DENVER – The Colorado experience with medical marijuana products for the treatment of pediatric epilepsy holds useful lessons for physicians in states where legal marijuana is a far more recent development, Amy R. Brooks-Kayal, MD, said at the annual meeting of the Teratology Society.

Medical marijuana has been legal in Colorado for nearly 20 years. But the drug’s potential role in treating intractable pediatric epilepsy started getting a lot more attention in 2013 when a CNN report by Sanjay Gupta, MD, chronicled a child’s remarkable turnaround in response to medical marijuana. The story triggered a migration to the state by what has been termed “marijuana refugees”: desperate families with children who had the most severe, complex, treatment-refractory seizure disorders, said Dr. Brooks-Kayal, professor of pediatrics and neurology and chief of pediatric neurology at the University of Colorado at Denver, Aurora.

• Provide families with the current data, discuss what’s known and still unknown, and encourage families to disclose the use of cannabinoids so the child can be monitored.
• Have the family keep a seizure diary. Get a baseline EEG and another at about 12 weeks. Do routine laboratory monitoring every 4 weeks, including liver function tests. “We think CBDs [cannabinoids] have the potential to worsen liver function,” she said.
• Stress the importance of leaving other seizure medications unchanged. “When this first started, the medical marijuana providers were recommending patients stop their other medications. The providers don’t do that anymore, fortunately,” Dr. Brooks-Kayal said. “Every week we were putting a child in a medically induced coma because they had status epilepticus, and it was the only way to stop their seizures. They started using marijuana products, they were sure it was going to be the cure, they stopped all their other medications, and they developed status epilepticus.”
• Establish policies with the hospital administration and pharmacy about how to handle marijuana products when a child is in the hospital. The Children’s Hospital Colorado pharmacy cannot store or dispense marijuana products because of federal regulations. And again, it’s unsafe to stop seizure medications abruptly, including marijuana products. Informed consent procedures need to be developed for when patients on cannabinoids are hospitalized.
• Encourage families to participate in one of the six Food and Drug Administration–approved double-blind, placebo-controlled trials of Epidiolex for Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, and infantile spasms sponsored by GW Pharmaceuticals.

Breaking down the evidence

Here’s what’s known and what is still unknown about the safety and efficacy of cannabinoids for the treatment of refractory pediatric epilepsy, according to Dr. Brooks-Kayal.

The knowns

Cannabinoids show activity against seizures in animal models. Moreover, initial clinical data suggest they may decrease seizures in some children with refractory epilepsy. This evidence includes a retrospective study from Children’s Hospital Colorado reliant upon parental reports of improvement (Epilepsy Behav. 2015 Apr;45:49-52), an Israeli retrospective study (Seizure. 2016 Feb;35:41-4), a positive open-label trial of an investigational oral oil-based solution of a pharmaceutical-grade cannabidiol known as Epidiolex (Lancet Neurol. 2016 Mar;15[3]:270-8), and evidence from a Food and Drug Administration–authorized phase 3, randomized clinical trial of Epidiolex (N Engl J Med. 2017 May 25;376[21]:2011-20).

The incidence of short-term adverse events associated with cannabinoids is substantial. The rate seems to be higher with Epidiolex than with many other medical marijuana products, although the potency is greater, too. These include somnolence, fatigue, and convulsions.

In addition, gastrointestinal side effects are common with Epidiolex. “Some are probably due to the oil base; some [are] probably due to the cannabidiol itself,” said Dr. Brooks-Kayal.
 

The unknowns

What types of seizures does it work for? This is under study in a series of FDA-authorized phase 3 randomized trials.

What is the placebo-subtracted response rate to cannabidiol? In the randomized trial published in the New England Journal of Medicine, the median monthly frequency of seizures decreased from 12.4 to 5.9 with cannabidiol, compared with a reduction from 14.9 to 14.1 with placebo. This needs confirmation in additional trials.

What’s the optimal dose? The randomized trial tested just one dose – 20 mg/kg per day.

What are the drug interactions and their possible impact on cannabidiol efficacy? Outcomes appear to be better in patients on concomitant clobazam (Onfi), perhaps because of the significantly higher blood levels of clobazam’s major metabolite in children on cannabidiol.
 

Long-term effects

The jury is still out on the long-term adverse effects. “These medical marijuana products are being given by families to 2- and 3-month-olds. It will be years before we know about potential long-term cognitive and behavioral effects,” Dr. Brooks-Kayal said.

Dr. Brooks-Kayal reported having no financial conflicts of interest regarding her presentation.
 

[email protected]

DENVER – The Colorado experience with medical marijuana products for the treatment of pediatric epilepsy holds useful lessons for physicians in states where legal marijuana is a far more recent development, Amy R. Brooks-Kayal, MD, said at the annual meeting of the Teratology Society.

Medical marijuana has been legal in Colorado for nearly 20 years. But the drug’s potential role in treating intractable pediatric epilepsy started getting a lot more attention in 2013 when a CNN report by Sanjay Gupta, MD, chronicled a child’s remarkable turnaround in response to medical marijuana. The story triggered a migration to the state by what has been termed “marijuana refugees”: desperate families with children who had the most severe, complex, treatment-refractory seizure disorders, said Dr. Brooks-Kayal, professor of pediatrics and neurology and chief of pediatric neurology at the University of Colorado at Denver, Aurora.

• Provide families with the current data, discuss what’s known and still unknown, and encourage families to disclose the use of cannabinoids so the child can be monitored.
• Have the family keep a seizure diary. Get a baseline EEG and another at about 12 weeks. Do routine laboratory monitoring every 4 weeks, including liver function tests. “We think CBDs [cannabinoids] have the potential to worsen liver function,” she said.
• Stress the importance of leaving other seizure medications unchanged. “When this first started, the medical marijuana providers were recommending patients stop their other medications. The providers don’t do that anymore, fortunately,” Dr. Brooks-Kayal said. “Every week we were putting a child in a medically induced coma because they had status epilepticus, and it was the only way to stop their seizures. They started using marijuana products, they were sure it was going to be the cure, they stopped all their other medications, and they developed status epilepticus.”
• Establish policies with the hospital administration and pharmacy about how to handle marijuana products when a child is in the hospital. The Children’s Hospital Colorado pharmacy cannot store or dispense marijuana products because of federal regulations. And again, it’s unsafe to stop seizure medications abruptly, including marijuana products. Informed consent procedures need to be developed for when patients on cannabinoids are hospitalized.
• Encourage families to participate in one of the six Food and Drug Administration–approved double-blind, placebo-controlled trials of Epidiolex for Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, and infantile spasms sponsored by GW Pharmaceuticals.

Breaking down the evidence

Here’s what’s known and what is still unknown about the safety and efficacy of cannabinoids for the treatment of refractory pediatric epilepsy, according to Dr. Brooks-Kayal.

The knowns

Cannabinoids show activity against seizures in animal models. Moreover, initial clinical data suggest they may decrease seizures in some children with refractory epilepsy. This evidence includes a retrospective study from Children’s Hospital Colorado reliant upon parental reports of improvement (Epilepsy Behav. 2015 Apr;45:49-52), an Israeli retrospective study (Seizure. 2016 Feb;35:41-4), a positive open-label trial of an investigational oral oil-based solution of a pharmaceutical-grade cannabidiol known as Epidiolex (Lancet Neurol. 2016 Mar;15[3]:270-8), and evidence from a Food and Drug Administration–authorized phase 3, randomized clinical trial of Epidiolex (N Engl J Med. 2017 May 25;376[21]:2011-20).

The incidence of short-term adverse events associated with cannabinoids is substantial. The rate seems to be higher with Epidiolex than with many other medical marijuana products, although the potency is greater, too. These include somnolence, fatigue, and convulsions.

In addition, gastrointestinal side effects are common with Epidiolex. “Some are probably due to the oil base; some [are] probably due to the cannabidiol itself,” said Dr. Brooks-Kayal.
 

The unknowns

What types of seizures does it work for? This is under study in a series of FDA-authorized phase 3 randomized trials.

What is the placebo-subtracted response rate to cannabidiol? In the randomized trial published in the New England Journal of Medicine, the median monthly frequency of seizures decreased from 12.4 to 5.9 with cannabidiol, compared with a reduction from 14.9 to 14.1 with placebo. This needs confirmation in additional trials.

What’s the optimal dose? The randomized trial tested just one dose – 20 mg/kg per day.

What are the drug interactions and their possible impact on cannabidiol efficacy? Outcomes appear to be better in patients on concomitant clobazam (Onfi), perhaps because of the significantly higher blood levels of clobazam’s major metabolite in children on cannabidiol.
 

Long-term effects

The jury is still out on the long-term adverse effects. “These medical marijuana products are being given by families to 2- and 3-month-olds. It will be years before we know about potential long-term cognitive and behavioral effects,” Dr. Brooks-Kayal said.

Dr. Brooks-Kayal reported having no financial conflicts of interest regarding her presentation.
 

[email protected]

DENVER – The Colorado experience with medical marijuana products for the treatment of pediatric epilepsy holds useful lessons for physicians in states where legal marijuana is a far more recent development, Amy R. Brooks-Kayal, MD, said at the annual meeting of the Teratology Society.

Medical marijuana has been legal in Colorado for nearly 20 years. But the drug’s potential role in treating intractable pediatric epilepsy started getting a lot more attention in 2013 when a CNN report by Sanjay Gupta, MD, chronicled a child’s remarkable turnaround in response to medical marijuana. The story triggered a migration to the state by what has been termed “marijuana refugees”: desperate families with children who had the most severe, complex, treatment-refractory seizure disorders, said Dr. Brooks-Kayal, professor of pediatrics and neurology and chief of pediatric neurology at the University of Colorado at Denver, Aurora.

• Provide families with the current data, discuss what’s known and still unknown, and encourage families to disclose the use of cannabinoids so the child can be monitored.
• Have the family keep a seizure diary. Get a baseline EEG and another at about 12 weeks. Do routine laboratory monitoring every 4 weeks, including liver function tests. “We think CBDs [cannabinoids] have the potential to worsen liver function,” she said.
• Stress the importance of leaving other seizure medications unchanged. “When this first started, the medical marijuana providers were recommending patients stop their other medications. The providers don’t do that anymore, fortunately,” Dr. Brooks-Kayal said. “Every week we were putting a child in a medically induced coma because they had status epilepticus, and it was the only way to stop their seizures. They started using marijuana products, they were sure it was going to be the cure, they stopped all their other medications, and they developed status epilepticus.”
• Establish policies with the hospital administration and pharmacy about how to handle marijuana products when a child is in the hospital. The Children’s Hospital Colorado pharmacy cannot store or dispense marijuana products because of federal regulations. And again, it’s unsafe to stop seizure medications abruptly, including marijuana products. Informed consent procedures need to be developed for when patients on cannabinoids are hospitalized.
• Encourage families to participate in one of the six Food and Drug Administration–approved double-blind, placebo-controlled trials of Epidiolex for Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, and infantile spasms sponsored by GW Pharmaceuticals.

Breaking down the evidence

Here’s what’s known and what is still unknown about the safety and efficacy of cannabinoids for the treatment of refractory pediatric epilepsy, according to Dr. Brooks-Kayal.

The knowns

Cannabinoids show activity against seizures in animal models. Moreover, initial clinical data suggest they may decrease seizures in some children with refractory epilepsy. This evidence includes a retrospective study from Children’s Hospital Colorado reliant upon parental reports of improvement (Epilepsy Behav. 2015 Apr;45:49-52), an Israeli retrospective study (Seizure. 2016 Feb;35:41-4), a positive open-label trial of an investigational oral oil-based solution of a pharmaceutical-grade cannabidiol known as Epidiolex (Lancet Neurol. 2016 Mar;15[3]:270-8), and evidence from a Food and Drug Administration–authorized phase 3, randomized clinical trial of Epidiolex (N Engl J Med. 2017 May 25;376[21]:2011-20).

The incidence of short-term adverse events associated with cannabinoids is substantial. The rate seems to be higher with Epidiolex than with many other medical marijuana products, although the potency is greater, too. These include somnolence, fatigue, and convulsions.

In addition, gastrointestinal side effects are common with Epidiolex. “Some are probably due to the oil base; some [are] probably due to the cannabidiol itself,” said Dr. Brooks-Kayal.
 

The unknowns

What types of seizures does it work for? This is under study in a series of FDA-authorized phase 3 randomized trials.

What is the placebo-subtracted response rate to cannabidiol? In the randomized trial published in the New England Journal of Medicine, the median monthly frequency of seizures decreased from 12.4 to 5.9 with cannabidiol, compared with a reduction from 14.9 to 14.1 with placebo. This needs confirmation in additional trials.

What’s the optimal dose? The randomized trial tested just one dose – 20 mg/kg per day.

What are the drug interactions and their possible impact on cannabidiol efficacy? Outcomes appear to be better in patients on concomitant clobazam (Onfi), perhaps because of the significantly higher blood levels of clobazam’s major metabolite in children on cannabidiol.
 

Long-term effects

The jury is still out on the long-term adverse effects. “These medical marijuana products are being given by families to 2- and 3-month-olds. It will be years before we know about potential long-term cognitive and behavioral effects,” Dr. Brooks-Kayal said.

Dr. Brooks-Kayal reported having no financial conflicts of interest regarding her presentation.
 

[email protected]

Case Report

A 54-year-old woman presented with a painful pruritic rash on the hands and feet of 7 years’ duration. She reported intermittent joint pain but denied muscle weakness. Physical examination revealed fissured fingertips and heavy scaling of the palms and lateral fingers (Figure 1). Violaceous scaly papules were seen on the distal and proximal interphalangeal joints (Figure 2). A severe plantar keratoderma also was noted (Figure 3). Pink scaly plaques were present on the bilateral elbows and postauricular skin. Diffuse mat telangiectases covered the malar skin. Extensive poikilodermatous skin changes covered approximately 20% of the total body surface area. Salt-and-pepper patches and papules were noted over the bilateral thighs. She reported an uncertain history of recent radiographs of one or both hands, which showed no joint degeneration characteristic of psoriatic arthritis. She previously had been given a diagnosis of psoriasis by an outside dermatologist but was not responding to topical therapy.

Several skin biopsies showed histologic evidence of dermatomyositis (DM)(Figure 4). Prominent basement thickening also was seen on periodic acid–Schiff staining (not shown). Laboratory workup showed negative antinuclear antibodies and anti–Jo-1, anti-Ku, and anti-Mi2 antibodies. Muscle enzymes including creatinine kinase and aldolase were within reference range. Pelvic ultrasonography and mammography were negative. Pulmonary function tests were unremarkable. High-resolution chest computed tomography (CT) was ordered because of a history of chronic cough; however, no evidence of malignancy or interstitial lung disease was seen. The patient was diagnosed with amyopathic dermatomyositis (ADM). Rheumatology was consulted and initiated oral hydroxychloroquine therapy. After 3 months, the patient’s cutaneous disease did not respond and she reported having headaches associated with this medication; therefore, methotrexate was started. Within 2 months of treatment, full resolution of the plantar keratoderma (Figure 5) and clearance of the scaling/fissuring of the hands as well as the psoriatic-appearing plaques on the elbows was noted.

