Dermatology

Signs and symptoms of moderate to severe atopic dermatitis (AD) were significantly reduced with baricitinib 4 mg on top of topical corticosteroids, compared with placebo in the phase 3, double-blind, placebo-controlled, BREEZE-AD7 study.

The study enrolled patients with inadequate responses to topical corticosteroids, according to Kristian Reich, MD, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and his coauthors.
 

First test of baricitinib plus topical steroids

Baricitinib, an oral selective Janus kinase (JAK)1/JAK2 inhibitor, inhibits several cytokines in AD pathogenesis, and in two monotherapy studies (BREEZE-AD1 and BREEZE-AD2), it was superior to placebo for reducing several AD clinical signs and symptoms. The current BREEZE-AD7 study is the first to test baricitinib plus background topical corticosteroid therapy, more closely mirroring clinical practice, the authors noted.

BREEZE-AD7 was conducted at 68 centers in 10 countries in Asia, Australia, Europe, and South America. It included 329 adults with moderate to severe AD (mean age around 34 years, and around 34% were female) with inadequate responses to topical corticosteroids documented within the last 6 months. They were randomized 1:1:1 to daily baricitinib 4 mg, daily baricitinib 2 mg, or placebo for 16 weeks. All patients received moderate- and/or low-potency topical corticosteroids (such as 0.1%triamcinolone cream and 2.5% hydrocortisone ointment, respectively) for active lesions.
 

Significant benefit at 4 mg

At week 16, 31% of AD patients receiving baricitinib 4 mg achieved Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) scores of 0 (clear) or 1 (almost clear) versus 15% in the placebo group (odds ratio, 2.8; 95% confidence interval, 1.4-5.6; P = .004). Among patients receiving baricitinib 2 mg, 24% achieved vI-GA-AD scores of 0 or 1 (OR, 1.9; 95% CI, 0.9-3.9; P = .08).

The same pattern of improving scores from placebo to baricitinib 2 mg to baricitinib 4 mg persisted, as reflected with secondary endpoints at week 16. Among patients receiving baricitinib 4 mg, 48% achieved Eczema Area Severity Index (EASI) 75 responses, versus 43% and 23% in 2 mg and placebo groups, respectively. Percent changes from baseline in total EASI score were –67%, –58%, –45% for baricitinib 4 mg, baricitinib 2 mg, and placebo, respectively; the proportion of patients achieving 4-point or greater improvements in Itch Numeric Rating Scale (NRS) was 44%, 38%, and 20% for baricitinib 4 mg, baricitinib 2 mg and placebo, respectively.

Similarly, mean change from baseline on the Skin Pain numeric rating scale was –3.7, –3.2, and –2.1 for baricitinib 4 mg, baricitinib 2 mg and placebo. Nighttime itch awakenings were also reduced in a similar progression from placebo to the higher baricitinib dose.
 

Adverse events dose related

Treatment-related adverse events were reported more frequently in the baricitinib groups (58% baricitinib 4 mg, 56% baricitinib 2 mg) versus placebo 38%. Nasopharyngitis was most common, followed by oral herpes, upper respiratory tract infection, acne, diarrhea, and back pain. Serious adverse event rates were similar across treatment groups. Permanent discontinuation rates were low at 5% for baricitinib 4 mg, 0% for baricitinib 2 mg, and 1% for placebo. The side-effect profile for baricitinib was consistent with prior studies, Dr. Reich and his coauthors reported.

The authors noted further, “data in this study suggest that patients with AD treated with baricitinib may be able to reduce the frequency and total quantity of concomitant TCSs [topical corticosteroids] used, thus mitigating concerns associated with continual or sustained application of topical treatments.”

“Overall, this study provides further evidence to support the efficacy and safety profile of baricitinib for the treatment of moderate-severe AD,” commented one of the authors, Jonathan I. Silverberg, MD, PhD, MPH, of the department of dermatology at George Washington University in Washington.

“In particular, this study shows that adding topical corticosteroids to baricitinib increases the rate of treatment success compared with the efficacy seen in baricitinib monotherapy studies. These data will be important to guide the use of baricitinib with topical corticosteroids in clinical practice. I think these data are also important because they show that baricitinib 4 mg may be more effective than 2 mg in some patients,” he said in an interview.

In late September, the European Medicines Agency’s Committee for Medicinal Products for Human Use recommended approval of oral baricitinib for adults with moderate to severe AD who are candidates for systemic therapy. Baricitinib is approved in the European Union and the United States to treat moderate to severe active rheumatoid arthritis. If approved in Europe, it will be the first JAK inhibitor and first oral medication indicated to treat patients with AD.

The study was funded by Eli Lilly and Company under license from Incyte Corporation. Dr. Reich reported receiving fees to the institution for participation in clinical trials from Eli Lilly and Company during the conduct of the study and personal fees for lectures. Dr. Silverberg reported receiving fees from Eli Lilly and Company during the conduct of the study, and fees from companies outside of this work. Other authors also reported disclosures related to Eli Lilly and other pharmaceutical companies, and several authors were Eli Lilly employees.
 

SOURCE: Reich K et al. JAMA Dermatol. 2020 Sep 30. doi: 10.1001/jamadermatol.2020.3260.

Signs and symptoms of moderate to severe atopic dermatitis (AD) were significantly reduced with baricitinib 4 mg on top of topical corticosteroids, compared with placebo in the phase 3, double-blind, placebo-controlled, BREEZE-AD7 study.

The study enrolled patients with inadequate responses to topical corticosteroids, according to Kristian Reich, MD, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and his coauthors.
 

First test of baricitinib plus topical steroids

Baricitinib, an oral selective Janus kinase (JAK)1/JAK2 inhibitor, inhibits several cytokines in AD pathogenesis, and in two monotherapy studies (BREEZE-AD1 and BREEZE-AD2), it was superior to placebo for reducing several AD clinical signs and symptoms. The current BREEZE-AD7 study is the first to test baricitinib plus background topical corticosteroid therapy, more closely mirroring clinical practice, the authors noted.

BREEZE-AD7 was conducted at 68 centers in 10 countries in Asia, Australia, Europe, and South America. It included 329 adults with moderate to severe AD (mean age around 34 years, and around 34% were female) with inadequate responses to topical corticosteroids documented within the last 6 months. They were randomized 1:1:1 to daily baricitinib 4 mg, daily baricitinib 2 mg, or placebo for 16 weeks. All patients received moderate- and/or low-potency topical corticosteroids (such as 0.1%triamcinolone cream and 2.5% hydrocortisone ointment, respectively) for active lesions.
 

Significant benefit at 4 mg

At week 16, 31% of AD patients receiving baricitinib 4 mg achieved Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) scores of 0 (clear) or 1 (almost clear) versus 15% in the placebo group (odds ratio, 2.8; 95% confidence interval, 1.4-5.6; P = .004). Among patients receiving baricitinib 2 mg, 24% achieved vI-GA-AD scores of 0 or 1 (OR, 1.9; 95% CI, 0.9-3.9; P = .08).

The same pattern of improving scores from placebo to baricitinib 2 mg to baricitinib 4 mg persisted, as reflected with secondary endpoints at week 16. Among patients receiving baricitinib 4 mg, 48% achieved Eczema Area Severity Index (EASI) 75 responses, versus 43% and 23% in 2 mg and placebo groups, respectively. Percent changes from baseline in total EASI score were –67%, –58%, –45% for baricitinib 4 mg, baricitinib 2 mg, and placebo, respectively; the proportion of patients achieving 4-point or greater improvements in Itch Numeric Rating Scale (NRS) was 44%, 38%, and 20% for baricitinib 4 mg, baricitinib 2 mg and placebo, respectively.

