab-nivolumab regimen justify further study.

The biospecimens collected in DART will provide a rich source of data to identify common themes among responders and nonresponders, among patients who experience durable remissions and those who do not.

Angiosarcoma is not the only rare cancer for which combinatorial ICB has been valuable under the auspices of the DART trial. In Clinical Cancer Research, investigators reported an ORR of 44% among patients with high-grade neuroendocrine cancers, independent of primary site of origin. Progression-free survival at 6 months was 31%.

The DART trial is available at more than 800 sites, providing access to potentially promising treatment in a rigorous, scientifically valuable study for geographically underserved populations, including patients who live in rural areas.

The key message for practicing oncologists and clinical investigators is that clinical trials in rare tumors are feasible and can yield hope for patients who might lack it otherwise.

DART is funded by the National Cancer Institute and Bristol-Myers Squibb. Dr. Wagner disclosed relationships with Deciphera, Adaptimmune, GlaxoSmithKline, Athenex, and Incyte.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Wagner M et al. SITC 2020, Abstract 795.