Comment

Amyopathic DM is a subset of DM that accounts for 10% to 20% of DM cases.^1,2 Sontheimer’s³ diagnostic criteria for ADM require histopathologic confirmation of the hallmark skin findings of classic DM and lack of muscle weakness or muscle enzyme (creatine kinase/aldolase) elevation for at least 2 years.

Similar to classic DM, ADM typically presents in the fifth decade of life and has a female predilection.^1,4 The term hypomyopathic DM is used to describe patients who exhibit classic skin findings and evidence of muscle involvement on magnetic resonance imaging, electromyography, biopsy, or serum enzymes but have no clinical evidence of muscle weakness for at least 6 months. Together, hypomyopathic DM and ADM are referred to as clinically ADM (CADM). Patients who have met the criteria for hypomyopathic DM or ADM may later develop frank myopathy, progressing to a diagnosis of CADM, which may occur in as many as 10% to 13% of cases of CADM.^1,2 Clinical evidence of muscle weakness typically is heralded by elevation of creatine kinase and aldolase; therefore, patients with ADM should have muscle enzymes periodically checked.

Cutaneous findings of ADM are the same as the hallmark skin findings in CADM.³ Poikiloderma appears as thin telangiectatic skin in a background of mottled hyperpigmentation and hypopigmentation. It represents chronic inflammation and often occurs in sun-exposed areas. Poikiloderma located on the posterior neck and shoulders is known as the shawl sign and on the lateral thighs as the holster sign.⁵ The term mechanic’s hands is used to describe the clinical finding of palmar erythema with scaling and fissuring of the fingertips.⁶ Scalp findings include erythematous, atrophic, scaly plaques resembling psoriasis and nonscarring alopecia.⁷ Gottron papules are nearly pathognomonic for DM. These violaceous papules often are pruritic and found over the finger joints, in contrast to the hand rash of lupus erythematosus that involves the skin between finger joints.⁸ Psoriatic-appearing plaques overlying the elbows and knees are known as Gottron sign and can contribute to misdiagnosis as psoriasis.⁸ The classic heliotrope rash presents as a violaceous hue in the periorbital area and may be associated with periorbital edema.⁹ Calcinosis cutis is common in CADM but rarely is reported in ADM.¹⁰ Nail findings include periungual hyperemia, cuticular overgrowth, and nail bed changes due to avascular areas and dilated capillaries. The cutaneous histopathologic findings in ADM are the same as with CADM: a smudged dermoepidermal interface, vacuolar alterations of the basal layer, and dermal mucin deposits.

Palmoplantar keratoderma rarely is reported as a cutaneous finding in DM. The finding of keratoderma has mainly been reported in association with Wong-type DM, a rare subtype of DM with features of pityriasis rubra pilaris.^11-13 Palmoplantar keratoderma also has been reported in a case of an ADM-like hydroxyurea-induced eruption¹⁴ and as an early presenting feature in one patient with CADM and one with juvenile DM.^15,16

The autoantibody profile in patients with ADM varies from that of CADM and can be helpful in both diagnosis and prognosis. Similar to CADM, the majority of patients with ADM have positive antinuclear antibodies.^2,17 Anti–Jo-1 (an anti–aminoacyl-transfer RNA synthetase) antibody frequently is found in CADM but rarely in ADM.² Anti–Jo-1 is predictive of interstitial lung disease (ILD) in CADM. Positive anti–Jo-1 in combination with Raynaud phenomenon and mechanic’s hands is referred to as antisynthetase syndrome in patients with CADM.^18,19 An antibody uniquely linked with CADM is the anti–CADM-140/MDA5 antibody and can be a marker of rapidly progressing ILD in these patients.²⁰ Anti–Mi-2 is another myositis-specific antibody not commonly found in ADM but is present in 15% to 30% of DM cases.^2,21 In CADM, the anti–Mi-2 antibody is associated with the shawl sign, ragged cuticles, and carpal tunnel syndrome and has a favorable prognosis.^17,21 Myositis-associated autoantibodies (eg, anti-Ku) are found in patients with symptoms overlapping both DM and scleroderma or other connective tissue diseases.²² More recently described, the anti-p155/140 antibody is highly specific (up to 89%) for occult malignancy in DM.²³

Lung disease is an important association in ADM. When it develops, it may be more aggressive compared to lung disease associated with CADM.^24-26 In a systematic review of 197 cases of ADM by Gerami et al,² 10% of patients had ILD, and it was fatal in 42% of cases. Most cases of ILD associated with CADM were diagnosed as interstitial pneumonitis or diffuse alveolar disease; bronchiolitis obliterans organizing pneumonia and basilar fibrosis also were recorded.² Anti–Jo-1 antibodies often accompany lung disease in CADM but are not typically found in lung disease associated with ADM. The anti–CADM-140/MDA5 antibody is associated with an increased risk for rapidly progressing ILD in patients with CADM.²⁰ Recommended baseline screening for lung disease in DM includes chest radiography, pulmonary function tests with diffusion capacity,⁸ and in some instances high-resolution chest CT.²⁷ Follow-up visits should include screening for symptoms of ILD such as cough, shortness of breath, or dyspnea. Treatment of myopathy-associated ILD is systemic steroids combined with various immunosuppressants including cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, and intravenous immunoglobulin.^28,29

The risk of malignancy in ADM is thought to be similar to the rate of 20% to 25% found in CADM.^1,30-32 The most commonly reported malignancies associated with ADM are nasopharyngeal, breast, lung, ovarian, colorectal, pancreatic, and stomach cancers and lymphoma/leukemia.^2,33 Patients with ADM should be screened for malignancy at diagnosis, then yearly for 3 years.^8,31,33 In addition to history, physical examination, and age/sex-appropriate screening, a complete blood cell count, chemistry panel, urinalysis, stool guaiac, CA 125, CA 19-9, chest radiograph, and abdominal ultrasound should be performed. For women, mammography and pelvic ultrasonography should be completed.³¹ Some experts also recommend a full-body CT scan. Because Asian patients have a higher risk for nasopharyngeal carcinoma, referral to an ear, nose, and throat surgeon for direct visualization also can be considered.³³ The risk of cancer in patients with DM compared to the general population is increased for at least the first 5 years after diagnosis, but most associated cancers are found within the first 3 years.³⁴

Several therapies have been found useful in ADM. Because lesions often are photoexacerbated, sun protection is essential. Antimalarials such as hydroxychloroquine are considered first-line therapy. Clinicians must be aware of 2 possible hydroxychloroquine side effects that can uniquely confuse the clinical picture in ADM. The first is a rash, most often morbilliform and pruritic, that occurs in DM more frequently than in other diseases.³⁵ The second is a myopathy found in as many as 6.7% of patients using antimalarials for rheumatic disease,³⁶ which can clinically mimic the progression of ADM to CADM.³⁷ Two small retrospective case series found that methotrexate was beneficial in ADM.^38,39 Methotrexate also has been reported as an efficacious treatment of ILD in patients with connective tissue diseases.^40,41 Intravenous immunoglobulin and other immunosuppressants are additional agents to be considered.⁴²

In summary, ADM is an important subset of DM and is more likely to present to dermatology practices than to other specialists. Amyopathic DM shares cutaneous findings with DM, and both overlap and differ with respect to other key disease characteristics including autoantibody profile, associated lung disease, and malignancy risk. Palmoplantar keratoderma is a rarely reported skin finding in DM. We report a case of ADM with the unique finding of severe plantar keratoderma. The fact that our patient’s keratoderma and other skin findings resolved concomitantly during methotrexate therapy leads us to believe that the keratoderma was a unique skin manifestation of the ADM itself.

Case Report

A 54-year-old woman presented with a painful pruritic rash on the hands and feet of 7 years’ duration. She reported intermittent joint pain but denied muscle weakness. Physical examination revealed fissured fingertips and heavy scaling of the palms and lateral fingers (Figure 1). Violaceous scaly papules were seen on the distal and proximal interphalangeal joints (Figure 2). A severe plantar keratoderma also was noted (Figure 3). Pink scaly plaques were present on the bilateral elbows and postauricular skin. Diffuse mat telangiectases covered the malar skin. Extensive poikilodermatous skin changes covered approximately 20% of the total body surface area. Salt-and-pepper patches and papules were noted over the bilateral thighs. She reported an uncertain history of recent radiographs of one or both hands, which showed no joint degeneration characteristic of psoriatic arthritis. She previously had been given a diagnosis of psoriasis by an outside dermatologist but was not responding to topical therapy.

Several skin biopsies showed histologic evidence of dermatomyositis (DM)(Figure 4). Prominent basement thickening also was seen on periodic acid–Schiff staining (not shown). Laboratory workup showed negative antinuclear antibodies and anti–Jo-1, anti-Ku, and anti-Mi2 antibodies. Muscle enzymes including creatinine kinase and aldolase were within reference range. Pelvic ultrasonography and mammography were negative. Pulmonary function tests were unremarkable. High-resolution chest computed tomography (CT) was ordered because of a history of chronic cough; however, no evidence of malignancy or interstitial lung disease was seen. The patient was diagnosed with amyopathic dermatomyositis (ADM). Rheumatology was consulted and initiated oral hydroxychloroquine therapy. After 3 months, the patient’s cutaneous disease did not respond and she reported having headaches associated with this medication; therefore, methotrexate was started. Within 2 months of treatment, full resolution of the plantar keratoderma (Figure 5) and clearance of the scaling/fissuring of the hands as well as the psoriatic-appearing plaques on the elbows was noted.

Comment

Amyopathic DM is a subset of DM that accounts for 10% to 20% of DM cases.^1,2 Sontheimer’s³ diagnostic criteria for ADM require histopathologic confirmation of the hallmark skin findings of classic DM and lack of muscle weakness or muscle enzyme (creatine kinase/aldolase) elevation for at least 2 years.

Similar to classic DM, ADM typically presents in the fifth decade of life and has a female predilection.^1,4 The term hypomyopathic DM is used to describe patients who exhibit classic skin findings and evidence of muscle involvement on magnetic resonance imaging, electromyography, biopsy, or serum enzymes but have no clinical evidence of muscle weakness for at least 6 months. Together, hypomyopathic DM and ADM are referred to as clinically ADM (CADM). Patients who have met the criteria for hypomyopathic DM or ADM may later develop frank myopathy, progressing to a diagnosis of CADM, which may occur in as many as 10% to 13% of cases of CADM.^1,2 Clinical evidence of muscle weakness typically is heralded by elevation of creatine kinase and aldolase; therefore, patients with ADM should have muscle enzymes periodically checked.

Cutaneous findings of ADM are the same as the hallmark skin findings in CADM.³ Poikiloderma appears as thin telangiectatic skin in a background of mottled hyperpigmentation and hypopigmentation. It represents chronic inflammation and often occurs in sun-exposed areas. Poikiloderma located on the posterior neck and shoulders is known as the shawl sign and on the lateral thighs as the holster sign.⁵ The term mechanic’s hands is used to describe the clinical finding of palmar erythema with scaling and fissuring of the fingertips.⁶ Scalp findings include erythematous, atrophic, scaly plaques resembling psoriasis and nonscarring alopecia.⁷ Gottron papules are nearly pathognomonic for DM. These violaceous papules often are pruritic and found over the finger joints, in contrast to the hand rash of lupus erythematosus that involves the skin between finger joints.⁸ Psoriatic-appearing plaques overlying the elbows and knees are known as Gottron sign and can contribute to misdiagnosis as psoriasis.⁸ The classic heliotrope rash presents as a violaceous hue in the periorbital area and may be associated with periorbital edema.⁹ Calcinosis cutis is common in CADM but rarely is reported in ADM.¹⁰ Nail findings include periungual hyperemia, cuticular overgrowth, and nail bed changes due to avascular areas and dilated capillaries. The cutaneous histopathologic findings in ADM are the same as with CADM: a smudged dermoepidermal interface, vacuolar alterations of the basal layer, and dermal mucin deposits.

Palmoplantar keratoderma rarely is reported as a cutaneous finding in DM. The finding of keratoderma has mainly been reported in association with Wong-type DM, a rare subtype of DM with features of pityriasis rubra pilaris.^11-13 Palmoplantar keratoderma also has been reported in a case of an ADM-like hydroxyurea-induced eruption¹⁴ and as an early presenting feature in one patient with CADM and one with juvenile DM.^15,16

The autoantibody profile in patients with ADM varies from that of CADM and can be helpful in both diagnosis and prognosis. Similar to CADM, the majority of patients with ADM have positive antinuclear antibodies.^2,17 Anti–Jo-1 (an anti–aminoacyl-transfer RNA synthetase) antibody frequently is found in CADM but rarely in ADM.² Anti–Jo-1 is predictive of interstitial lung disease (ILD) in CADM. Positive anti–Jo-1 in combination with Raynaud phenomenon and mechanic’s hands is referred to as antisynthetase syndrome in patients with CADM.^18,19 An antibody uniquely linked with CADM is the anti–CADM-140/MDA5 antibody and can be a marker of rapidly progressing ILD in these patients.²⁰ Anti–Mi-2 is another myositis-specific antibody not commonly found in ADM but is present in 15% to 30% of DM cases.^2,21 In CADM, the anti–Mi-2 antibody is associated with the shawl sign, ragged cuticles, and carpal tunnel syndrome and has a favorable prognosis.^17,21 Myositis-associated autoantibodies (eg, anti-Ku) are found in patients with symptoms overlapping both DM and scleroderma or other connective tissue diseases.²² More recently described, the anti-p155/140 antibody is highly specific (up to 89%) for occult malignancy in DM.²³

Lung disease is an important association in ADM. When it develops, it may be more aggressive compared to lung disease associated with CADM.^24-26 In a systematic review of 197 cases of ADM by Gerami et al,² 10% of patients had ILD, and it was fatal in 42% of cases. Most cases of ILD associated with CADM were diagnosed as interstitial pneumonitis or diffuse alveolar disease; bronchiolitis obliterans organizing pneumonia and basilar fibrosis also were recorded.² Anti–Jo-1 antibodies often accompany lung disease in CADM but are not typically found in lung disease associated with ADM. The anti–CADM-140/MDA5 antibody is associated with an increased risk for rapidly progressing ILD in patients with CADM.²⁰ Recommended baseline screening for lung disease in DM includes chest radiography, pulmonary function tests with diffusion capacity,⁸ and in some instances high-resolution chest CT.²⁷ Follow-up visits should include screening for symptoms of ILD such as cough, shortness of breath, or dyspnea. Treatment of myopathy-associated ILD is systemic steroids combined with various immunosuppressants including cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, and intravenous immunoglobulin.^28,29