Similarly, mean change from baseline on the Skin Pain numeric rating scale was –3.7, –3.2, and –2.1 for baricitinib 4 mg, baricitinib 2 mg and placebo. Nighttime itch awakenings were also reduced in a similar progression from placebo to the higher baricitinib dose.
 

Adverse events dose related

Treatment-related adverse events were reported more frequently in the baricitinib groups (58% baricitinib 4 mg, 56% baricitinib 2 mg) versus placebo 38%. Nasopharyngitis was most common, followed by oral herpes, upper respiratory tract infection, acne, diarrhea, and back pain. Serious adverse event rates were similar across treatment groups. Permanent discontinuation rates were low at 5% for baricitinib 4 mg, 0% for baricitinib 2 mg, and 1% for placebo. The side-effect profile for baricitinib was consistent with prior studies, Dr. Reich and his coauthors reported.

The authors noted further, “data in this study suggest that patients with AD treated with baricitinib may be able to reduce the frequency and total quantity of concomitant TCSs [topical corticosteroids] used, thus mitigating concerns associated with continual or sustained application of topical treatments.”

“Overall, this study provides further evidence to support the efficacy and safety profile of baricitinib for the treatment of moderate-severe AD,” commented one of the authors, Jonathan I. Silverberg, MD, PhD, MPH, of the department of dermatology at George Washington University in Washington.

“In particular, this study shows that adding topical corticosteroids to baricitinib increases the rate of treatment success compared with the efficacy seen in baricitinib monotherapy studies. These data will be important to guide the use of baricitinib with topical corticosteroids in clinical practice. I think these data are also important because they show that baricitinib 4 mg may be more effective than 2 mg in some patients,” he said in an interview.

In late September, the European Medicines Agency’s Committee for Medicinal Products for Human Use recommended approval of oral baricitinib for adults with moderate to severe AD who are candidates for systemic therapy. Baricitinib is approved in the European Union and the United States to treat moderate to severe active rheumatoid arthritis. If approved in Europe, it will be the first JAK inhibitor and first oral medication indicated to treat patients with AD.

The study was funded by Eli Lilly and Company under license from Incyte Corporation. Dr. Reich reported receiving fees to the institution for participation in clinical trials from Eli Lilly and Company during the conduct of the study and personal fees for lectures. Dr. Silverberg reported receiving fees from Eli Lilly and Company during the conduct of the study, and fees from companies outside of this work. Other authors also reported disclosures related to Eli Lilly and other pharmaceutical companies, and several authors were Eli Lilly employees.
 

SOURCE: Reich K et al. JAMA Dermatol. 2020 Sep 30. doi: 10.1001/jamadermatol.2020.3260.

Signs and symptoms of moderate to severe atopic dermatitis (AD) were significantly reduced with baricitinib 4 mg on top of topical corticosteroids, compared with placebo in the phase 3, double-blind, placebo-controlled, BREEZE-AD7 study.

The study enrolled patients with inadequate responses to topical corticosteroids, according to Kristian Reich, MD, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and his coauthors.
 

First test of baricitinib plus topical steroids

Baricitinib, an oral selective Janus kinase (JAK)1/JAK2 inhibitor, inhibits several cytokines in AD pathogenesis, and in two monotherapy studies (BREEZE-AD1 and BREEZE-AD2), it was superior to placebo for reducing several AD clinical signs and symptoms. The current BREEZE-AD7 study is the first to test baricitinib plus background topical corticosteroid therapy, more closely mirroring clinical practice, the authors noted.

BREEZE-AD7 was conducted at 68 centers in 10 countries in Asia, Australia, Europe, and South America. It included 329 adults with moderate to severe AD (mean age around 34 years, and around 34% were female) with inadequate responses to topical corticosteroids documented within the last 6 months. They were randomized 1:1:1 to daily baricitinib 4 mg, daily baricitinib 2 mg, or placebo for 16 weeks. All patients received moderate- and/or low-potency topical corticosteroids (such as 0.1%triamcinolone cream and 2.5% hydrocortisone ointment, respectively) for active lesions.
 

Significant benefit at 4 mg

At week 16, 31% of AD patients receiving baricitinib 4 mg achieved Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) scores of 0 (clear) or 1 (almost clear) versus 15% in the placebo group (odds ratio, 2.8; 95% confidence interval, 1.4-5.6; P = .004). Among patients receiving baricitinib 2 mg, 24% achieved vI-GA-AD scores of 0 or 1 (OR, 1.9; 95% CI, 0.9-3.9; P = .08).

The same pattern of improving scores from placebo to baricitinib 2 mg to baricitinib 4 mg persisted, as reflected with secondary endpoints at week 16. Among patients receiving baricitinib 4 mg, 48% achieved Eczema Area Severity Index (EASI) 75 responses, versus 43% and 23% in 2 mg and placebo groups, respectively. Percent changes from baseline in total EASI score were –67%, –58%, –45% for baricitinib 4 mg, baricitinib 2 mg, and placebo, respectively; the proportion of patients achieving 4-point or greater improvements in Itch Numeric Rating Scale (NRS) was 44%, 38%, and 20% for baricitinib 4 mg, baricitinib 2 mg and placebo, respectively.

Similarly, mean change from baseline on the Skin Pain numeric rating scale was –3.7, –3.2, and –2.1 for baricitinib 4 mg, baricitinib 2 mg and placebo. Nighttime itch awakenings were also reduced in a similar progression from placebo to the higher baricitinib dose.
 

Adverse events dose related

Treatment-related adverse events were reported more frequently in the baricitinib groups (58% baricitinib 4 mg, 56% baricitinib 2 mg) versus placebo 38%. Nasopharyngitis was most common, followed by oral herpes, upper respiratory tract infection, acne, diarrhea, and back pain. Serious adverse event rates were similar across treatment groups. Permanent discontinuation rates were low at 5% for baricitinib 4 mg, 0% for baricitinib 2 mg, and 1% for placebo. The side-effect profile for baricitinib was consistent with prior studies, Dr. Reich and his coauthors reported.

The authors noted further, “data in this study suggest that patients with AD treated with baricitinib may be able to reduce the frequency and total quantity of concomitant TCSs [topical corticosteroids] used, thus mitigating concerns associated with continual or sustained application of topical treatments.”

“Overall, this study provides further evidence to support the efficacy and safety profile of baricitinib for the treatment of moderate-severe AD,” commented one of the authors, Jonathan I. Silverberg, MD, PhD, MPH, of the department of dermatology at George Washington University in Washington.

“In particular, this study shows that adding topical corticosteroids to baricitinib increases the rate of treatment success compared with the efficacy seen in baricitinib monotherapy studies. These data will be important to guide the use of baricitinib with topical corticosteroids in clinical practice. I think these data are also important because they show that baricitinib 4 mg may be more effective than 2 mg in some patients,” he said in an interview.

In late September, the European Medicines Agency’s Committee for Medicinal Products for Human Use recommended approval of oral baricitinib for adults with moderate to severe AD who are candidates for systemic therapy. Baricitinib is approved in the European Union and the United States to treat moderate to severe active rheumatoid arthritis. If approved in Europe, it will be the first JAK inhibitor and first oral medication indicated to treat patients with AD.

The study was funded by Eli Lilly and Company under license from Incyte Corporation. Dr. Reich reported receiving fees to the institution for participation in clinical trials from Eli Lilly and Company during the conduct of the study and personal fees for lectures. Dr. Silverberg reported receiving fees from Eli Lilly and Company during the conduct of the study, and fees from companies outside of this work. Other authors also reported disclosures related to Eli Lilly and other pharmaceutical companies, and several authors were Eli Lilly employees.
 