The risk of malignancy in ADM is thought to be similar to the rate of 20% to 25% found in CADM.^1,30-32 The most commonly reported malignancies associated with ADM are nasopharyngeal, breast, lung, ovarian, colorectal, pancreatic, and stomach cancers and lymphoma/leukemia.^2,33 Patients with ADM should be screened for malignancy at diagnosis, then yearly for 3 years.^8,31,33 In addition to history, physical examination, and age/sex-appropriate screening, a complete blood cell count, chemistry panel, urinalysis, stool guaiac, CA 125, CA 19-9, chest radiograph, and abdominal ultrasound should be performed. For women, mammography and pelvic ultrasonography should be completed.³¹ Some experts also recommend a full-body CT scan. Because Asian patients have a higher risk for nasopharyngeal carcinoma, referral to an ear, nose, and throat surgeon for direct visualization also can be considered.³³ The risk of cancer in patients with DM compared to the general population is increased for at least the first 5 years after diagnosis, but most associated cancers are found within the first 3 years.³⁴

Several therapies have been found useful in ADM. Because lesions often are photoexacerbated, sun protection is essential. Antimalarials such as hydroxychloroquine are considered first-line therapy. Clinicians must be aware of 2 possible hydroxychloroquine side effects that can uniquely confuse the clinical picture in ADM. The first is a rash, most often morbilliform and pruritic, that occurs in DM more frequently than in other diseases.³⁵ The second is a myopathy found in as many as 6.7% of patients using antimalarials for rheumatic disease,³⁶ which can clinically mimic the progression of ADM to CADM.³⁷ Two small retrospective case series found that methotrexate was beneficial in ADM.^38,39 Methotrexate also has been reported as an efficacious treatment of ILD in patients with connective tissue diseases.^40,41 Intravenous immunoglobulin and other immunosuppressants are additional agents to be considered.⁴²

In summary, ADM is an important subset of DM and is more likely to present to dermatology practices than to other specialists. Amyopathic DM shares cutaneous findings with DM, and both overlap and differ with respect to other key disease characteristics including autoantibody profile, associated lung disease, and malignancy risk. Palmoplantar keratoderma is a rarely reported skin finding in DM. We report a case of ADM with the unique finding of severe plantar keratoderma. The fact that our patient’s keratoderma and other skin findings resolved concomitantly during methotrexate therapy leads us to believe that the keratoderma was a unique skin manifestation of the ADM itself.

Case Report

A 54-year-old woman presented with a painful pruritic rash on the hands and feet of 7 years’ duration. She reported intermittent joint pain but denied muscle weakness. Physical examination revealed fissured fingertips and heavy scaling of the palms and lateral fingers (Figure 1). Violaceous scaly papules were seen on the distal and proximal interphalangeal joints (Figure 2). A severe plantar keratoderma also was noted (Figure 3). Pink scaly plaques were present on the bilateral elbows and postauricular skin. Diffuse mat telangiectases covered the malar skin. Extensive poikilodermatous skin changes covered approximately 20% of the total body surface area. Salt-and-pepper patches and papules were noted over the bilateral thighs. She reported an uncertain history of recent radiographs of one or both hands, which showed no joint degeneration characteristic of psoriatic arthritis. She previously had been given a diagnosis of psoriasis by an outside dermatologist but was not responding to topical therapy.

Several skin biopsies showed histologic evidence of dermatomyositis (DM)(Figure 4). Prominent basement thickening also was seen on periodic acid–Schiff staining (not shown). Laboratory workup showed negative antinuclear antibodies and anti–Jo-1, anti-Ku, and anti-Mi2 antibodies. Muscle enzymes including creatinine kinase and aldolase were within reference range. Pelvic ultrasonography and mammography were negative. Pulmonary function tests were unremarkable. High-resolution chest computed tomography (CT) was ordered because of a history of chronic cough; however, no evidence of malignancy or interstitial lung disease was seen. The patient was diagnosed with amyopathic dermatomyositis (ADM). Rheumatology was consulted and initiated oral hydroxychloroquine therapy. After 3 months, the patient’s cutaneous disease did not respond and she reported having headaches associated with this medication; therefore, methotrexate was started. Within 2 months of treatment, full resolution of the plantar keratoderma (Figure 5) and clearance of the scaling/fissuring of the hands as well as the psoriatic-appearing plaques on the elbows was noted.

Comment

Amyopathic DM is a subset of DM that accounts for 10% to 20% of DM cases.^1,2 Sontheimer’s³ diagnostic criteria for ADM require histopathologic confirmation of the hallmark skin findings of classic DM and lack of muscle weakness or muscle enzyme (creatine kinase/aldolase) elevation for at least 2 years.

Similar to classic DM, ADM typically presents in the fifth decade of life and has a female predilection.^1,4 The term hypomyopathic DM is used to describe patients who exhibit classic skin findings and evidence of muscle involvement on magnetic resonance imaging, electromyography, biopsy, or serum enzymes but have no clinical evidence of muscle weakness for at least 6 months. Together, hypomyopathic DM and ADM are referred to as clinically ADM (CADM). Patients who have met the criteria for hypomyopathic DM or ADM may later develop frank myopathy, progressing to a diagnosis of CADM, which may occur in as many as 10% to 13% of cases of CADM.^1,2 Clinical evidence of muscle weakness typically is heralded by elevation of creatine kinase and aldolase; therefore, patients with ADM should have muscle enzymes periodically checked.

Cutaneous findings of ADM are the same as the hallmark skin findings in CADM.³ Poikiloderma appears as thin telangiectatic skin in a background of mottled hyperpigmentation and hypopigmentation. It represents chronic inflammation and often occurs in sun-exposed areas. Poikiloderma located on the posterior neck and shoulders is known as the shawl sign and on the lateral thighs as the holster sign.⁵ The term mechanic’s hands is used to describe the clinical finding of palmar erythema with scaling and fissuring of the fingertips.⁶ Scalp findings include erythematous, atrophic, scaly plaques resembling psoriasis and nonscarring alopecia.⁷ Gottron papules are nearly pathognomonic for DM. These violaceous papules often are pruritic and found over the finger joints, in contrast to the hand rash of lupus erythematosus that involves the skin between finger joints.⁸ Psoriatic-appearing plaques overlying the elbows and knees are known as Gottron sign and can contribute to misdiagnosis as psoriasis.⁸ The classic heliotrope rash presents as a violaceous hue in the periorbital area and may be associated with periorbital edema.⁹ Calcinosis cutis is common in CADM but rarely is reported in ADM.¹⁰ Nail findings include periungual hyperemia, cuticular overgrowth, and nail bed changes due to avascular areas and dilated capillaries. The cutaneous histopathologic findings in ADM are the same as with CADM: a smudged dermoepidermal interface, vacuolar alterations of the basal layer, and dermal mucin deposits.

Palmoplantar keratoderma rarely is reported as a cutaneous finding in DM. The finding of keratoderma has mainly been reported in association with Wong-type DM, a rare subtype of DM with features of pityriasis rubra pilaris.^11-13 Palmoplantar keratoderma also has been reported in a case of an ADM-like hydroxyurea-induced eruption¹⁴ and as an early presenting feature in one patient with CADM and one with juvenile DM.^15,16

The autoantibody profile in patients with ADM varies from that of CADM and can be helpful in both diagnosis and prognosis. Similar to CADM, the majority of patients with ADM have positive antinuclear antibodies.^2,17 Anti–Jo-1 (an anti–aminoacyl-transfer RNA synthetase) antibody frequently is found in CADM but rarely in ADM.² Anti–Jo-1 is predictive of interstitial lung disease (ILD) in CADM. Positive anti–Jo-1 in combination with Raynaud phenomenon and mechanic’s hands is referred to as antisynthetase syndrome in patients with CADM.^18,19 An antibody uniquely linked with CADM is the anti–CADM-140/MDA5 antibody and can be a marker of rapidly progressing ILD in these patients.²⁰ Anti–Mi-2 is another myositis-specific antibody not commonly found in ADM but is present in 15% to 30% of DM cases.^2,21 In CADM, the anti–Mi-2 antibody is associated with the shawl sign, ragged cuticles, and carpal tunnel syndrome and has a favorable prognosis.^17,21 Myositis-associated autoantibodies (eg, anti-Ku) are found in patients with symptoms overlapping both DM and scleroderma or other connective tissue diseases.²² More recently described, the anti-p155/140 antibody is highly specific (up to 89%) for occult malignancy in DM.²³

Lung disease is an important association in ADM. When it develops, it may be more aggressive compared to lung disease associated with CADM.^24-26 In a systematic review of 197 cases of ADM by Gerami et al,² 10% of patients had ILD, and it was fatal in 42% of cases. Most cases of ILD associated with CADM were diagnosed as interstitial pneumonitis or diffuse alveolar disease; bronchiolitis obliterans organizing pneumonia and basilar fibrosis also were recorded.² Anti–Jo-1 antibodies often accompany lung disease in CADM but are not typically found in lung disease associated with ADM. The anti–CADM-140/MDA5 antibody is associated with an increased risk for rapidly progressing ILD in patients with CADM.²⁰ Recommended baseline screening for lung disease in DM includes chest radiography, pulmonary function tests with diffusion capacity,⁸ and in some instances high-resolution chest CT.²⁷ Follow-up visits should include screening for symptoms of ILD such as cough, shortness of breath, or dyspnea. Treatment of myopathy-associated ILD is systemic steroids combined with various immunosuppressants including cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, and intravenous immunoglobulin.^28,29

The risk of malignancy in ADM is thought to be similar to the rate of 20% to 25% found in CADM.^1,30-32 The most commonly reported malignancies associated with ADM are nasopharyngeal, breast, lung, ovarian, colorectal, pancreatic, and stomach cancers and lymphoma/leukemia.^2,33 Patients with ADM should be screened for malignancy at diagnosis, then yearly for 3 years.^8,31,33 In addition to history, physical examination, and age/sex-appropriate screening, a complete blood cell count, chemistry panel, urinalysis, stool guaiac, CA 125, CA 19-9, chest radiograph, and abdominal ultrasound should be performed. For women, mammography and pelvic ultrasonography should be completed.³¹ Some experts also recommend a full-body CT scan. Because Asian patients have a higher risk for nasopharyngeal carcinoma, referral to an ear, nose, and throat surgeon for direct visualization also can be considered.³³ The risk of cancer in patients with DM compared to the general population is increased for at least the first 5 years after diagnosis, but most associated cancers are found within the first 3 years.³⁴

Several therapies have been found useful in ADM. Because lesions often are photoexacerbated, sun protection is essential. Antimalarials such as hydroxychloroquine are considered first-line therapy. Clinicians must be aware of 2 possible hydroxychloroquine side effects that can uniquely confuse the clinical picture in ADM. The first is a rash, most often morbilliform and pruritic, that occurs in DM more frequently than in other diseases.³⁵ The second is a myopathy found in as many as 6.7% of patients using antimalarials for rheumatic disease,³⁶ which can clinically mimic the progression of ADM to CADM.³⁷ Two small retrospective case series found that methotrexate was beneficial in ADM.^38,39 Methotrexate also has been reported as an efficacious treatment of ILD in patients with connective tissue diseases.^40,41 Intravenous immunoglobulin and other immunosuppressants are additional agents to be considered.⁴²

In summary, ADM is an important subset of DM and is more likely to present to dermatology practices than to other specialists. Amyopathic DM shares cutaneous findings with DM, and both overlap and differ with respect to other key disease characteristics including autoantibody profile, associated lung disease, and malignancy risk. Palmoplantar keratoderma is a rarely reported skin finding in DM. We report a case of ADM with the unique finding of severe plantar keratoderma. The fact that our patient’s keratoderma and other skin findings resolved concomitantly during methotrexate therapy leads us to believe that the keratoderma was a unique skin manifestation of the ADM itself.

Traumatic ulcerative granuloma with stromal eosinophilia (TUGSE) is an uncommon, benign, self-limited condition that is restricted to the oral mucosa, most commonly seen in the fifth to seventh decades of life.^1-3 The pathogenesis of TUGSE is unknown, but current theory suggests trauma is the instigating factor. The presence of CD30⁺ mononuclear cells within TUGSE raises the possibility of a CD30⁺ lymphoproliferative disorder in some cases.⁴ However, because CD30⁺ cells are not uncommon in other benign reactive processes, they may simply represent a reactive phenomenon.³

Traumatic ulcerative granuloma with stromal eosinophilia traverses multiple disciplines, including dermatology, oral surgery, dentistry, and pathology, resulting in a diverse nomenclature including traumatic granuloma of the tongue, traumatic eosinophilic granuloma of the oral mucosa, ulcerated granuloma eosinophilicum diutinum, and eosinophilic ulcer of the oral mucosa.^1,4-6 It is important to differentiate eosinophilic granuloma of the oral mucosa from the eosinophilic granuloma that is associated with Langerhans cell histiocytosis. Although both may present with oral ulceration, Langerhans cell–associated eosinophilic granuloma typically develops from underlying bone, whereas eosinophilic granuloma of the oral mucosa (TUGSE) is described as nonosseous.^7,8 Furthermore, the gingiva is the most common oral site in Langerhans cell–associated eosinophilic granuloma, whereas the tongue is most commonly involved in TUGSE.⁸ Shapiro and Juhlin⁹ clearly distinguished TUGSE from Langerhans cell–associated eosinophilic granuloma in 1970. Histologically, the 2 conditions are completely different.

When ulcerative granulomas develop in the pediatric population, usually in children younger than 2 years, it is termed Riga-Fede disease.¹⁰ These children were typically breastfeeding, suckling, or teething, suggesting trauma as a triggering event. In 1961, Hjorting-Hansen and Schmidt⁵ described 3 separate lesions similar to Riga-Fede disease in an adult patient. Subsequently, Riga-Fede disease was grouped under TUGSE.³

Histologically, TUGSE shows an ulcerated epithelium with a polymorphic inflammatory cell infiltrate that has a large predominance of eosinophils. The infiltrate affects the superficial and deep layers of the muscle tissue and penetrates into the salivary glands. Large atypical mononuclear cells with an ovoid and pale-appearing nucleus often are present. These cells may be mitotically active and stain positively for CD30.^1,4,11 CD68⁺ macrophages, T lymphocytes, and factor XIIIa–positive dendritic cells commonly are present.¹²

Given the presence of large atypical CD30⁺ cells in many lesions, the possibility of a CD30⁺ lymphoproliferative disorder has been postulated by some authors. Indeed, lymphomatoid papulosis (LyP) has been documented to involve the oral mucosa.^2,4

Case Report

An 81-year-old man presented with a rapidly enlarging, 1.7×1.3-cm, vascular-appearing nodule with a collarette of mucosal epithelium on the left side of the dorsal surface of the tongue of 2 weeks’ duration (Figure 1). He denied any history of trauma, tobacco chewing, weight change, fever, or fatigue; however, he did report a 30 pack-year smoking history. There was no other pertinent medical history to include medications or allergies.

The differential diagnosis included pyogenic granuloma, granular cell tumor, squamous cell carcinoma, other neoplasms (eg, oral lymphoma, salivary gland tumors), and a traumatic blood blister from tongue biting. The patient was referred to the oral maxillofacial surgery department for an excisional biopsy, which showed a solitary ulcerated nodule with associated granulation tissue, thrombus, and fibrinoid debris (Figure 2). A surrounding dense mixed inflammatory cell infiltrate composed of lymphocytes, histiocytes, and numerous eosinophils was noted extending through the submucosal tissue and underlying striated muscle fibers (Figure 3). The adjacent mucosal epithelium appeared normal. CD30 staining showed only rare positive cells. These findings were consistent with TUGSE.

Due to the benign nature of TUGSE, the patient was released with symptomatic care and instructed to return for any new growth. The growth spontaneously resolved over 1 month and no recurrence or new lesions were reported 1 year later.

Comment

Despite encompassing multiple disciplines of medicine, TUGSE has minimal exposure in the dermatologic literature. It is an important clinical and histologic diagnosis that will provide reassurance to the patient when accurately identified and reduce potentially harmful treatments.

Clinical Presentation
Typically, TUGSE presents as a painful solitary nodule with a central ulcer and yellow fibrinous base. The margins of the ulcer typically have an indurated and rolled appearance.^1,4 More than 50% of the lesions develop on the tongue, specifically the dorsal or lateral surfaces, but they may present anywhere in the oral mucosa.⁷ Traumatic ulcerative granuloma with stromal eosinophilia is a fast-growing lesion, typically developing in days to weeks. Although it spontaneously regresses, the lesion may take weeks or months to resolve. In one case, it resolved 1 year later.¹ Traumatic ulcerative granuloma with stromal eosinophilia has a bimodal age distribution, generally appearing in the first 2 years of life and later in the fifth through seventh decades. The male-to-female predominance is equal.^1,7,11 Reoccurrence is rare, but some reports have shown patients with multiple episodes of TUGSE.^13,14

Differential Diagnosis
The clinical differential diagnosis for TUGSE includes squamous cell carcinoma, pyogenic granuloma, lymphoproliferative disorder, traumatic neuroma, Langerhans cell histiocytosis, granulomatous disorders, and oral lymphoma. Inflammatory disorders such as syphilis, Behçet’s disease, herpes, histoplasmosis, Wegener granulomatosis, and others also should be considered.

Immunohistochemistry
Immunohistochemical analysis of TUGSE lesions recently has revealed the presence of CD30⁺ cells. These cells are associated with cutaneous lymphoproliferative disorders including LyP, anaplastic large cell lymphoma (ALCL), and borderline CD30⁺ lesions, among others. Systemic diseases with CD30⁺ cells include mycosis fungoides, other T-cell lymphomas, and Hodgkin lymphoma.^15,16 Once CD30⁺ cells were recognized, multiple authors began speculating there was a correlation between TUGSE and the CD30⁺ lymphoproliferative disorders.^1,2,13 Anaplastic large cell lymphoma and LyP of the oral mucosa have been reported in several cases.^17-20 One report described 2 cases of ulcerated CD30⁺ T-cell non-Hodgkin lymphoma of the oral mucosa, one of which showed eosinophilic infiltrates and was initially thought to be TUGSE. Based on these overlapping clinical and histologic features, the authors hypothesized there was a correlation between oral ALCL, LyP, and TUGSE.¹⁷ In one report, a patient developed multiple TUGSE lesions throughout his life, suggesting a pathologic process similar to LyP. The lesion biopsied showed that 70% of the T cells expressed CD30 (Ki-1) antigen.¹³

Underlying Causes
In support of an underlying immunologic process that augments the growth of these lesions, 2 separate case reports of TUGSE in the presence of human T-lymphotropic virus 1 (HTLV-1) and Epstein-Barr virus have been documented.^2,21 Concurrent presentation of TUGSE and HTLV-1 in one report demonstrated eosinophilia in both the oral lesion and peripheral blood, suggesting an immunologic relationship. Furthermore, the authors postulated that local trauma initiated the development of TUGSE, providing the catalyst for the HTLV-1 carrier to develop peripheral eosinophilia.²¹

In the second case, a 12-year-old boy developed TUGSE in the presence of Epstein-Barr virus.² Immunologically, this virus can be reactivated from its latent stage during immunosuppression. Epstein-Barr virus has been implicated in lymphoproliferative diseases of both B- and T-cell origin, including CD30⁺ ALCL and LyP.^22,23 The authors in this report again hypothesized there was a correlation between lymphoproliferative disorders and TUGSE lesions.^2,24

Alternatively, TUGSE may simply be a reactive process to trauma or another underlying trigger. It has been speculated that the presence of eosinophils correlates with antigen insertion into the oral mucosa, whereas other ulcers of the oral mucosa are devoid of eosinophils.¹ These antigens may include microorganisms, endogenous degradation products, or foreign proteins.^7,25 Additionally, the presence of CD30⁺ lymphocytes is not isolated to lymphoproliferative disorders. CD30⁺ cells have been documented in arthropod bite reactions, atopic dermatitis, drug reactions, molluscum contagiosum, and scabies, among others.^1,26

Healing and Management
The length of healing in TUGSE ulcers has substantial variability, from days to up to 1 year in an isolated case.^1,24 Sequential expression of transforming growth factor (TGF) α and TGF-β expressed by tissue eosinophils may be underlying factors associated with a quicker healing response as demonstrated by similar ulcers in hamsters.²⁷ Chronic nonhealing oral ulcers, particularly TUGSE lesions that demonstrated the typical increase in eosinophils in 11 of 12 cases, showed minimal TGF-α or TGF-β expression by eosinophils, perhaps indicating a possible mechanism leading to delayed wound healing in some cases. Interestingly, incisional biopsies often led to rapid wound healing, suggesting that the biopsy itself allowed for a transition back to the regular wound-healing processes.²⁸

Traumatic ulcerative granuloma with stromal eosinophilia spontaneously resolves on its own in most cases; however, because of the concern for malignancy, it has the potential to be overtreated.²⁶ Symptomatic treatment only is the mainstay of therapy. The patient should be instructed to avoid trauma, and referral to a dental professional is indicated when associated with dentures or other periprosthetic devices. Diet should consist of soft foods while avoiding spicy foods. Topical or oral analgesics may be necessary if substantial pain is associated with the lesion.² Oral prednisolone was used in a patient with concurrent HTLV-1 and TUGSE to treat peripheral eosinophilia.²¹ The patient’s peripheral eosinophils dropped to 1% in 1 day, and the patient’s oral lesion began to improve at day 3 and disappeared by day 10. Although TUGSE may spontaneously resolve within a 10-day period without steroids, it may be a reasonable treatment to improve healing time in an otherwise healthy individual.^21,26 If there is concern for malignancy, the patient should have the lesion biopsied to provide reassurance and for the added benefit of a transition to normal healing response and decreased healing time.²⁸

Clinical Recognition
The clinician should be aware of the possibility of a CD30⁺ lymphoproliferative disorder, which has been associated with TUGSE in some cases, or may simulate TUGSE both clinically and histologically. Further studies are needed to clarify the relationship between these 2 entities. Whether it is a true relationship, simple coincidence, or simply overlapping clinical and histologic features remains to be determined.

Traumatic ulcerative granuloma with stromal eosinophilia (TUGSE) is an uncommon, benign, self-limited condition that is restricted to the oral mucosa, most commonly seen in the fifth to seventh decades of life.^1-3 The pathogenesis of TUGSE is unknown, but current theory suggests trauma is the instigating factor. The presence of CD30⁺ mononuclear cells within TUGSE raises the possibility of a CD30⁺ lymphoproliferative disorder in some cases.⁴ However, because CD30⁺ cells are not uncommon in other benign reactive processes, they may simply represent a reactive phenomenon.³

Traumatic ulcerative granuloma with stromal eosinophilia traverses multiple disciplines, including dermatology, oral surgery, dentistry, and pathology, resulting in a diverse nomenclature including traumatic granuloma of the tongue, traumatic eosinophilic granuloma of the oral mucosa, ulcerated granuloma eosinophilicum diutinum, and eosinophilic ulcer of the oral mucosa.^1,4-6 It is important to differentiate eosinophilic granuloma of the oral mucosa from the eosinophilic granuloma that is associated with Langerhans cell histiocytosis. Although both may present with oral ulceration, Langerhans cell–associated eosinophilic granuloma typically develops from underlying bone, whereas eosinophilic granuloma of the oral mucosa (TUGSE) is described as nonosseous.^7,8 Furthermore, the gingiva is the most common oral site in Langerhans cell–associated eosinophilic granuloma, whereas the tongue is most commonly involved in TUGSE.⁸ Shapiro and Juhlin⁹ clearly distinguished TUGSE from Langerhans cell–associated eosinophilic granuloma in 1970. Histologically, the 2 conditions are completely different.

When ulcerative granulomas develop in the pediatric population, usually in children younger than 2 years, it is termed Riga-Fede disease.¹⁰ These children were typically breastfeeding, suckling, or teething, suggesting trauma as a triggering event. In 1961, Hjorting-Hansen and Schmidt⁵ described 3 separate lesions similar to Riga-Fede disease in an adult patient. Subsequently, Riga-Fede disease was grouped under TUGSE.³

Histologically, TUGSE shows an ulcerated epithelium with a polymorphic inflammatory cell infiltrate that has a large predominance of eosinophils. The infiltrate affects the superficial and deep layers of the muscle tissue and penetrates into the salivary glands. Large atypical mononuclear cells with an ovoid and pale-appearing nucleus often are present. These cells may be mitotically active and stain positively for CD30.^1,4,11 CD68⁺ macrophages, T lymphocytes, and factor XIIIa–positive dendritic cells commonly are present.¹²

Given the presence of large atypical CD30⁺ cells in many lesions, the possibility of a CD30⁺ lymphoproliferative disorder has been postulated by some authors. Indeed, lymphomatoid papulosis (LyP) has been documented to involve the oral mucosa.^2,4

Case Report

An 81-year-old man presented with a rapidly enlarging, 1.7×1.3-cm, vascular-appearing nodule with a collarette of mucosal epithelium on the left side of the dorsal surface of the tongue of 2 weeks’ duration (Figure 1). He denied any history of trauma, tobacco chewing, weight change, fever, or fatigue; however, he did report a 30 pack-year smoking history. There was no other pertinent medical history to include medications or allergies.

The differential diagnosis included pyogenic granuloma, granular cell tumor, squamous cell carcinoma, other neoplasms (eg, oral lymphoma, salivary gland tumors), and a traumatic blood blister from tongue biting. The patient was referred to the oral maxillofacial surgery department for an excisional biopsy, which showed a solitary ulcerated nodule with associated granulation tissue, thrombus, and fibrinoid debris (Figure 2). A surrounding dense mixed inflammatory cell infiltrate composed of lymphocytes, histiocytes, and numerous eosinophils was noted extending through the submucosal tissue and underlying striated muscle fibers (Figure 3). The adjacent mucosal epithelium appeared normal. CD30 staining showed only rare positive cells. These findings were consistent with TUGSE.

Due to the benign nature of TUGSE, the patient was released with symptomatic care and instructed to return for any new growth. The growth spontaneously resolved over 1 month and no recurrence or new lesions were reported 1 year later.

Comment

Despite encompassing multiple disciplines of medicine, TUGSE has minimal exposure in the dermatologic literature. It is an important clinical and histologic diagnosis that will provide reassurance to the patient when accurately identified and reduce potentially harmful treatments.

Clinical Presentation
Typically, TUGSE presents as a painful solitary nodule with a central ulcer and yellow fibrinous base. The margins of the ulcer typically have an indurated and rolled appearance.^1,4 More than 50% of the lesions develop on the tongue, specifically the dorsal or lateral surfaces, but they may present anywhere in the oral mucosa.⁷ Traumatic ulcerative granuloma with stromal eosinophilia is a fast-growing lesion, typically developing in days to weeks. Although it spontaneously regresses, the lesion may take weeks or months to resolve. In one case, it resolved 1 year later.¹ Traumatic ulcerative granuloma with stromal eosinophilia has a bimodal age distribution, generally appearing in the first 2 years of life and later in the fifth through seventh decades. The male-to-female predominance is equal.^1,7,11 Reoccurrence is rare, but some reports have shown patients with multiple episodes of TUGSE.^13,14

Differential Diagnosis
The clinical differential diagnosis for TUGSE includes squamous cell carcinoma, pyogenic granuloma, lymphoproliferative disorder, traumatic neuroma, Langerhans cell histiocytosis, granulomatous disorders, and oral lymphoma. Inflammatory disorders such as syphilis, Behçet’s disease, herpes, histoplasmosis, Wegener granulomatosis, and others also should be considered.