SOURCE: Reich K et al. JAMA Dermatol. 2020 Sep 30. doi: 10.1001/jamadermatol.2020.3260.

ANSWER

The correct answer is koebnerization of pre-existing psoriasis (choice “c”).

DISCUSSION

Tattoos have been known to cause bacterial infection (choice “a”), but this was unlikely given the diffuse nature of the rash and the lack of pain or adenopathy. Allergic reactions to tattoo dyes (choice “b”) are certainly common, but usually red or yellow dyes—which were not used for this tattoo—provoke the worst reactions. Furthermore, itching would have been a more prominent feature of the patient's complaint. Had it been fungal infection (choice “d”), the steroid cream would have made it worse.

One possibility remained: the so-called isomorphic phenomenon (otherwise known as koebnerization). First described by Heinrich Koebner in the mid-19th century, koebnerization is characterized by the appearance of psoriasis in traumatized skin such as surgical wounds, abrasions, burns, or even tattoos. Several other conditions also exhibit this same linear response to trauma, including warts, molluscum, and lichen planus.

To test for this diagnosis, corroborative findings of psoriasis were sought and found in the patient’s nails. His history of rashes on the knees and elbows also contributed to establishing the diagnosis. Moreover, his complaint of arthritis was quite suggestive of psoriatic arthropathy, which afflicts about 25% of patients with psoriasis and has little to do with the severity of the skin disease itself. Once the diagnosis became more apparent, the patient recalled a family history of psoriasis. Had any question remained, a biopsy could remove doubt.

TREATMENT

For the patient, twice-daily application of a stronger steroid cream (augmented betamethasone) was prescribed. Though this quickly cleared the koebnerizing psoriasis, it is likely we haven’t seen the last of this disease.

ANSWER

The correct answer is koebnerization of pre-existing psoriasis (choice “c”).

DISCUSSION

Tattoos have been known to cause bacterial infection (choice “a”), but this was unlikely given the diffuse nature of the rash and the lack of pain or adenopathy. Allergic reactions to tattoo dyes (choice “b”) are certainly common, but usually red or yellow dyes—which were not used for this tattoo—provoke the worst reactions. Furthermore, itching would have been a more prominent feature of the patient's complaint. Had it been fungal infection (choice “d”), the steroid cream would have made it worse.

One possibility remained: the so-called isomorphic phenomenon (otherwise known as koebnerization). First described by Heinrich Koebner in the mid-19th century, koebnerization is characterized by the appearance of psoriasis in traumatized skin such as surgical wounds, abrasions, burns, or even tattoos. Several other conditions also exhibit this same linear response to trauma, including warts, molluscum, and lichen planus.

To test for this diagnosis, corroborative findings of psoriasis were sought and found in the patient’s nails. His history of rashes on the knees and elbows also contributed to establishing the diagnosis. Moreover, his complaint of arthritis was quite suggestive of psoriatic arthropathy, which afflicts about 25% of patients with psoriasis and has little to do with the severity of the skin disease itself. Once the diagnosis became more apparent, the patient recalled a family history of psoriasis. Had any question remained, a biopsy could remove doubt.

TREATMENT

For the patient, twice-daily application of a stronger steroid cream (augmented betamethasone) was prescribed. Though this quickly cleared the koebnerizing psoriasis, it is likely we haven’t seen the last of this disease.

ANSWER

The correct answer is koebnerization of pre-existing psoriasis (choice “c”).

DISCUSSION

Tattoos have been known to cause bacterial infection (choice “a”), but this was unlikely given the diffuse nature of the rash and the lack of pain or adenopathy. Allergic reactions to tattoo dyes (choice “b”) are certainly common, but usually red or yellow dyes—which were not used for this tattoo—provoke the worst reactions. Furthermore, itching would have been a more prominent feature of the patient's complaint. Had it been fungal infection (choice “d”), the steroid cream would have made it worse.

One possibility remained: the so-called isomorphic phenomenon (otherwise known as koebnerization). First described by Heinrich Koebner in the mid-19th century, koebnerization is characterized by the appearance of psoriasis in traumatized skin such as surgical wounds, abrasions, burns, or even tattoos. Several other conditions also exhibit this same linear response to trauma, including warts, molluscum, and lichen planus.

To test for this diagnosis, corroborative findings of psoriasis were sought and found in the patient’s nails. His history of rashes on the knees and elbows also contributed to establishing the diagnosis. Moreover, his complaint of arthritis was quite suggestive of psoriatic arthropathy, which afflicts about 25% of patients with psoriasis and has little to do with the severity of the skin disease itself. Once the diagnosis became more apparent, the patient recalled a family history of psoriasis. Had any question remained, a biopsy could remove doubt.

TREATMENT

For the patient, twice-daily application of a stronger steroid cream (augmented betamethasone) was prescribed. Though this quickly cleared the koebnerizing psoriasis, it is likely we haven’t seen the last of this disease.

“There’s rue for you, and here’s some for me; we may call it herb of grace o’ Sundays. O, you must wear your rue with a difference.”

— Ophelia in Hamlet by William Shakespeare

The patient was admitted to the hospital for IV fluids, pain control, and observation. The following day she admitted using the leaves of a plant on the trail as a bug repellent, as one time was taught by her grandfather. She rubbed some of the leaves on the brother as well. The grandfather shared some pictures of the bushes, and the plant was identified as Ruta graveolens.

The blisters were deroofed, cleaned with saline, and wrapped with triamcinolone ointment and petrolatum. The patient was also started on a prednisone taper and received analgesics for the severe pain.

Ruta graveolens also known as common rue or herb of grace, is an ornamental plant from the Rutaceae family. This plant is also used as a medicinal herb, condiment, and as an insect repellent. If ingested in large doses, it can cause severe abdominal pain and vomiting. It also can be hepatotoxic.

When applied to the skin and then exposed to the sun, it can cause severe phytophotodermatitis which can mimic a severe second-degree burn. The herb contains furocumarines, such as 8-methoxypsoralen and 5-methoxypsoralen and furoquinoline alkaloids. These chemicals when exposed to UVA radiation cause cell injury and inflammation of the skin. This is considered a phototoxic reaction of the skin, compared with allergic reactions, such as poison ivy dermatitis, which need a prior sensitization to the allergen for the T cells to be activated and cause injury in the skin. Other common plants and fruits that can cause phytophotodermatitis include citrus fruits, figs, carrots, celery, parsnips, parsley, and other wildflowers like hogweed.

Depending on the degree of injury, the patients can be treated with topical corticosteroids, petrolatum wraps, and pain control. In severe cases like our patient, systemic prednisone may help stop the progression of the lesions and help with the inflammation. Skin hyperpigmentation after the initial injury may take months to clear, and some patient can develop scars.

The differential diagnosis should include severe bullous contact dermatitis like exposure to urushiol in poison ivy; second- and third-degree burns; severe medications reactions such Stevens-Johnson syndrome or toxic epidermal necrolysis, and inmunobullous diseases such as bullous lupus erythematosus, pemphigus vulgaris, or bullous pemphigoid. If there is no history of exposure or there are any other systemic symptoms, consider performing a skin biopsy of one of the lesions.

In this patient’s case, the history of exposure and skin findings helped the dermatologist on call make the right diagnosis.
 

Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego. Email her at pdnews@mdedge.com.

References

J Burn Care Res. 2018 Oct 23;39(6):1064-6.