Immunohistochemistry
Immunohistochemical analysis of TUGSE lesions recently has revealed the presence of CD30⁺ cells. These cells are associated with cutaneous lymphoproliferative disorders including LyP, anaplastic large cell lymphoma (ALCL), and borderline CD30⁺ lesions, among others. Systemic diseases with CD30⁺ cells include mycosis fungoides, other T-cell lymphomas, and Hodgkin lymphoma.^15,16 Once CD30⁺ cells were recognized, multiple authors began speculating there was a correlation between TUGSE and the CD30⁺ lymphoproliferative disorders.^1,2,13 Anaplastic large cell lymphoma and LyP of the oral mucosa have been reported in several cases.^17-20 One report described 2 cases of ulcerated CD30⁺ T-cell non-Hodgkin lymphoma of the oral mucosa, one of which showed eosinophilic infiltrates and was initially thought to be TUGSE. Based on these overlapping clinical and histologic features, the authors hypothesized there was a correlation between oral ALCL, LyP, and TUGSE.¹⁷ In one report, a patient developed multiple TUGSE lesions throughout his life, suggesting a pathologic process similar to LyP. The lesion biopsied showed that 70% of the T cells expressed CD30 (Ki-1) antigen.¹³

Underlying Causes
In support of an underlying immunologic process that augments the growth of these lesions, 2 separate case reports of TUGSE in the presence of human T-lymphotropic virus 1 (HTLV-1) and Epstein-Barr virus have been documented.^2,21 Concurrent presentation of TUGSE and HTLV-1 in one report demonstrated eosinophilia in both the oral lesion and peripheral blood, suggesting an immunologic relationship. Furthermore, the authors postulated that local trauma initiated the development of TUGSE, providing the catalyst for the HTLV-1 carrier to develop peripheral eosinophilia.²¹

In the second case, a 12-year-old boy developed TUGSE in the presence of Epstein-Barr virus.² Immunologically, this virus can be reactivated from its latent stage during immunosuppression. Epstein-Barr virus has been implicated in lymphoproliferative diseases of both B- and T-cell origin, including CD30⁺ ALCL and LyP.^22,23 The authors in this report again hypothesized there was a correlation between lymphoproliferative disorders and TUGSE lesions.^2,24

Alternatively, TUGSE may simply be a reactive process to trauma or another underlying trigger. It has been speculated that the presence of eosinophils correlates with antigen insertion into the oral mucosa, whereas other ulcers of the oral mucosa are devoid of eosinophils.¹ These antigens may include microorganisms, endogenous degradation products, or foreign proteins.^7,25 Additionally, the presence of CD30⁺ lymphocytes is not isolated to lymphoproliferative disorders. CD30⁺ cells have been documented in arthropod bite reactions, atopic dermatitis, drug reactions, molluscum contagiosum, and scabies, among others.^1,26

Healing and Management
The length of healing in TUGSE ulcers has substantial variability, from days to up to 1 year in an isolated case.^1,24 Sequential expression of transforming growth factor (TGF) α and TGF-β expressed by tissue eosinophils may be underlying factors associated with a quicker healing response as demonstrated by similar ulcers in hamsters.²⁷ Chronic nonhealing oral ulcers, particularly TUGSE lesions that demonstrated the typical increase in eosinophils in 11 of 12 cases, showed minimal TGF-α or TGF-β expression by eosinophils, perhaps indicating a possible mechanism leading to delayed wound healing in some cases. Interestingly, incisional biopsies often led to rapid wound healing, suggesting that the biopsy itself allowed for a transition back to the regular wound-healing processes.²⁸

Traumatic ulcerative granuloma with stromal eosinophilia spontaneously resolves on its own in most cases; however, because of the concern for malignancy, it has the potential to be overtreated.²⁶ Symptomatic treatment only is the mainstay of therapy. The patient should be instructed to avoid trauma, and referral to a dental professional is indicated when associated with dentures or other periprosthetic devices. Diet should consist of soft foods while avoiding spicy foods. Topical or oral analgesics may be necessary if substantial pain is associated with the lesion.² Oral prednisolone was used in a patient with concurrent HTLV-1 and TUGSE to treat peripheral eosinophilia.²¹ The patient’s peripheral eosinophils dropped to 1% in 1 day, and the patient’s oral lesion began to improve at day 3 and disappeared by day 10. Although TUGSE may spontaneously resolve within a 10-day period without steroids, it may be a reasonable treatment to improve healing time in an otherwise healthy individual.^21,26 If there is concern for malignancy, the patient should have the lesion biopsied to provide reassurance and for the added benefit of a transition to normal healing response and decreased healing time.²⁸

Clinical Recognition
The clinician should be aware of the possibility of a CD30⁺ lymphoproliferative disorder, which has been associated with TUGSE in some cases, or may simulate TUGSE both clinically and histologically. Further studies are needed to clarify the relationship between these 2 entities. Whether it is a true relationship, simple coincidence, or simply overlapping clinical and histologic features remains to be determined.

Traumatic ulcerative granuloma with stromal eosinophilia (TUGSE) is an uncommon, benign, self-limited condition that is restricted to the oral mucosa, most commonly seen in the fifth to seventh decades of life.^1-3 The pathogenesis of TUGSE is unknown, but current theory suggests trauma is the instigating factor. The presence of CD30⁺ mononuclear cells within TUGSE raises the possibility of a CD30⁺ lymphoproliferative disorder in some cases.⁴ However, because CD30⁺ cells are not uncommon in other benign reactive processes, they may simply represent a reactive phenomenon.³

Traumatic ulcerative granuloma with stromal eosinophilia traverses multiple disciplines, including dermatology, oral surgery, dentistry, and pathology, resulting in a diverse nomenclature including traumatic granuloma of the tongue, traumatic eosinophilic granuloma of the oral mucosa, ulcerated granuloma eosinophilicum diutinum, and eosinophilic ulcer of the oral mucosa.^1,4-6 It is important to differentiate eosinophilic granuloma of the oral mucosa from the eosinophilic granuloma that is associated with Langerhans cell histiocytosis. Although both may present with oral ulceration, Langerhans cell–associated eosinophilic granuloma typically develops from underlying bone, whereas eosinophilic granuloma of the oral mucosa (TUGSE) is described as nonosseous.^7,8 Furthermore, the gingiva is the most common oral site in Langerhans cell–associated eosinophilic granuloma, whereas the tongue is most commonly involved in TUGSE.⁸ Shapiro and Juhlin⁹ clearly distinguished TUGSE from Langerhans cell–associated eosinophilic granuloma in 1970. Histologically, the 2 conditions are completely different.

When ulcerative granulomas develop in the pediatric population, usually in children younger than 2 years, it is termed Riga-Fede disease.¹⁰ These children were typically breastfeeding, suckling, or teething, suggesting trauma as a triggering event. In 1961, Hjorting-Hansen and Schmidt⁵ described 3 separate lesions similar to Riga-Fede disease in an adult patient. Subsequently, Riga-Fede disease was grouped under TUGSE.³

Histologically, TUGSE shows an ulcerated epithelium with a polymorphic inflammatory cell infiltrate that has a large predominance of eosinophils. The infiltrate affects the superficial and deep layers of the muscle tissue and penetrates into the salivary glands. Large atypical mononuclear cells with an ovoid and pale-appearing nucleus often are present. These cells may be mitotically active and stain positively for CD30.^1,4,11 CD68⁺ macrophages, T lymphocytes, and factor XIIIa–positive dendritic cells commonly are present.¹²

Given the presence of large atypical CD30⁺ cells in many lesions, the possibility of a CD30⁺ lymphoproliferative disorder has been postulated by some authors. Indeed, lymphomatoid papulosis (LyP) has been documented to involve the oral mucosa.^2,4

Case Report

An 81-year-old man presented with a rapidly enlarging, 1.7×1.3-cm, vascular-appearing nodule with a collarette of mucosal epithelium on the left side of the dorsal surface of the tongue of 2 weeks’ duration (Figure 1). He denied any history of trauma, tobacco chewing, weight change, fever, or fatigue; however, he did report a 30 pack-year smoking history. There was no other pertinent medical history to include medications or allergies.

The differential diagnosis included pyogenic granuloma, granular cell tumor, squamous cell carcinoma, other neoplasms (eg, oral lymphoma, salivary gland tumors), and a traumatic blood blister from tongue biting. The patient was referred to the oral maxillofacial surgery department for an excisional biopsy, which showed a solitary ulcerated nodule with associated granulation tissue, thrombus, and fibrinoid debris (Figure 2). A surrounding dense mixed inflammatory cell infiltrate composed of lymphocytes, histiocytes, and numerous eosinophils was noted extending through the submucosal tissue and underlying striated muscle fibers (Figure 3). The adjacent mucosal epithelium appeared normal. CD30 staining showed only rare positive cells. These findings were consistent with TUGSE.

Due to the benign nature of TUGSE, the patient was released with symptomatic care and instructed to return for any new growth. The growth spontaneously resolved over 1 month and no recurrence or new lesions were reported 1 year later.

Comment

Despite encompassing multiple disciplines of medicine, TUGSE has minimal exposure in the dermatologic literature. It is an important clinical and histologic diagnosis that will provide reassurance to the patient when accurately identified and reduce potentially harmful treatments.

Clinical Presentation
Typically, TUGSE presents as a painful solitary nodule with a central ulcer and yellow fibrinous base. The margins of the ulcer typically have an indurated and rolled appearance.^1,4 More than 50% of the lesions develop on the tongue, specifically the dorsal or lateral surfaces, but they may present anywhere in the oral mucosa.⁷ Traumatic ulcerative granuloma with stromal eosinophilia is a fast-growing lesion, typically developing in days to weeks. Although it spontaneously regresses, the lesion may take weeks or months to resolve. In one case, it resolved 1 year later.¹ Traumatic ulcerative granuloma with stromal eosinophilia has a bimodal age distribution, generally appearing in the first 2 years of life and later in the fifth through seventh decades. The male-to-female predominance is equal.^1,7,11 Reoccurrence is rare, but some reports have shown patients with multiple episodes of TUGSE.^13,14

Differential Diagnosis
The clinical differential diagnosis for TUGSE includes squamous cell carcinoma, pyogenic granuloma, lymphoproliferative disorder, traumatic neuroma, Langerhans cell histiocytosis, granulomatous disorders, and oral lymphoma. Inflammatory disorders such as syphilis, Behçet’s disease, herpes, histoplasmosis, Wegener granulomatosis, and others also should be considered.

Immunohistochemistry
Immunohistochemical analysis of TUGSE lesions recently has revealed the presence of CD30⁺ cells. These cells are associated with cutaneous lymphoproliferative disorders including LyP, anaplastic large cell lymphoma (ALCL), and borderline CD30⁺ lesions, among others. Systemic diseases with CD30⁺ cells include mycosis fungoides, other T-cell lymphomas, and Hodgkin lymphoma.^15,16 Once CD30⁺ cells were recognized, multiple authors began speculating there was a correlation between TUGSE and the CD30⁺ lymphoproliferative disorders.^1,2,13 Anaplastic large cell lymphoma and LyP of the oral mucosa have been reported in several cases.^17-20 One report described 2 cases of ulcerated CD30⁺ T-cell non-Hodgkin lymphoma of the oral mucosa, one of which showed eosinophilic infiltrates and was initially thought to be TUGSE. Based on these overlapping clinical and histologic features, the authors hypothesized there was a correlation between oral ALCL, LyP, and TUGSE.¹⁷ In one report, a patient developed multiple TUGSE lesions throughout his life, suggesting a pathologic process similar to LyP. The lesion biopsied showed that 70% of the T cells expressed CD30 (Ki-1) antigen.¹³

Underlying Causes
In support of an underlying immunologic process that augments the growth of these lesions, 2 separate case reports of TUGSE in the presence of human T-lymphotropic virus 1 (HTLV-1) and Epstein-Barr virus have been documented.^2,21 Concurrent presentation of TUGSE and HTLV-1 in one report demonstrated eosinophilia in both the oral lesion and peripheral blood, suggesting an immunologic relationship. Furthermore, the authors postulated that local trauma initiated the development of TUGSE, providing the catalyst for the HTLV-1 carrier to develop peripheral eosinophilia.²¹

In the second case, a 12-year-old boy developed TUGSE in the presence of Epstein-Barr virus.² Immunologically, this virus can be reactivated from its latent stage during immunosuppression. Epstein-Barr virus has been implicated in lymphoproliferative diseases of both B- and T-cell origin, including CD30⁺ ALCL and LyP.^22,23 The authors in this report again hypothesized there was a correlation between lymphoproliferative disorders and TUGSE lesions.^2,24

Alternatively, TUGSE may simply be a reactive process to trauma or another underlying trigger. It has been speculated that the presence of eosinophils correlates with antigen insertion into the oral mucosa, whereas other ulcers of the oral mucosa are devoid of eosinophils.¹ These antigens may include microorganisms, endogenous degradation products, or foreign proteins.^7,25 Additionally, the presence of CD30⁺ lymphocytes is not isolated to lymphoproliferative disorders. CD30⁺ cells have been documented in arthropod bite reactions, atopic dermatitis, drug reactions, molluscum contagiosum, and scabies, among others.^1,26

Healing and Management
The length of healing in TUGSE ulcers has substantial variability, from days to up to 1 year in an isolated case.^1,24 Sequential expression of transforming growth factor (TGF) α and TGF-β expressed by tissue eosinophils may be underlying factors associated with a quicker healing response as demonstrated by similar ulcers in hamsters.²⁷ Chronic nonhealing oral ulcers, particularly TUGSE lesions that demonstrated the typical increase in eosinophils in 11 of 12 cases, showed minimal TGF-α or TGF-β expression by eosinophils, perhaps indicating a possible mechanism leading to delayed wound healing in some cases. Interestingly, incisional biopsies often led to rapid wound healing, suggesting that the biopsy itself allowed for a transition back to the regular wound-healing processes.²⁸

Traumatic ulcerative granuloma with stromal eosinophilia spontaneously resolves on its own in most cases; however, because of the concern for malignancy, it has the potential to be overtreated.²⁶ Symptomatic treatment only is the mainstay of therapy. The patient should be instructed to avoid trauma, and referral to a dental professional is indicated when associated with dentures or other periprosthetic devices. Diet should consist of soft foods while avoiding spicy foods. Topical or oral analgesics may be necessary if substantial pain is associated with the lesion.² Oral prednisolone was used in a patient with concurrent HTLV-1 and TUGSE to treat peripheral eosinophilia.²¹ The patient’s peripheral eosinophils dropped to 1% in 1 day, and the patient’s oral lesion began to improve at day 3 and disappeared by day 10. Although TUGSE may spontaneously resolve within a 10-day period without steroids, it may be a reasonable treatment to improve healing time in an otherwise healthy individual.^21,26 If there is concern for malignancy, the patient should have the lesion biopsied to provide reassurance and for the added benefit of a transition to normal healing response and decreased healing time.²⁸

Clinical Recognition
The clinician should be aware of the possibility of a CD30⁺ lymphoproliferative disorder, which has been associated with TUGSE in some cases, or may simulate TUGSE both clinically and histologically. Further studies are needed to clarify the relationship between these 2 entities. Whether it is a true relationship, simple coincidence, or simply overlapping clinical and histologic features remains to be determined.

The American Society of Clinical Oncology has updated its clinical practice guideline on systemic therapy for stage IV non–small-cell lung cancer (NSCLC), incorporating recommendations on using checkpoint inhibitors in these patients.

The guideline was published recently on the Journal of Clinical Oncology website (J Clin Oncol. 2017 Aug 14. doi: 10.1200/JCO.2017.74.6065).

Among the recommendations is that, for patients with non–squamous cell carcinoma or squamous cell carcinoma without positive markers such as epidermal growth factor receptor who have high programmed death ligand 1 (PD-L1) expression, first-line treatment should be pembrolizumab alone. For those with low PD-L1 expression, standard chemotherapy should be used.

For second-line treatment in patients who received first-line chemotherapy without prior immune checkpoint treatment, if the NSCLC tumor is positive for PD-L1 expression, single-agent nivolumab, pembrolizumab, or atezolizumab should be used.

The guideline is an update of its 2015 recommendations. An expert panel made the changes after a systematic review of randomized controlled trials from February 2014 to December 2016.

Panelists said that there’s still a lot to learn about the use of checkpoint inhibitors in these patients.

“Cancer immunotherapy allows some patients to live longer with a better quality of life than chemotherapy; however, not all patients respond to this treatment,” panelists wrote. “Many factors remain unknown in the understanding of optimal sequencing of immune checkpoint therapy and other agents previously recommended in ASCO guidelines. Contraindications to receiving immune checkpoint therapy are not yet well defined.”

Several panelists report receiving research funding and/or consulting fees from Merck, Bristol-Meyers Squibb, Peloton Therapeutics, Genentech, and other companies.

The American Society of Clinical Oncology has updated its clinical practice guideline on systemic therapy for stage IV non–small-cell lung cancer (NSCLC), incorporating recommendations on using checkpoint inhibitors in these patients.

The guideline was published recently on the Journal of Clinical Oncology website (J Clin Oncol. 2017 Aug 14. doi: 10.1200/JCO.2017.74.6065).

Among the recommendations is that, for patients with non–squamous cell carcinoma or squamous cell carcinoma without positive markers such as epidermal growth factor receptor who have high programmed death ligand 1 (PD-L1) expression, first-line treatment should be pembrolizumab alone. For those with low PD-L1 expression, standard chemotherapy should be used.

For second-line treatment in patients who received first-line chemotherapy without prior immune checkpoint treatment, if the NSCLC tumor is positive for PD-L1 expression, single-agent nivolumab, pembrolizumab, or atezolizumab should be used.

The guideline is an update of its 2015 recommendations. An expert panel made the changes after a systematic review of randomized controlled trials from February 2014 to December 2016.

Panelists said that there’s still a lot to learn about the use of checkpoint inhibitors in these patients.

“Cancer immunotherapy allows some patients to live longer with a better quality of life than chemotherapy; however, not all patients respond to this treatment,” panelists wrote. “Many factors remain unknown in the understanding of optimal sequencing of immune checkpoint therapy and other agents previously recommended in ASCO guidelines. Contraindications to receiving immune checkpoint therapy are not yet well defined.”

Several panelists report receiving research funding and/or consulting fees from Merck, Bristol-Meyers Squibb, Peloton Therapeutics, Genentech, and other companies.

The American Society of Clinical Oncology has updated its clinical practice guideline on systemic therapy for stage IV non–small-cell lung cancer (NSCLC), incorporating recommendations on using checkpoint inhibitors in these patients.

The guideline was published recently on the Journal of Clinical Oncology website (J Clin Oncol. 2017 Aug 14. doi: 10.1200/JCO.2017.74.6065).

Among the recommendations is that, for patients with non–squamous cell carcinoma or squamous cell carcinoma without positive markers such as epidermal growth factor receptor who have high programmed death ligand 1 (PD-L1) expression, first-line treatment should be pembrolizumab alone. For those with low PD-L1 expression, standard chemotherapy should be used.

For second-line treatment in patients who received first-line chemotherapy without prior immune checkpoint treatment, if the NSCLC tumor is positive for PD-L1 expression, single-agent nivolumab, pembrolizumab, or atezolizumab should be used.

The guideline is an update of its 2015 recommendations. An expert panel made the changes after a systematic review of randomized controlled trials from February 2014 to December 2016.

Panelists said that there’s still a lot to learn about the use of checkpoint inhibitors in these patients.

“Cancer immunotherapy allows some patients to live longer with a better quality of life than chemotherapy; however, not all patients respond to this treatment,” panelists wrote. “Many factors remain unknown in the understanding of optimal sequencing of immune checkpoint therapy and other agents previously recommended in ASCO guidelines. Contraindications to receiving immune checkpoint therapy are not yet well defined.”

Several panelists report receiving research funding and/or consulting fees from Merck, Bristol-Meyers Squibb, Peloton Therapeutics, Genentech, and other companies.

Patients who are on hemodialysis and who have cancer present a “unique challenge,” say clinicians from Dartmouth-Hitchcock in New Hampshire.

Patients with end-stage renal disease (ESRD) are at risk of drug accumulation and toxicity. Many anticancer drugs and their metabolites are excreted by the kidney, but data to guide dose and schedule adjustments in renal dialysis are “scant,” the clinicians say. They cite a study that found 72% of dialysis patients receiving anticancer drugs needed dosage adjustments for at least 1 drug. The study researchers also found a significant number of chemotherapy drugs for which there were no available recommendations in dialysis patients.

However, a safe and effective alternative for these patients may exist. The clinicians report on a case—to the best of their knowledge, the first such—of a patient with metastatic melanoma who was successfully treated with pembrolizumab while on hemodialysis.

The patient, who had diabetes and ESRD, also had melanoma in his ear, which metastasized. After discussing his therapeutic options—including the limited data on available immunotherapy drugs—clinicians and the patient agreed to proceed with pembrolizumab, an IgG4-κ human antiprogrammed cell death protein 1 (PD-1) monoclonal antibody. Pembrolizumab has been shown to improve survival rates in patients with melanoma, although it had not been reported in patients with melanoma on dialysis.

The patient received pembrolizumab 2 mg/kg/dose, repeated every 3 weeks. After 1 dose, his abdominal pain and appetite improved. Serum lactate dehydrogenase dropped from 1,182 to 354 units/L. He continued on dialysis 3 times a week with stable serum creatinine levels. After 3 cycles, the computerized tomography scan showed the pulmonary nodules had resolved,  and retroperitoneal lymphadenopathy was significantly reduced. After 10 cycles, he was in complete remission.

Pembrolizumab has distinct benefits for patients like theirs, the clinicians suggest. For one, the molecular weight of the antibody means it is not dialysable, so ultrafiltration (reducing drug exposure) is not the issue it might be. The drug can likely be given without regard to the timing of dialysis. Another benefit for these patients who are usually immunocompromised is that PD-1 antibodies “disrupt” the interactions that create an “immune-suppressive tumor microenvironment” and allow T-cell antitumor activity, the clinicians say.

Their report demonstrates that PD-1 antibodies can be effective in dialysis-dependent ESRD, they say, but add that further research into the induced immune response is warranted. In clinical trials, a small number of patients on pembrolizumab (0.4%) developed immune-mediated nephritis. That might not be as crucial for patients who are already on hemodialysis, the clinicians note, but they caution that the adverse effect (AE) could be a risk for patients with normal renal function or chronic kidney disease. However, their patient experienced no pembrolizumab-related AEs other than mild fatigue.

Source:

Chang R, Shirai K. BMJ Case Rep. 2016; pii: bcr2016216426.

doi: 10.1136/bcr-2016-216426.

Patients who are on hemodialysis and who have cancer present a “unique challenge,” say clinicians from Dartmouth-Hitchcock in New Hampshire.

Patients with end-stage renal disease (ESRD) are at risk of drug accumulation and toxicity. Many anticancer drugs and their metabolites are excreted by the kidney, but data to guide dose and schedule adjustments in renal dialysis are “scant,” the clinicians say. They cite a study that found 72% of dialysis patients receiving anticancer drugs needed dosage adjustments for at least 1 drug. The study researchers also found a significant number of chemotherapy drugs for which there were no available recommendations in dialysis patients.

However, a safe and effective alternative for these patients may exist. The clinicians report on a case—to the best of their knowledge, the first such—of a patient with metastatic melanoma who was successfully treated with pembrolizumab while on hemodialysis.

The patient, who had diabetes and ESRD, also had melanoma in his ear, which metastasized. After discussing his therapeutic options—including the limited data on available immunotherapy drugs—clinicians and the patient agreed to proceed with pembrolizumab, an IgG4-κ human antiprogrammed cell death protein 1 (PD-1) monoclonal antibody. Pembrolizumab has been shown to improve survival rates in patients with melanoma, although it had not been reported in patients with melanoma on dialysis.

The patient received pembrolizumab 2 mg/kg/dose, repeated every 3 weeks. After 1 dose, his abdominal pain and appetite improved. Serum lactate dehydrogenase dropped from 1,182 to 354 units/L. He continued on dialysis 3 times a week with stable serum creatinine levels. After 3 cycles, the computerized tomography scan showed the pulmonary nodules had resolved,  and retroperitoneal lymphadenopathy was significantly reduced. After 10 cycles, he was in complete remission.

Pembrolizumab has distinct benefits for patients like theirs, the clinicians suggest. For one, the molecular weight of the antibody means it is not dialysable, so ultrafiltration (reducing drug exposure) is not the issue it might be. The drug can likely be given without regard to the timing of dialysis. Another benefit for these patients who are usually immunocompromised is that PD-1 antibodies “disrupt” the interactions that create an “immune-suppressive tumor microenvironment” and allow T-cell antitumor activity, the clinicians say.

Their report demonstrates that PD-1 antibodies can be effective in dialysis-dependent ESRD, they say, but add that further research into the induced immune response is warranted. In clinical trials, a small number of patients on pembrolizumab (0.4%) developed immune-mediated nephritis. That might not be as crucial for patients who are already on hemodialysis, the clinicians note, but they caution that the adverse effect (AE) could be a risk for patients with normal renal function or chronic kidney disease. However, their patient experienced no pembrolizumab-related AEs other than mild fatigue.

Source:

Chang R, Shirai K. BMJ Case Rep. 2016; pii: bcr2016216426.

doi: 10.1136/bcr-2016-216426.

Patients who are on hemodialysis and who have cancer present a “unique challenge,” say clinicians from Dartmouth-Hitchcock in New Hampshire.

Patients with end-stage renal disease (ESRD) are at risk of drug accumulation and toxicity. Many anticancer drugs and their metabolites are excreted by the kidney, but data to guide dose and schedule adjustments in renal dialysis are “scant,” the clinicians say. They cite a study that found 72% of dialysis patients receiving anticancer drugs needed dosage adjustments for at least 1 drug. The study researchers also found a significant number of chemotherapy drugs for which there were no available recommendations in dialysis patients.

However, a safe and effective alternative for these patients may exist. The clinicians report on a case—to the best of their knowledge, the first such—of a patient with metastatic melanoma who was successfully treated with pembrolizumab while on hemodialysis.

The patient, who had diabetes and ESRD, also had melanoma in his ear, which metastasized. After discussing his therapeutic options—including the limited data on available immunotherapy drugs—clinicians and the patient agreed to proceed with pembrolizumab, an IgG4-κ human antiprogrammed cell death protein 1 (PD-1) monoclonal antibody. Pembrolizumab has been shown to improve survival rates in patients with melanoma, although it had not been reported in patients with melanoma on dialysis.

The patient received pembrolizumab 2 mg/kg/dose, repeated every 3 weeks. After 1 dose, his abdominal pain and appetite improved. Serum lactate dehydrogenase dropped from 1,182 to 354 units/L. He continued on dialysis 3 times a week with stable serum creatinine levels. After 3 cycles, the computerized tomography scan showed the pulmonary nodules had resolved,  and retroperitoneal lymphadenopathy was significantly reduced. After 10 cycles, he was in complete remission.

Pembrolizumab has distinct benefits for patients like theirs, the clinicians suggest. For one, the molecular weight of the antibody means it is not dialysable, so ultrafiltration (reducing drug exposure) is not the issue it might be. The drug can likely be given without regard to the timing of dialysis. Another benefit for these patients who are usually immunocompromised is that PD-1 antibodies “disrupt” the interactions that create an “immune-suppressive tumor microenvironment” and allow T-cell antitumor activity, the clinicians say.

Their report demonstrates that PD-1 antibodies can be effective in dialysis-dependent ESRD, they say, but add that further research into the induced immune response is warranted. In clinical trials, a small number of patients on pembrolizumab (0.4%) developed immune-mediated nephritis. That might not be as crucial for patients who are already on hemodialysis, the clinicians note, but they caution that the adverse effect (AE) could be a risk for patients with normal renal function or chronic kidney disease. However, their patient experienced no pembrolizumab-related AEs other than mild fatigue.

Source:

Chang R, Shirai K. BMJ Case Rep. 2016; pii: bcr2016216426.

doi: 10.1136/bcr-2016-216426.

Photo by Bill Branson

New research suggests survivors of childhood cancer can incur high out-of-pocket medical costs into adulthood and may forgo healthcare to lessen this financial burden.

The study showed that childhood cancer survivors (CCSs) were more likely than non-CCSs to have out-of-pocket medical costs that were at least 10% of their annual income.

And these high costs were associated with delaying care or skipping it altogether.

These findings were published in the Journal of Clinical Oncology.

“Survivors who reported spending a higher percentage of their income on out-of-pocket medical costs were not only more likely to report financial burden, they also were at risk for undertaking behaviors potentially detrimental to their health in order to save money,” said study author Ryan Nipp, MD, of Massachusetts General Hospital Cancer Center in Boston.

“While studies have identified associations between financial burden and patients’ treatment outcomes, quality of life, and even survival among adults with cancer, as far as we know, this is the first to report these associations in survivors of childhood cancer.”

For this research, Dr Nipp and his colleagues surveyed participants in the Childhood Cancer Survivor Study. This included adults who had been treated for childhood cancers between 1970 and 1986 along with a control group of siblings not affected by cancer.

In 2011 and 2012, participants were asked to provide information about their health insurance, the out-of-pocket healthcare costs they paid during the previous year, and sociodemographic information such as annual income and employment status.

The researchers also asked participants whether medical costs posed a financial burden and, if so, what measures they had taken to deal with that burden.

Study population

The researchers received complete responses from 580 CCSs and 173 of their siblings without a history of cancer. The most common cancer diagnosis was leukemia (33%), followed by Hodgkin lymphoma (14%), while non-Hodgkin lymphoma was less common (7%).

CCSs were a mean of 30.2 years from diagnosis. Use of chemotherapy (77%), radiation (66%), and surgery (81%) were common. Few patients had cancer recurrence (13%) or second cancers (5%).

There was no significant difference between CCSs and their siblings with regard to age at the time of the survey (P=0.071), household income (P=0.053), education (P=0.345), health insurance status (P=0.317), or having at least 1 hospitalization in the past year (P=0.270).

However, CCSs were significantly more likely than siblings to have chronic health conditions (P<0.001). Forty percent of CCSs had severe or life-threatening chronic conditions, compared to 17% of siblings.

Seventy-six percent of CCSs and 80% of siblings were employed. Twenty-nine percent of CCSs and 39% of siblings had household incomes exceeding $100,000. Twelve percent of CCSs and 5% of siblings had household incomes below $20,000.

Ninety-one percent of CCSs and 93% of siblings were insured. Most subjects in both groups (81% and 87%, respectively) had employer-sponsored insurance.

Results

CCSs were significantly more likely than their siblings to have out-of-pocket medical costs that were at least 10% of their annual income—10% and 3%, respectively (P<0.001).

Among CCSs, those with higher out-of-pocket costs (≥10% vs <10% of income) were more likely to have household incomes below $50,000 (odds ratio [OR]=5.5) and to report being hospitalized in the past year (OR=2.3).