Dermatitis. 2007 Mar;18(1):52-5.

BMJ Case Rep. 2015 Dec 23;2015:bcr2015213388.

“There’s rue for you, and here’s some for me; we may call it herb of grace o’ Sundays. O, you must wear your rue with a difference.”

— Ophelia in Hamlet by William Shakespeare

The patient was admitted to the hospital for IV fluids, pain control, and observation. The following day she admitted using the leaves of a plant on the trail as a bug repellent, as one time was taught by her grandfather. She rubbed some of the leaves on the brother as well. The grandfather shared some pictures of the bushes, and the plant was identified as Ruta graveolens.

The blisters were deroofed, cleaned with saline, and wrapped with triamcinolone ointment and petrolatum. The patient was also started on a prednisone taper and received analgesics for the severe pain.

Ruta graveolens also known as common rue or herb of grace, is an ornamental plant from the Rutaceae family. This plant is also used as a medicinal herb, condiment, and as an insect repellent. If ingested in large doses, it can cause severe abdominal pain and vomiting. It also can be hepatotoxic.

When applied to the skin and then exposed to the sun, it can cause severe phytophotodermatitis which can mimic a severe second-degree burn. The herb contains furocumarines, such as 8-methoxypsoralen and 5-methoxypsoralen and furoquinoline alkaloids. These chemicals when exposed to UVA radiation cause cell injury and inflammation of the skin. This is considered a phototoxic reaction of the skin, compared with allergic reactions, such as poison ivy dermatitis, which need a prior sensitization to the allergen for the T cells to be activated and cause injury in the skin. Other common plants and fruits that can cause phytophotodermatitis include citrus fruits, figs, carrots, celery, parsnips, parsley, and other wildflowers like hogweed.

Depending on the degree of injury, the patients can be treated with topical corticosteroids, petrolatum wraps, and pain control. In severe cases like our patient, systemic prednisone may help stop the progression of the lesions and help with the inflammation. Skin hyperpigmentation after the initial injury may take months to clear, and some patient can develop scars.

The differential diagnosis should include severe bullous contact dermatitis like exposure to urushiol in poison ivy; second- and third-degree burns; severe medications reactions such Stevens-Johnson syndrome or toxic epidermal necrolysis, and inmunobullous diseases such as bullous lupus erythematosus, pemphigus vulgaris, or bullous pemphigoid. If there is no history of exposure or there are any other systemic symptoms, consider performing a skin biopsy of one of the lesions.

In this patient’s case, the history of exposure and skin findings helped the dermatologist on call make the right diagnosis.
 

Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego. Email her at pdnews@mdedge.com.

References

J Burn Care Res. 2018 Oct 23;39(6):1064-6.

Dermatitis. 2007 Mar;18(1):52-5.

BMJ Case Rep. 2015 Dec 23;2015:bcr2015213388.

“There’s rue for you, and here’s some for me; we may call it herb of grace o’ Sundays. O, you must wear your rue with a difference.”

— Ophelia in Hamlet by William Shakespeare

The patient was admitted to the hospital for IV fluids, pain control, and observation. The following day she admitted using the leaves of a plant on the trail as a bug repellent, as one time was taught by her grandfather. She rubbed some of the leaves on the brother as well. The grandfather shared some pictures of the bushes, and the plant was identified as Ruta graveolens.

The blisters were deroofed, cleaned with saline, and wrapped with triamcinolone ointment and petrolatum. The patient was also started on a prednisone taper and received analgesics for the severe pain.

Ruta graveolens also known as common rue or herb of grace, is an ornamental plant from the Rutaceae family. This plant is also used as a medicinal herb, condiment, and as an insect repellent. If ingested in large doses, it can cause severe abdominal pain and vomiting. It also can be hepatotoxic.

When applied to the skin and then exposed to the sun, it can cause severe phytophotodermatitis which can mimic a severe second-degree burn. The herb contains furocumarines, such as 8-methoxypsoralen and 5-methoxypsoralen and furoquinoline alkaloids. These chemicals when exposed to UVA radiation cause cell injury and inflammation of the skin. This is considered a phototoxic reaction of the skin, compared with allergic reactions, such as poison ivy dermatitis, which need a prior sensitization to the allergen for the T cells to be activated and cause injury in the skin. Other common plants and fruits that can cause phytophotodermatitis include citrus fruits, figs, carrots, celery, parsnips, parsley, and other wildflowers like hogweed.

Depending on the degree of injury, the patients can be treated with topical corticosteroids, petrolatum wraps, and pain control. In severe cases like our patient, systemic prednisone may help stop the progression of the lesions and help with the inflammation. Skin hyperpigmentation after the initial injury may take months to clear, and some patient can develop scars.

The differential diagnosis should include severe bullous contact dermatitis like exposure to urushiol in poison ivy; second- and third-degree burns; severe medications reactions such Stevens-Johnson syndrome or toxic epidermal necrolysis, and inmunobullous diseases such as bullous lupus erythematosus, pemphigus vulgaris, or bullous pemphigoid. If there is no history of exposure or there are any other systemic symptoms, consider performing a skin biopsy of one of the lesions.

In this patient’s case, the history of exposure and skin findings helped the dermatologist on call make the right diagnosis.
 

Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego. Email her at pdnews@mdedge.com.

References

J Burn Care Res. 2018 Oct 23;39(6):1064-6.

Dermatitis. 2007 Mar;18(1):52-5.

BMJ Case Rep. 2015 Dec 23;2015:bcr2015213388.

A 23-month-old girl with a history of well-controlled atopic dermatitis was admitted to the hospital with fever and a widespread vesicular eruption of 2 days’ duration. Two days prior to admission, the patient had 3 episodes of nonbloody diarrhea and redness in the diaper area. The child’s parents reported that the red areas spread to her arms and legs later that day, and that she subsequently developed a fever, cough, and rhinorrhea. She was taken to an urgent care facility where she was diagnosed with vulvovaginitis and an upper respiratory infection; amoxicillin was prescribed. Shortly thereafter, the patient developed more lesions in and around the mouth, as well as on the trunk, prompting the parents to bring her to the emergency department.

The history revealed that the patient had spent time with her aunt and cousins who had “red spots” on their palms and soles. The patient’s sister had a flare of “cold sores,” about 2 weeks prior to the current presentation. The patient had received a varicella zoster virus (VZV) vaccine several months earlier.

Physical examination was notable for an uncomfortable infant with erythematous macules on the bilateral palms and soles and an erythematous hard palate. The child also had scattered vesicles on an erythematous base with confluent crusted plaques on her lips, perioral skin (FIGURE 1A), abdomen, back, buttocks, arms, legs (FIGURE 1B), and dorsal aspects of her hands and feet.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Eczema coxsackium

Given the history of atopic dermatitis; prodromal diarrhea/rhinorrhea; papulovesicular eruption involving areas of prior dermatitis as well as the palms, soles, and mouth; recent contacts with suspected hand-foot-mouth disease (HFMD); and history of VZV vaccination, the favored diagnosis was eczema coxsackium.

Eczema coxsackium is an atypical form of HFMD that occurs in patients with a history of eczema. Classic HFMD usually is caused by coxsackievirus A16 or enterovirus 71, while atypical HFMD often is caused by coxsackievirus A6.^1,2,3 Patients with HFMD present with painful oral vesicles and ulcers and a papulovesicular eruption on the palms, soles, and sometimes the buttocks and genitalia. Patients may have prodromal fever, fussiness, and diarrhea. Painful oral lesions may result in poor oral intake.^1,2

Differential includes viral eruptions

Other conditions may manifest similarly to eczema coxsackium and must be ruled out before initiating proper treatment.

Eczema herpeticum (EH). In atypical HFMD, the virus can show tropism for active or previously inflamed areas of eczematous skin, leading to a widespread vesicular eruption, which can be difficult to distinguish from EH.¹ Similar to EH, eczema coxsackium does not exclusively affect children with atopic dermatitis. It also has been described in adults and patients with Darier disease, incontinentia pigmenti, and epidermolytic ichthyosis.^4-6

Prompt diagnosis and treatment for eczema coxsackium is critical to prevent unnecessary antiviral therapy.

In cases of vesicular eruptions in eczema patients, it is imperative to rule out EH. One prospective study of atypical HFMD compared similarities of the conditions. Both have a predilection for mucosa during primary infection and develop vesicular eruptions on cutaneous eczematous skin.¹ One key difference between eczema coxsackium and EH is that EH tends to produce intraoral vesicles beyond simple erythema; it also tends to predominate in the area of the head and neck.⁷

Continue to: Eczema varicellicum

Eczema varicellicum has been reported, and it has been suggested that some cases of EH may actually be caused by VZV as the 2 are clinically indistinguishable and less than half of EH cases are diagnosed with laboratory confirmation.⁸

Confirm Dx before you treat

To guide management, cases of suspected eczema coxsackium should be confirmed, and HSV/VZV should be ruled out.⁹ Testing modalities include swabbing vesicular fluid for enterovirus polymerase chain reaction (PCR) analysis (preferred modality), oropharyngeal swab up to 2 weeks after infection, or viral isolate from stool samples up to 3 months after infection.^2,3

Treatment for eczema coxsackium involves supportive care such as intravenous (IV) hydration and antipyretics. Some studies show potential benefit with IV immunoglobulin in treating severe HFMD, while other studies show the exacerbation of widespread HFMD with this treatment.^7,10

Prompt diagnosis and treatment for eczema coxsackium is critical to prevent unnecessary antiviral therapy and to help guide monitoring for associated morbidities including Gianotti-Crosti syndrome–like eruptions, purpuric eruptions, and onychomadesis.

Our patient. Because EH was in the differential, our patient was started on empiric IV acyclovir 10 mg/kg every 8 hours while test results were pending. In addition, she received acetaminophen, IV fluids, gentle sponge baths, and diligent emollient application. Scraping from a vesicle revealed negative herpes simplex virus 1/2 PCR, negative VZV direct fluorescent antibody, and a positive enterovirus PCR—confirming the diagnosis of eczema coxsackium. Interestingly, a viral culture was negative in our patient, consistent with prior reports of enterovirus being difficult to culture.¹¹

With confirmation of the diagnosis of eczema coxsackium, the IV acyclovir was discontinued, and symptoms resolved after 7 days.

CORRESPONDENCE
Shane M. Swink, DO, MS, Division of Dermatology, 1200 South Cedar Crest Boulevard, Allentown, PA 18103; shanesw@pcom.edu

A 23-month-old girl with a history of well-controlled atopic dermatitis was admitted to the hospital with fever and a widespread vesicular eruption of 2 days’ duration. Two days prior to admission, the patient had 3 episodes of nonbloody diarrhea and redness in the diaper area. The child’s parents reported that the red areas spread to her arms and legs later that day, and that she subsequently developed a fever, cough, and rhinorrhea. She was taken to an urgent care facility where she was diagnosed with vulvovaginitis and an upper respiratory infection; amoxicillin was prescribed. Shortly thereafter, the patient developed more lesions in and around the mouth, as well as on the trunk, prompting the parents to bring her to the emergency department.

The history revealed that the patient had spent time with her aunt and cousins who had “red spots” on their palms and soles. The patient’s sister had a flare of “cold sores,” about 2 weeks prior to the current presentation. The patient had received a varicella zoster virus (VZV) vaccine several months earlier.

Physical examination was notable for an uncomfortable infant with erythematous macules on the bilateral palms and soles and an erythematous hard palate. The child also had scattered vesicles on an erythematous base with confluent crusted plaques on her lips, perioral skin (FIGURE 1A), abdomen, back, buttocks, arms, legs (FIGURE 1B), and dorsal aspects of her hands and feet.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Eczema coxsackium

Given the history of atopic dermatitis; prodromal diarrhea/rhinorrhea; papulovesicular eruption involving areas of prior dermatitis as well as the palms, soles, and mouth; recent contacts with suspected hand-foot-mouth disease (HFMD); and history of VZV vaccination, the favored diagnosis was eczema coxsackium.

Eczema coxsackium is an atypical form of HFMD that occurs in patients with a history of eczema. Classic HFMD usually is caused by coxsackievirus A16 or enterovirus 71, while atypical HFMD often is caused by coxsackievirus A6.^1,2,3 Patients with HFMD present with painful oral vesicles and ulcers and a papulovesicular eruption on the palms, soles, and sometimes the buttocks and genitalia. Patients may have prodromal fever, fussiness, and diarrhea. Painful oral lesions may result in poor oral intake.^1,2

Differential includes viral eruptions

Other conditions may manifest similarly to eczema coxsackium and must be ruled out before initiating proper treatment.

Eczema herpeticum (EH). In atypical HFMD, the virus can show tropism for active or previously inflamed areas of eczematous skin, leading to a widespread vesicular eruption, which can be difficult to distinguish from EH.¹ Similar to EH, eczema coxsackium does not exclusively affect children with atopic dermatitis. It also has been described in adults and patients with Darier disease, incontinentia pigmenti, and epidermolytic ichthyosis.^4-6

Prompt diagnosis and treatment for eczema coxsackium is critical to prevent unnecessary antiviral therapy.

In cases of vesicular eruptions in eczema patients, it is imperative to rule out EH. One prospective study of atypical HFMD compared similarities of the conditions. Both have a predilection for mucosa during primary infection and develop vesicular eruptions on cutaneous eczematous skin.¹ One key difference between eczema coxsackium and EH is that EH tends to produce intraoral vesicles beyond simple erythema; it also tends to predominate in the area of the head and neck.⁷

Continue to: Eczema varicellicum

Eczema varicellicum has been reported, and it has been suggested that some cases of EH may actually be caused by VZV as the 2 are clinically indistinguishable and less than half of EH cases are diagnosed with laboratory confirmation.⁸

Confirm Dx before you treat

To guide management, cases of suspected eczema coxsackium should be confirmed, and HSV/VZV should be ruled out.⁹ Testing modalities include swabbing vesicular fluid for enterovirus polymerase chain reaction (PCR) analysis (preferred modality), oropharyngeal swab up to 2 weeks after infection, or viral isolate from stool samples up to 3 months after infection.^2,3

Treatment for eczema coxsackium involves supportive care such as intravenous (IV) hydration and antipyretics. Some studies show potential benefit with IV immunoglobulin in treating severe HFMD, while other studies show the exacerbation of widespread HFMD with this treatment.^7,10

Prompt diagnosis and treatment for eczema coxsackium is critical to prevent unnecessary antiviral therapy and to help guide monitoring for associated morbidities including Gianotti-Crosti syndrome–like eruptions, purpuric eruptions, and onychomadesis.

Our patient. Because EH was in the differential, our patient was started on empiric IV acyclovir 10 mg/kg every 8 hours while test results were pending. In addition, she received acetaminophen, IV fluids, gentle sponge baths, and diligent emollient application. Scraping from a vesicle revealed negative herpes simplex virus 1/2 PCR, negative VZV direct fluorescent antibody, and a positive enterovirus PCR—confirming the diagnosis of eczema coxsackium. Interestingly, a viral culture was negative in our patient, consistent with prior reports of enterovirus being difficult to culture.¹¹

With confirmation of the diagnosis of eczema coxsackium, the IV acyclovir was discontinued, and symptoms resolved after 7 days.