CCSs with a higher percentage of their income spent on out-of-pocket costs were also more likely to:

• Have problems paying their medical bills (OR=8.8)
• Report inability to pay for basic costs of living such as food, heat, or rent (OR=6.1)
• Defer healthcare for a medical problem (OR=3.1)
• Skip a test, treatment, or follow-up (OR=2.1)
• Consider filing for bankruptcy (OR=6.4).

“A more comprehensive understanding of the relationship between high out-of-pocket medical costs and the adverse effects of increased financial burden on cancer survivors could be instrumental in helping us identify those at risk for higher costs to help us address their financial challenges and improve health outcomes,” Dr Nipp said.

“It could also help inform policy changes to help meet the unique needs of cancer survivors and improve our understanding of how both higher costs and resulting financial burden influence patients’ approach to their medical care and decision-making.”

Photo by Bill Branson

New research suggests survivors of childhood cancer can incur high out-of-pocket medical costs into adulthood and may forgo healthcare to lessen this financial burden.

The study showed that childhood cancer survivors (CCSs) were more likely than non-CCSs to have out-of-pocket medical costs that were at least 10% of their annual income.

And these high costs were associated with delaying care or skipping it altogether.

These findings were published in the Journal of Clinical Oncology.

“Survivors who reported spending a higher percentage of their income on out-of-pocket medical costs were not only more likely to report financial burden, they also were at risk for undertaking behaviors potentially detrimental to their health in order to save money,” said study author Ryan Nipp, MD, of Massachusetts General Hospital Cancer Center in Boston.

“While studies have identified associations between financial burden and patients’ treatment outcomes, quality of life, and even survival among adults with cancer, as far as we know, this is the first to report these associations in survivors of childhood cancer.”

For this research, Dr Nipp and his colleagues surveyed participants in the Childhood Cancer Survivor Study. This included adults who had been treated for childhood cancers between 1970 and 1986 along with a control group of siblings not affected by cancer.

In 2011 and 2012, participants were asked to provide information about their health insurance, the out-of-pocket healthcare costs they paid during the previous year, and sociodemographic information such as annual income and employment status.

The researchers also asked participants whether medical costs posed a financial burden and, if so, what measures they had taken to deal with that burden.

Study population

The researchers received complete responses from 580 CCSs and 173 of their siblings without a history of cancer. The most common cancer diagnosis was leukemia (33%), followed by Hodgkin lymphoma (14%), while non-Hodgkin lymphoma was less common (7%).

CCSs were a mean of 30.2 years from diagnosis. Use of chemotherapy (77%), radiation (66%), and surgery (81%) were common. Few patients had cancer recurrence (13%) or second cancers (5%).

There was no significant difference between CCSs and their siblings with regard to age at the time of the survey (P=0.071), household income (P=0.053), education (P=0.345), health insurance status (P=0.317), or having at least 1 hospitalization in the past year (P=0.270).

However, CCSs were significantly more likely than siblings to have chronic health conditions (P<0.001). Forty percent of CCSs had severe or life-threatening chronic conditions, compared to 17% of siblings.

Seventy-six percent of CCSs and 80% of siblings were employed. Twenty-nine percent of CCSs and 39% of siblings had household incomes exceeding $100,000. Twelve percent of CCSs and 5% of siblings had household incomes below $20,000.

Ninety-one percent of CCSs and 93% of siblings were insured. Most subjects in both groups (81% and 87%, respectively) had employer-sponsored insurance.

Results

CCSs were significantly more likely than their siblings to have out-of-pocket medical costs that were at least 10% of their annual income—10% and 3%, respectively (P<0.001).

Among CCSs, those with higher out-of-pocket costs (≥10% vs <10% of income) were more likely to have household incomes below $50,000 (odds ratio [OR]=5.5) and to report being hospitalized in the past year (OR=2.3).

CCSs with a higher percentage of their income spent on out-of-pocket costs were also more likely to:

• Have problems paying their medical bills (OR=8.8)
• Report inability to pay for basic costs of living such as food, heat, or rent (OR=6.1)
• Defer healthcare for a medical problem (OR=3.1)
• Skip a test, treatment, or follow-up (OR=2.1)
• Consider filing for bankruptcy (OR=6.4).

“A more comprehensive understanding of the relationship between high out-of-pocket medical costs and the adverse effects of increased financial burden on cancer survivors could be instrumental in helping us identify those at risk for higher costs to help us address their financial challenges and improve health outcomes,” Dr Nipp said.

“It could also help inform policy changes to help meet the unique needs of cancer survivors and improve our understanding of how both higher costs and resulting financial burden influence patients’ approach to their medical care and decision-making.”

Photo by Bill Branson

New research suggests survivors of childhood cancer can incur high out-of-pocket medical costs into adulthood and may forgo healthcare to lessen this financial burden.

The study showed that childhood cancer survivors (CCSs) were more likely than non-CCSs to have out-of-pocket medical costs that were at least 10% of their annual income.

And these high costs were associated with delaying care or skipping it altogether.

These findings were published in the Journal of Clinical Oncology.

“Survivors who reported spending a higher percentage of their income on out-of-pocket medical costs were not only more likely to report financial burden, they also were at risk for undertaking behaviors potentially detrimental to their health in order to save money,” said study author Ryan Nipp, MD, of Massachusetts General Hospital Cancer Center in Boston.

“While studies have identified associations between financial burden and patients’ treatment outcomes, quality of life, and even survival among adults with cancer, as far as we know, this is the first to report these associations in survivors of childhood cancer.”

For this research, Dr Nipp and his colleagues surveyed participants in the Childhood Cancer Survivor Study. This included adults who had been treated for childhood cancers between 1970 and 1986 along with a control group of siblings not affected by cancer.

In 2011 and 2012, participants were asked to provide information about their health insurance, the out-of-pocket healthcare costs they paid during the previous year, and sociodemographic information such as annual income and employment status.

The researchers also asked participants whether medical costs posed a financial burden and, if so, what measures they had taken to deal with that burden.

Study population

The researchers received complete responses from 580 CCSs and 173 of their siblings without a history of cancer. The most common cancer diagnosis was leukemia (33%), followed by Hodgkin lymphoma (14%), while non-Hodgkin lymphoma was less common (7%).

CCSs were a mean of 30.2 years from diagnosis. Use of chemotherapy (77%), radiation (66%), and surgery (81%) were common. Few patients had cancer recurrence (13%) or second cancers (5%).

There was no significant difference between CCSs and their siblings with regard to age at the time of the survey (P=0.071), household income (P=0.053), education (P=0.345), health insurance status (P=0.317), or having at least 1 hospitalization in the past year (P=0.270).

However, CCSs were significantly more likely than siblings to have chronic health conditions (P<0.001). Forty percent of CCSs had severe or life-threatening chronic conditions, compared to 17% of siblings.

Seventy-six percent of CCSs and 80% of siblings were employed. Twenty-nine percent of CCSs and 39% of siblings had household incomes exceeding $100,000. Twelve percent of CCSs and 5% of siblings had household incomes below $20,000.

Ninety-one percent of CCSs and 93% of siblings were insured. Most subjects in both groups (81% and 87%, respectively) had employer-sponsored insurance.

Results

CCSs were significantly more likely than their siblings to have out-of-pocket medical costs that were at least 10% of their annual income—10% and 3%, respectively (P<0.001).

Among CCSs, those with higher out-of-pocket costs (≥10% vs <10% of income) were more likely to have household incomes below $50,000 (odds ratio [OR]=5.5) and to report being hospitalized in the past year (OR=2.3).

CCSs with a higher percentage of their income spent on out-of-pocket costs were also more likely to:

• Have problems paying their medical bills (OR=8.8)
• Report inability to pay for basic costs of living such as food, heat, or rent (OR=6.1)
• Defer healthcare for a medical problem (OR=3.1)
• Skip a test, treatment, or follow-up (OR=2.1)
• Consider filing for bankruptcy (OR=6.4).

“A more comprehensive understanding of the relationship between high out-of-pocket medical costs and the adverse effects of increased financial burden on cancer survivors could be instrumental in helping us identify those at risk for higher costs to help us address their financial challenges and improve health outcomes,” Dr Nipp said.

“It could also help inform policy changes to help meet the unique needs of cancer survivors and improve our understanding of how both higher costs and resulting financial burden influence patients’ approach to their medical care and decision-making.”

Image by Lance Liotta

Researchers have described a molecular mechanism that could help explain the link between low vitamin C (ascorbate) levels and acute myeloid leukemia (AML).

The team found that mice with low levels of ascorbate in their blood experience a notable increase in hematopoietic stem cell (HSC) frequency and function.

This, in turn, accelerates AML development, partly by inhibiting the tumor suppressor Tet2.

Sean Morrison, PhD, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues reported these findings in Nature.

“We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we haven’t fully understood why,” Dr Morrison said. “Our research provides part of the explanation, at least for the blood-forming system.”

Dr Morrison and his colleagues developed a technique for analyzing the metabolic profiles of rare cell populations and used it to compare HSCs to restricted hematopoietic progenitors.

The researchers found that each hematopoietic cell type had a “distinct metabolic signature,” and both human and mouse HSCs had “unusually high” levels of ascorbate, which decreased as the cells differentiated.

To determine if ascorbate is important for HSC function, the team studied mice that lacked gulonolactone oxidase (Gulo), an enzyme mice use to synthesize their own ascorbate. Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do.

So when the researchers fed the mice a standard diet, which contains little ascorbate, the animals’ ascorbate levels were depleted.

The team expected ascorbate depletion might lead to loss of HSC function, but they found the opposite was true. HSCs actually gained function, and this increased the incidence of AML in the mice.

This increase is partly tied to how ascorbate affects Tet2. The researchers found that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of AML.

In addition, ascorbate depletion cooperated with Flt3 internal tandem duplication mutations to accelerate leukemogenesis. But the researchers were able to suppress leukemogenesis by feeding animals higher levels of ascorbate.

“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said study author Michalis Agathocleous, PhD, of the University of Texas Southwestern Medical Center.

“So when stem cells don’t receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukemia.”

The researchers said further studies are needed to better understand the potential clinical implications of these findings.

However, the findings may have implications for older patients with clonal hematopoiesis. This condition increases a person’s risk of developing leukemia, but it is not well understood why certain patients develop leukemia and others do not. The results of this study might offer an explanation.

“One of the most common mutations in patients with clonal hematopoiesis is a loss of one copy of TET2,” Dr Morrison said. “Our results suggest patients with clonal hematopoiesis and a TET2 mutation should be particularly careful to get 100% of their daily vitamin C requirement. Because these patients only have one good copy of TET2 left, they need to maximize the residual TET2 tumor-suppressor activity to protect themselves from cancer.” 

Image by Lance Liotta

Researchers have described a molecular mechanism that could help explain the link between low vitamin C (ascorbate) levels and acute myeloid leukemia (AML).

The team found that mice with low levels of ascorbate in their blood experience a notable increase in hematopoietic stem cell (HSC) frequency and function.

This, in turn, accelerates AML development, partly by inhibiting the tumor suppressor Tet2.

Sean Morrison, PhD, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues reported these findings in Nature.

“We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we haven’t fully understood why,” Dr Morrison said. “Our research provides part of the explanation, at least for the blood-forming system.”

Dr Morrison and his colleagues developed a technique for analyzing the metabolic profiles of rare cell populations and used it to compare HSCs to restricted hematopoietic progenitors.

The researchers found that each hematopoietic cell type had a “distinct metabolic signature,” and both human and mouse HSCs had “unusually high” levels of ascorbate, which decreased as the cells differentiated.

To determine if ascorbate is important for HSC function, the team studied mice that lacked gulonolactone oxidase (Gulo), an enzyme mice use to synthesize their own ascorbate. Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do.

So when the researchers fed the mice a standard diet, which contains little ascorbate, the animals’ ascorbate levels were depleted.

The team expected ascorbate depletion might lead to loss of HSC function, but they found the opposite was true. HSCs actually gained function, and this increased the incidence of AML in the mice.

This increase is partly tied to how ascorbate affects Tet2. The researchers found that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of AML.

In addition, ascorbate depletion cooperated with Flt3 internal tandem duplication mutations to accelerate leukemogenesis. But the researchers were able to suppress leukemogenesis by feeding animals higher levels of ascorbate.

“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said study author Michalis Agathocleous, PhD, of the University of Texas Southwestern Medical Center.

“So when stem cells don’t receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukemia.”

The researchers said further studies are needed to better understand the potential clinical implications of these findings.

However, the findings may have implications for older patients with clonal hematopoiesis. This condition increases a person’s risk of developing leukemia, but it is not well understood why certain patients develop leukemia and others do not. The results of this study might offer an explanation.

“One of the most common mutations in patients with clonal hematopoiesis is a loss of one copy of TET2,” Dr Morrison said. “Our results suggest patients with clonal hematopoiesis and a TET2 mutation should be particularly careful to get 100% of their daily vitamin C requirement. Because these patients only have one good copy of TET2 left, they need to maximize the residual TET2 tumor-suppressor activity to protect themselves from cancer.” 

Image by Lance Liotta

Researchers have described a molecular mechanism that could help explain the link between low vitamin C (ascorbate) levels and acute myeloid leukemia (AML).

The team found that mice with low levels of ascorbate in their blood experience a notable increase in hematopoietic stem cell (HSC) frequency and function.

This, in turn, accelerates AML development, partly by inhibiting the tumor suppressor Tet2.

Sean Morrison, PhD, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues reported these findings in Nature.

“We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we haven’t fully understood why,” Dr Morrison said. “Our research provides part of the explanation, at least for the blood-forming system.”

Dr Morrison and his colleagues developed a technique for analyzing the metabolic profiles of rare cell populations and used it to compare HSCs to restricted hematopoietic progenitors.

The researchers found that each hematopoietic cell type had a “distinct metabolic signature,” and both human and mouse HSCs had “unusually high” levels of ascorbate, which decreased as the cells differentiated.

To determine if ascorbate is important for HSC function, the team studied mice that lacked gulonolactone oxidase (Gulo), an enzyme mice use to synthesize their own ascorbate. Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do.

So when the researchers fed the mice a standard diet, which contains little ascorbate, the animals’ ascorbate levels were depleted.

The team expected ascorbate depletion might lead to loss of HSC function, but they found the opposite was true. HSCs actually gained function, and this increased the incidence of AML in the mice.

This increase is partly tied to how ascorbate affects Tet2. The researchers found that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of AML.

In addition, ascorbate depletion cooperated with Flt3 internal tandem duplication mutations to accelerate leukemogenesis. But the researchers were able to suppress leukemogenesis by feeding animals higher levels of ascorbate.

“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said study author Michalis Agathocleous, PhD, of the University of Texas Southwestern Medical Center.