CORRESPONDENCE
Shane M. Swink, DO, MS, Division of Dermatology, 1200 South Cedar Crest Boulevard, Allentown, PA 18103; shanesw@pcom.edu

A 23-month-old girl with a history of well-controlled atopic dermatitis was admitted to the hospital with fever and a widespread vesicular eruption of 2 days’ duration. Two days prior to admission, the patient had 3 episodes of nonbloody diarrhea and redness in the diaper area. The child’s parents reported that the red areas spread to her arms and legs later that day, and that she subsequently developed a fever, cough, and rhinorrhea. She was taken to an urgent care facility where she was diagnosed with vulvovaginitis and an upper respiratory infection; amoxicillin was prescribed. Shortly thereafter, the patient developed more lesions in and around the mouth, as well as on the trunk, prompting the parents to bring her to the emergency department.

The history revealed that the patient had spent time with her aunt and cousins who had “red spots” on their palms and soles. The patient’s sister had a flare of “cold sores,” about 2 weeks prior to the current presentation. The patient had received a varicella zoster virus (VZV) vaccine several months earlier.

Physical examination was notable for an uncomfortable infant with erythematous macules on the bilateral palms and soles and an erythematous hard palate. The child also had scattered vesicles on an erythematous base with confluent crusted plaques on her lips, perioral skin (FIGURE 1A), abdomen, back, buttocks, arms, legs (FIGURE 1B), and dorsal aspects of her hands and feet.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Eczema coxsackium

Given the history of atopic dermatitis; prodromal diarrhea/rhinorrhea; papulovesicular eruption involving areas of prior dermatitis as well as the palms, soles, and mouth; recent contacts with suspected hand-foot-mouth disease (HFMD); and history of VZV vaccination, the favored diagnosis was eczema coxsackium.

Eczema coxsackium is an atypical form of HFMD that occurs in patients with a history of eczema. Classic HFMD usually is caused by coxsackievirus A16 or enterovirus 71, while atypical HFMD often is caused by coxsackievirus A6.^1,2,3 Patients with HFMD present with painful oral vesicles and ulcers and a papulovesicular eruption on the palms, soles, and sometimes the buttocks and genitalia. Patients may have prodromal fever, fussiness, and diarrhea. Painful oral lesions may result in poor oral intake.^1,2

Differential includes viral eruptions

Other conditions may manifest similarly to eczema coxsackium and must be ruled out before initiating proper treatment.

Eczema herpeticum (EH). In atypical HFMD, the virus can show tropism for active or previously inflamed areas of eczematous skin, leading to a widespread vesicular eruption, which can be difficult to distinguish from EH.¹ Similar to EH, eczema coxsackium does not exclusively affect children with atopic dermatitis. It also has been described in adults and patients with Darier disease, incontinentia pigmenti, and epidermolytic ichthyosis.^4-6

Prompt diagnosis and treatment for eczema coxsackium is critical to prevent unnecessary antiviral therapy.

In cases of vesicular eruptions in eczema patients, it is imperative to rule out EH. One prospective study of atypical HFMD compared similarities of the conditions. Both have a predilection for mucosa during primary infection and develop vesicular eruptions on cutaneous eczematous skin.¹ One key difference between eczema coxsackium and EH is that EH tends to produce intraoral vesicles beyond simple erythema; it also tends to predominate in the area of the head and neck.⁷

Continue to: Eczema varicellicum

Eczema varicellicum has been reported, and it has been suggested that some cases of EH may actually be caused by VZV as the 2 are clinically indistinguishable and less than half of EH cases are diagnosed with laboratory confirmation.⁸

Confirm Dx before you treat

To guide management, cases of suspected eczema coxsackium should be confirmed, and HSV/VZV should be ruled out.⁹ Testing modalities include swabbing vesicular fluid for enterovirus polymerase chain reaction (PCR) analysis (preferred modality), oropharyngeal swab up to 2 weeks after infection, or viral isolate from stool samples up to 3 months after infection.^2,3

Treatment for eczema coxsackium involves supportive care such as intravenous (IV) hydration and antipyretics. Some studies show potential benefit with IV immunoglobulin in treating severe HFMD, while other studies show the exacerbation of widespread HFMD with this treatment.^7,10

Prompt diagnosis and treatment for eczema coxsackium is critical to prevent unnecessary antiviral therapy and to help guide monitoring for associated morbidities including Gianotti-Crosti syndrome–like eruptions, purpuric eruptions, and onychomadesis.

Our patient. Because EH was in the differential, our patient was started on empiric IV acyclovir 10 mg/kg every 8 hours while test results were pending. In addition, she received acetaminophen, IV fluids, gentle sponge baths, and diligent emollient application. Scraping from a vesicle revealed negative herpes simplex virus 1/2 PCR, negative VZV direct fluorescent antibody, and a positive enterovirus PCR—confirming the diagnosis of eczema coxsackium. Interestingly, a viral culture was negative in our patient, consistent with prior reports of enterovirus being difficult to culture.¹¹

With confirmation of the diagnosis of eczema coxsackium, the IV acyclovir was discontinued, and symptoms resolved after 7 days.

CORRESPONDENCE
Shane M. Swink, DO, MS, Division of Dermatology, 1200 South Cedar Crest Boulevard, Allentown, PA 18103; shanesw@pcom.edu

The characteristic finding of small, scattered vesicular lesions on the hands that sometimes coalesce, and often are itchy or irritated led to the diagnosis of vesicular hand dermatitis, a form of eczema. It also is referred to as dyshidrotic eczema or pompholyx. (Worth noting is the fact that common warts and flat warts usually present as raised papular—not vesicular—lesions on the hands.)

The exact etiology of vesicular hand dermatitis is unknown. It is more common in women than men and often occurs in patients 20 to 40 years of age who tend to have a positive family history of eczema. It usually develops acutely and often is triggered by topical irritants or frequent hand washing. Treatment during the acute phase includes topical steroids. Avoidance of topical irritants, use of mild cleansers instead of harsh soaps, reduction of hand washing frequency (if possible), and frequent application of emollients can reduce recurrence.

This patient’s eczema had been successfully treated with betamethasone dipropionate ointment 0.05% in the past. Since she still had some at home, she was instructed to use it twice daily along with topical emmolients. She reported great improvement within 1 week.

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

The characteristic finding of small, scattered vesicular lesions on the hands that sometimes coalesce, and often are itchy or irritated led to the diagnosis of vesicular hand dermatitis, a form of eczema. It also is referred to as dyshidrotic eczema or pompholyx. (Worth noting is the fact that common warts and flat warts usually present as raised papular—not vesicular—lesions on the hands.)

The exact etiology of vesicular hand dermatitis is unknown. It is more common in women than men and often occurs in patients 20 to 40 years of age who tend to have a positive family history of eczema. It usually develops acutely and often is triggered by topical irritants or frequent hand washing. Treatment during the acute phase includes topical steroids. Avoidance of topical irritants, use of mild cleansers instead of harsh soaps, reduction of hand washing frequency (if possible), and frequent application of emollients can reduce recurrence.

This patient’s eczema had been successfully treated with betamethasone dipropionate ointment 0.05% in the past. Since she still had some at home, she was instructed to use it twice daily along with topical emmolients. She reported great improvement within 1 week.

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

The characteristic finding of small, scattered vesicular lesions on the hands that sometimes coalesce, and often are itchy or irritated led to the diagnosis of vesicular hand dermatitis, a form of eczema. It also is referred to as dyshidrotic eczema or pompholyx. (Worth noting is the fact that common warts and flat warts usually present as raised papular—not vesicular—lesions on the hands.)

The exact etiology of vesicular hand dermatitis is unknown. It is more common in women than men and often occurs in patients 20 to 40 years of age who tend to have a positive family history of eczema. It usually develops acutely and often is triggered by topical irritants or frequent hand washing. Treatment during the acute phase includes topical steroids. Avoidance of topical irritants, use of mild cleansers instead of harsh soaps, reduction of hand washing frequency (if possible), and frequent application of emollients can reduce recurrence.

This patient’s eczema had been successfully treated with betamethasone dipropionate ointment 0.05% in the past. Since she still had some at home, she was instructed to use it twice daily along with topical emmolients. She reported great improvement within 1 week.

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

EVIDENCE SUMMARY

A 2016 systematic review identified 2 RCTs that examined whether early introduction of peanuts affects subsequent allergies.¹ The first RCT recruited 1303 3-month-old infants from the general population in the United Kingdom.² All patients had either a negative skin prick test (SPT) to peanuts or a negative oral peanut challenge (if an initial SPT was positive). The control group breastfed exclusively until age 6 months, at which time allergenic foods could be introduced at parental discretion.

Timing doesn’t affect peanut allergy in nonallergic patients

The intervention group received 6 common allergenic foods (peanuts, eggs, cow’s milk, wheat, sesame, and whitefish) twice weekly between ages 3 and 6 months. Researchers then performed double-blinded, placebo-controlled oral food challenges at ages 12 and 36 months.

More patients in the late-introduction group demonstrated peanut allergies by age 36 months than in the early-introduction group, but the difference wasn’t significant (2.5% vs 1.2%; P = 0.11).A key weakness of the study was combining peanuts with other common food allergens.²

Children with eczema, egg allergy benefit from earlier peanut introduction

The second RCT divided 640 infants with severe eczema, egg allergy, or both into 2 groups according to their response to an SPT to peanuts: patients with no wheal and patients with a positive wheal measuring 1 to 4 mm.³ Researchers then randomized patients to either early exposure (peanut products given from ages 4 to 11 months) or avoidance (no peanuts until age 60 months). The primary endpoint was a positive clinical response to oral peanut allergen at age 60 months.

In the negative SPT group (atopic children expected to have a lower risk for allergy), patients introduced to peanuts later had a higher rate of subsequent allergy than children exposed earlier (14% vs 2%; absolute risk reduction [ARR] = 12%; 95% confidence interval [CI], 3%-20%; number needed to treat [NNT] = 9).³

In the positive SPT group (atopic children expected to have a higher risk for allergy), later peanut introduction likewise increased risk compared to earlier introduction (35% vs 11%; ARR = 24%; 95% CI, 5%-43%; NNT = 5). Children in the early-exposure group, however, had more URIs, viral exanthems, gastroenteritis, urticaria, and conjunctivitis (4527 events in the early-exposure group vs 4287 in the avoidance group, P = 0.02; about 1 more event per patient over the course of the study).³

In a general pediatric population, introducing peanuts at ages 3 to 6 months doesn’t alter subsequent peanut allergy rates compared with introduction after age 6 months.

The authors of the systematic review performed a meta-analysis of the 2 RCTs (1793 patients). They concluded that early introduction of peanuts to an infant’s diet (between ages 3 and 11 months) decreased the risk for eventual peanut allergy (relative risk [RR] = 0.29; 95% CI, 0.11-0.74), compared with introduction at or after age 1 year.¹ A key weakness, however, was the researchers’ choice to combine trials with very different inclusion criteria (infants with severe eczema and a general population).

Continue to: RECOMMENDATIONS

RECOMMENDATIONS

A 2017 National Institute of Allergy and Infectious Diseases guideline recommends a 3-tiered approach to peanut introduction: ⁴

• For children with severe eczema or egg allergy who aren’t currently allergic to peanuts (per SPT or immunoglobulin E [IgE] test), the guideline advises adding peanuts to the diet between ages 4 and 6 months. (Patients with positive SPT or IgE should be referred to an allergy specialist.)
• Children with mild or moderate eczema can be introduced to peanuts around age 6 months “in accordance with family preferences and cultural practices.”
• Children with no evidence of allergy or eczema can be “freely introduced” to peanut-containing foods with no specific guidance on age.

Editor’s takeaway

Good-quality evidence supports family physicians encouraging introduction of foods containing peanuts at age 4 to 6 months for children at increased risk because of atopy, allergies, or eczema.

EVIDENCE SUMMARY

A 2016 systematic review identified 2 RCTs that examined whether early introduction of peanuts affects subsequent allergies.¹ The first RCT recruited 1303 3-month-old infants from the general population in the United Kingdom.² All patients had either a negative skin prick test (SPT) to peanuts or a negative oral peanut challenge (if an initial SPT was positive). The control group breastfed exclusively until age 6 months, at which time allergenic foods could be introduced at parental discretion.

Timing doesn’t affect peanut allergy in nonallergic patients

The intervention group received 6 common allergenic foods (peanuts, eggs, cow’s milk, wheat, sesame, and whitefish) twice weekly between ages 3 and 6 months. Researchers then performed double-blinded, placebo-controlled oral food challenges at ages 12 and 36 months.

More patients in the late-introduction group demonstrated peanut allergies by age 36 months than in the early-introduction group, but the difference wasn’t significant (2.5% vs 1.2%; P = 0.11).A key weakness of the study was combining peanuts with other common food allergens.²

Children with eczema, egg allergy benefit from earlier peanut introduction

The second RCT divided 640 infants with severe eczema, egg allergy, or both into 2 groups according to their response to an SPT to peanuts: patients with no wheal and patients with a positive wheal measuring 1 to 4 mm.³ Researchers then randomized patients to either early exposure (peanut products given from ages 4 to 11 months) or avoidance (no peanuts until age 60 months). The primary endpoint was a positive clinical response to oral peanut allergen at age 60 months.

In the negative SPT group (atopic children expected to have a lower risk for allergy), patients introduced to peanuts later had a higher rate of subsequent allergy than children exposed earlier (14% vs 2%; absolute risk reduction [ARR] = 12%; 95% confidence interval [CI], 3%-20%; number needed to treat [NNT] = 9).³

In the positive SPT group (atopic children expected to have a higher risk for allergy), later peanut introduction likewise increased risk compared to earlier introduction (35% vs 11%; ARR = 24%; 95% CI, 5%-43%; NNT = 5). Children in the early-exposure group, however, had more URIs, viral exanthems, gastroenteritis, urticaria, and conjunctivitis (4527 events in the early-exposure group vs 4287 in the avoidance group, P = 0.02; about 1 more event per patient over the course of the study).³

In a general pediatric population, introducing peanuts at ages 3 to 6 months doesn’t alter subsequent peanut allergy rates compared with introduction after age 6 months.

The authors of the systematic review performed a meta-analysis of the 2 RCTs (1793 patients). They concluded that early introduction of peanuts to an infant’s diet (between ages 3 and 11 months) decreased the risk for eventual peanut allergy (relative risk [RR] = 0.29; 95% CI, 0.11-0.74), compared with introduction at or after age 1 year.¹ A key weakness, however, was the researchers’ choice to combine trials with very different inclusion criteria (infants with severe eczema and a general population).