“So when stem cells don’t receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukemia.”

The researchers said further studies are needed to better understand the potential clinical implications of these findings.

However, the findings may have implications for older patients with clonal hematopoiesis. This condition increases a person’s risk of developing leukemia, but it is not well understood why certain patients develop leukemia and others do not. The results of this study might offer an explanation.

“One of the most common mutations in patients with clonal hematopoiesis is a loss of one copy of TET2,” Dr Morrison said. “Our results suggest patients with clonal hematopoiesis and a TET2 mutation should be particularly careful to get 100% of their daily vitamin C requirement. Because these patients only have one good copy of TET2 left, they need to maximize the residual TET2 tumor-suppressor activity to protect themselves from cancer.” 

Photo from Business Wire

The US Food and Drug Administration (FDA) has approved new product strengths for the factor VIII therapy simoctocog alfa (NUWIQ®).

Simoctocog alfa is the first B-domain-deleted recombinant factor VIII product derived from a human cell line—not chemically modified or fused with another protein—designed to treat hemophilia A.

Simoctocog alfa is FDA-approved to treat adults and children with hemophilia A. This includes on-demand treatment and control of bleeding episodes, routine prophylaxis to reduce the frequency of bleeding episodes, and perioperative management of bleeding.

Now, the FDA has approved single-dose simoctocog alfa vial strengths of 2500, 3000, and 4000 International Units (IU), which will be available for order in the US starting September 2017.

These new vial strengths will be provided in addition to the already available strengths of 250, 500, 1000, and 2000 IU.

“The new vial options will benefit patients, physicians, and healthcare professionals by providing greater treatment flexibility and convenience,” said Flemming Nielsen, president of Octapharma USA, makers of simoctocog alfa.

According to Octapharma, the additional vial strengths offer benefits beyond potentially reducing the number of vials used per patient. The new vial sizes may benefit heavier patients who could use fewer product vials and, in some cases, just one vial.

More vial options will increase dosing flexibility by allowing physicians to select various vial combinations to align closer to the prescribed dose. The new vial sizes could be particularly beneficial to patients using a pharmacokinetic (PK)-guided, personalized prophylaxis approach.

Results of Octapharma’s clinical trial on the PK-guided dosing with simoctocog alfa were published in Haemophilia in April.

This study, known as GENA-21 or NuPreviq, enrolled 66 previously treated adults with severe hemophilia A. Patients were originally started on infusions 3 times a week or every other day. Subsequent dosing intervals were then determined based on individual PK data.

The median dosing interval with PK-guided prophylaxis was 3.5 days, and 57% of patients were able to decrease infusions to twice-weekly or less.

The median weekly prophylaxis dose was reduced by 7.2%, from 100.0 IU kg⁻¹ with standard prophylaxis to 92.8 IU kg⁻¹ during the last 2 months of personalized prophylaxis.

For all bleeds, the mean annualized bleeding rate (ABR) during personalized prophylaxis was 1.45, and the median was 0 (interquartile range, [IQR]: 0, 1.9).

For spontaneous bleeds, the mean ABR was 0.79, and the median was 0 (IQR: 0, 0). For joint bleeds, the mean ABR was 0.91, and the median was 0 (IQR: 0, 0).

None of the patients developed FVIII inhibitors. There were no treatment-related serious or severe adverse events, clinically significant abnormalities in laboratory parameters, or cases of thromboembolism.

The ongoing trial GENA-21b is designed to confirm the results of GENA-21.

Photo from Business Wire

The US Food and Drug Administration (FDA) has approved new product strengths for the factor VIII therapy simoctocog alfa (NUWIQ®).

Simoctocog alfa is the first B-domain-deleted recombinant factor VIII product derived from a human cell line—not chemically modified or fused with another protein—designed to treat hemophilia A.

Simoctocog alfa is FDA-approved to treat adults and children with hemophilia A. This includes on-demand treatment and control of bleeding episodes, routine prophylaxis to reduce the frequency of bleeding episodes, and perioperative management of bleeding.

Now, the FDA has approved single-dose simoctocog alfa vial strengths of 2500, 3000, and 4000 International Units (IU), which will be available for order in the US starting September 2017.

These new vial strengths will be provided in addition to the already available strengths of 250, 500, 1000, and 2000 IU.

“The new vial options will benefit patients, physicians, and healthcare professionals by providing greater treatment flexibility and convenience,” said Flemming Nielsen, president of Octapharma USA, makers of simoctocog alfa.

According to Octapharma, the additional vial strengths offer benefits beyond potentially reducing the number of vials used per patient. The new vial sizes may benefit heavier patients who could use fewer product vials and, in some cases, just one vial.

More vial options will increase dosing flexibility by allowing physicians to select various vial combinations to align closer to the prescribed dose. The new vial sizes could be particularly beneficial to patients using a pharmacokinetic (PK)-guided, personalized prophylaxis approach.

Results of Octapharma’s clinical trial on the PK-guided dosing with simoctocog alfa were published in Haemophilia in April.

This study, known as GENA-21 or NuPreviq, enrolled 66 previously treated adults with severe hemophilia A. Patients were originally started on infusions 3 times a week or every other day. Subsequent dosing intervals were then determined based on individual PK data.

The median dosing interval with PK-guided prophylaxis was 3.5 days, and 57% of patients were able to decrease infusions to twice-weekly or less.

The median weekly prophylaxis dose was reduced by 7.2%, from 100.0 IU kg⁻¹ with standard prophylaxis to 92.8 IU kg⁻¹ during the last 2 months of personalized prophylaxis.

For all bleeds, the mean annualized bleeding rate (ABR) during personalized prophylaxis was 1.45, and the median was 0 (interquartile range, [IQR]: 0, 1.9).

For spontaneous bleeds, the mean ABR was 0.79, and the median was 0 (IQR: 0, 0). For joint bleeds, the mean ABR was 0.91, and the median was 0 (IQR: 0, 0).

None of the patients developed FVIII inhibitors. There were no treatment-related serious or severe adverse events, clinically significant abnormalities in laboratory parameters, or cases of thromboembolism.

The ongoing trial GENA-21b is designed to confirm the results of GENA-21.

Photo from Business Wire

The US Food and Drug Administration (FDA) has approved new product strengths for the factor VIII therapy simoctocog alfa (NUWIQ®).

Simoctocog alfa is the first B-domain-deleted recombinant factor VIII product derived from a human cell line—not chemically modified or fused with another protein—designed to treat hemophilia A.

Simoctocog alfa is FDA-approved to treat adults and children with hemophilia A. This includes on-demand treatment and control of bleeding episodes, routine prophylaxis to reduce the frequency of bleeding episodes, and perioperative management of bleeding.

Now, the FDA has approved single-dose simoctocog alfa vial strengths of 2500, 3000, and 4000 International Units (IU), which will be available for order in the US starting September 2017.

These new vial strengths will be provided in addition to the already available strengths of 250, 500, 1000, and 2000 IU.

“The new vial options will benefit patients, physicians, and healthcare professionals by providing greater treatment flexibility and convenience,” said Flemming Nielsen, president of Octapharma USA, makers of simoctocog alfa.

According to Octapharma, the additional vial strengths offer benefits beyond potentially reducing the number of vials used per patient. The new vial sizes may benefit heavier patients who could use fewer product vials and, in some cases, just one vial.

More vial options will increase dosing flexibility by allowing physicians to select various vial combinations to align closer to the prescribed dose. The new vial sizes could be particularly beneficial to patients using a pharmacokinetic (PK)-guided, personalized prophylaxis approach.

Results of Octapharma’s clinical trial on the PK-guided dosing with simoctocog alfa were published in Haemophilia in April.

This study, known as GENA-21 or NuPreviq, enrolled 66 previously treated adults with severe hemophilia A. Patients were originally started on infusions 3 times a week or every other day. Subsequent dosing intervals were then determined based on individual PK data.

The median dosing interval with PK-guided prophylaxis was 3.5 days, and 57% of patients were able to decrease infusions to twice-weekly or less.

The median weekly prophylaxis dose was reduced by 7.2%, from 100.0 IU kg⁻¹ with standard prophylaxis to 92.8 IU kg⁻¹ during the last 2 months of personalized prophylaxis.

For all bleeds, the mean annualized bleeding rate (ABR) during personalized prophylaxis was 1.45, and the median was 0 (interquartile range, [IQR]: 0, 1.9).

For spontaneous bleeds, the mean ABR was 0.79, and the median was 0 (IQR: 0, 0). For joint bleeds, the mean ABR was 0.91, and the median was 0 (IQR: 0, 0).

None of the patients developed FVIII inhibitors. There were no treatment-related serious or severe adverse events, clinically significant abnormalities in laboratory parameters, or cases of thromboembolism.

The ongoing trial GENA-21b is designed to confirm the results of GENA-21.

The FP suspected pustular psoriasis, which was confirmed by a dermatologist the patient saw the following day. The dermatologist confirmed this diagnosis by performing a 4-mm punch biopsy, which included an area of new pustules on the patient’s arm. When a rash is extensive, it’s best to biopsy new lesions from the upper body, rather than old lesions below the waist.

Pustular psoriasis can lead to confluent pustules, a condition in which the skin peels off in sheets, resulting in dehydration and a risk of sepsis. This is why you shouldn’t prescribe oral prednisone for any rash before you know that it’s not psoriasis. While oral prednisone may be an effective treatment for many types of dermatitis, it can exacerbate psoriasis (as it did with this patient), and is therefore not an effective or safe treatment for it.

Knowing that pustular psoriasis can become a dermatologic emergency, the FP prescribed oral cyclosporine for the most rapid result. The patient’s blood pressure and kidney function were normal, so it was only necessary for the FP to order baseline laboratory tests. At the follow-up appointment 2 days later, the patient’s condition was already improving and there were no new pustules. Her vital signs remained stable and the pathology report confirmed pustular psoriasis.

The dermatologist planned to transition the patient from cyclosporine to acitretin, determining it was safe to prescribe an oral retinoid. The patient’s hysterectomy 2 years earlier also eliminated concerns about acitretin’s teratogenic potency. The dermatologist prescribed acitretin with directions for the patient to begin taking it in one week, tapering off the cyclosporine once the pustular psoriasis was significantly better.

After a month, the patient was off of cyclosporine completely. Her skin was clear while using daily acitretin. Monitoring of lab tests did not show any adverse effects of the patient using these 2 potentially toxic medications.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Psoriasis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 878-895.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP suspected pustular psoriasis, which was confirmed by a dermatologist the patient saw the following day. The dermatologist confirmed this diagnosis by performing a 4-mm punch biopsy, which included an area of new pustules on the patient’s arm. When a rash is extensive, it’s best to biopsy new lesions from the upper body, rather than old lesions below the waist.

Pustular psoriasis can lead to confluent pustules, a condition in which the skin peels off in sheets, resulting in dehydration and a risk of sepsis. This is why you shouldn’t prescribe oral prednisone for any rash before you know that it’s not psoriasis. While oral prednisone may be an effective treatment for many types of dermatitis, it can exacerbate psoriasis (as it did with this patient), and is therefore not an effective or safe treatment for it.

Knowing that pustular psoriasis can become a dermatologic emergency, the FP prescribed oral cyclosporine for the most rapid result. The patient’s blood pressure and kidney function were normal, so it was only necessary for the FP to order baseline laboratory tests. At the follow-up appointment 2 days later, the patient’s condition was already improving and there were no new pustules. Her vital signs remained stable and the pathology report confirmed pustular psoriasis.

The dermatologist planned to transition the patient from cyclosporine to acitretin, determining it was safe to prescribe an oral retinoid. The patient’s hysterectomy 2 years earlier also eliminated concerns about acitretin’s teratogenic potency. The dermatologist prescribed acitretin with directions for the patient to begin taking it in one week, tapering off the cyclosporine once the pustular psoriasis was significantly better.

After a month, the patient was off of cyclosporine completely. Her skin was clear while using daily acitretin. Monitoring of lab tests did not show any adverse effects of the patient using these 2 potentially toxic medications.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Psoriasis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 878-895.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP suspected pustular psoriasis, which was confirmed by a dermatologist the patient saw the following day. The dermatologist confirmed this diagnosis by performing a 4-mm punch biopsy, which included an area of new pustules on the patient’s arm. When a rash is extensive, it’s best to biopsy new lesions from the upper body, rather than old lesions below the waist.

Pustular psoriasis can lead to confluent pustules, a condition in which the skin peels off in sheets, resulting in dehydration and a risk of sepsis. This is why you shouldn’t prescribe oral prednisone for any rash before you know that it’s not psoriasis. While oral prednisone may be an effective treatment for many types of dermatitis, it can exacerbate psoriasis (as it did with this patient), and is therefore not an effective or safe treatment for it.

Knowing that pustular psoriasis can become a dermatologic emergency, the FP prescribed oral cyclosporine for the most rapid result. The patient’s blood pressure and kidney function were normal, so it was only necessary for the FP to order baseline laboratory tests. At the follow-up appointment 2 days later, the patient’s condition was already improving and there were no new pustules. Her vital signs remained stable and the pathology report confirmed pustular psoriasis.

The dermatologist planned to transition the patient from cyclosporine to acitretin, determining it was safe to prescribe an oral retinoid. The patient’s hysterectomy 2 years earlier also eliminated concerns about acitretin’s teratogenic potency. The dermatologist prescribed acitretin with directions for the patient to begin taking it in one week, tapering off the cyclosporine once the pustular psoriasis was significantly better.

After a month, the patient was off of cyclosporine completely. Her skin was clear while using daily acitretin. Monitoring of lab tests did not show any adverse effects of the patient using these 2 potentially toxic medications.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Psoriasis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 878-895.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

Clinical Question: What is the epidemiology of meningitis and encephalitis in adults in the United States?

Background: Previous epidemiologic studies have been smaller with less clinical information available and without steroid usage rates.

Study Design: A retrospective database review.

Setting: The Premier HealthCare Database, including hospitals of all types and sizes.

Dr. Hall is an assistant professor in the University of Kentucky division of hospital medicine and pediatrics.

Clinical Question: What is the epidemiology of meningitis and encephalitis in adults in the United States?

Background: Previous epidemiologic studies have been smaller with less clinical information available and without steroid usage rates.

Study Design: A retrospective database review.

Setting: The Premier HealthCare Database, including hospitals of all types and sizes.

Dr. Hall is an assistant professor in the University of Kentucky division of hospital medicine and pediatrics.

Clinical Question: What is the epidemiology of meningitis and encephalitis in adults in the United States?

Background: Previous epidemiologic studies have been smaller with less clinical information available and without steroid usage rates.

Study Design: A retrospective database review.

Setting: The Premier HealthCare Database, including hospitals of all types and sizes.

Dr. Hall is an assistant professor in the University of Kentucky division of hospital medicine and pediatrics.