Continue to: RECOMMENDATIONS

RECOMMENDATIONS

A 2017 National Institute of Allergy and Infectious Diseases guideline recommends a 3-tiered approach to peanut introduction: ⁴

• For children with severe eczema or egg allergy who aren’t currently allergic to peanuts (per SPT or immunoglobulin E [IgE] test), the guideline advises adding peanuts to the diet between ages 4 and 6 months. (Patients with positive SPT or IgE should be referred to an allergy specialist.)
• Children with mild or moderate eczema can be introduced to peanuts around age 6 months “in accordance with family preferences and cultural practices.”
• Children with no evidence of allergy or eczema can be “freely introduced” to peanut-containing foods with no specific guidance on age.

Editor’s takeaway

Good-quality evidence supports family physicians encouraging introduction of foods containing peanuts at age 4 to 6 months for children at increased risk because of atopy, allergies, or eczema.

EVIDENCE SUMMARY

A 2016 systematic review identified 2 RCTs that examined whether early introduction of peanuts affects subsequent allergies.¹ The first RCT recruited 1303 3-month-old infants from the general population in the United Kingdom.² All patients had either a negative skin prick test (SPT) to peanuts or a negative oral peanut challenge (if an initial SPT was positive). The control group breastfed exclusively until age 6 months, at which time allergenic foods could be introduced at parental discretion.

Timing doesn’t affect peanut allergy in nonallergic patients

The intervention group received 6 common allergenic foods (peanuts, eggs, cow’s milk, wheat, sesame, and whitefish) twice weekly between ages 3 and 6 months. Researchers then performed double-blinded, placebo-controlled oral food challenges at ages 12 and 36 months.

More patients in the late-introduction group demonstrated peanut allergies by age 36 months than in the early-introduction group, but the difference wasn’t significant (2.5% vs 1.2%; P = 0.11).A key weakness of the study was combining peanuts with other common food allergens.²

Children with eczema, egg allergy benefit from earlier peanut introduction

The second RCT divided 640 infants with severe eczema, egg allergy, or both into 2 groups according to their response to an SPT to peanuts: patients with no wheal and patients with a positive wheal measuring 1 to 4 mm.³ Researchers then randomized patients to either early exposure (peanut products given from ages 4 to 11 months) or avoidance (no peanuts until age 60 months). The primary endpoint was a positive clinical response to oral peanut allergen at age 60 months.

In the negative SPT group (atopic children expected to have a lower risk for allergy), patients introduced to peanuts later had a higher rate of subsequent allergy than children exposed earlier (14% vs 2%; absolute risk reduction [ARR] = 12%; 95% confidence interval [CI], 3%-20%; number needed to treat [NNT] = 9).³

In the positive SPT group (atopic children expected to have a higher risk for allergy), later peanut introduction likewise increased risk compared to earlier introduction (35% vs 11%; ARR = 24%; 95% CI, 5%-43%; NNT = 5). Children in the early-exposure group, however, had more URIs, viral exanthems, gastroenteritis, urticaria, and conjunctivitis (4527 events in the early-exposure group vs 4287 in the avoidance group, P = 0.02; about 1 more event per patient over the course of the study).³

In a general pediatric population, introducing peanuts at ages 3 to 6 months doesn’t alter subsequent peanut allergy rates compared with introduction after age 6 months.

The authors of the systematic review performed a meta-analysis of the 2 RCTs (1793 patients). They concluded that early introduction of peanuts to an infant’s diet (between ages 3 and 11 months) decreased the risk for eventual peanut allergy (relative risk [RR] = 0.29; 95% CI, 0.11-0.74), compared with introduction at or after age 1 year.¹ A key weakness, however, was the researchers’ choice to combine trials with very different inclusion criteria (infants with severe eczema and a general population).

Continue to: RECOMMENDATIONS

RECOMMENDATIONS

A 2017 National Institute of Allergy and Infectious Diseases guideline recommends a 3-tiered approach to peanut introduction: ⁴

• For children with severe eczema or egg allergy who aren’t currently allergic to peanuts (per SPT or immunoglobulin E [IgE] test), the guideline advises adding peanuts to the diet between ages 4 and 6 months. (Patients with positive SPT or IgE should be referred to an allergy specialist.)
• Children with mild or moderate eczema can be introduced to peanuts around age 6 months “in accordance with family preferences and cultural practices.”
• Children with no evidence of allergy or eczema can be “freely introduced” to peanut-containing foods with no specific guidance on age.

Editor’s takeaway

Good-quality evidence supports family physicians encouraging introduction of foods containing peanuts at age 4 to 6 months for children at increased risk because of atopy, allergies, or eczema.

Case Report

A 19-year-old female marine with a 10-year history of hidradenitis suppurativa (HS) presented with hyperpigmented nodules in the inguinal folds and a recurrent cyst in the right groin area of 2 to 3 weeks’ duration. She denied axillary or inframammary involvement. She underwent several incision and drainage procedures 1 year prior to her enlistment in the US Marine Corps at 18 years of age. She previously had been treated by dermatology with doxycycline 100-mg tablets twice daily, benzoyl peroxide wash 5% applied to affected areas and rinsed daily, and clindamycin solution 1% with minimal improvement. She denied smoking or alcohol intake and said she typically wore a loose-fitting uniform to work. As a marine, she was expected to participate in daily physical training and exercises with her military unit, during which she wore a standardized physical training uniform, including nylon shorts and a cotton T-shirt. She requested light duty—military duty status with physical limitations or restrictions—to avoid physical training that would cause further friction and irritation to the inguinal region.

Physical examination demonstrated a woman with Fitzpatrick skin type III and normal body mass index. There were hyperpigmented nodules and scarring in the inguinal folds, most consistent with Hurley stage 2. A single, 0.5-cm, draining lesion was visualized. No hyperhidrosis was noted. The patient was placed on light duty for 7 days, with physical training only at her own pace and discretion. Moreover, she was restricted from field training, rifle range training, and other situations where she may excessively sweat or not be able to adequately maintain personal hygiene. She was encouraged to continue clindamycin solution 1% to the affected area twice daily and was prescribed chlorhexidine solution 4% to use when washing affected areas in the shower. The patient also was referred to the dermatology department at the Naval Hospital Camp Pendleton (Oceanside, California), where she was treated with laser hair removal in the inguinal region, thus avoiding waxing and further aggravation of HS flares. Due to the combination of topical therapies along with laser hair removal and duty restrictions, the patient had a dramatic decrease in development of severe nodular lesions.

Comment

Presentation
Historically, the incidence of HS is estimated at 0.5% to 4% of the general population with female predominance.¹ Predisposing factors include obesity, smoking, genetic predisposition to acne, apocrine duct obstruction, and secondary bacterial infection.² During acute flares, patients generally present with tender subcutaneous nodules that drain malodorous purulent material.^3,4 Acute flares are unpredictable, and patients deal with chronic, recurrent, draining wounds, leading to a poor quality of life with resulting physical, psychological, financial, social, and emotional distress.^3-5 The negative impact of HS on a patient’s quality of life has been reported to be greater than other dermatologic conditions.⁶ Lesions can be particularly painful and can cause disfiguration to the surface of the skin.⁷ Lesion severity is described using the Hurley staging system. Patient quality of life is directly correlated with disease severity and Hurley stage. In stage 1, abscesses develop, but no sinus tracts or cicatrization is present. In stage 2, recurrent abscesses will form tracts and cicatrization. In stage 3, the abscesses become diffuse or near diffuse, with multiple interconnected tracts and abscesses across the entire area of the body.^8,9

Severe or refractory HS within the physically active military population may require consideration of light or limited duty or even separation from service. Similarly, severe HS may pose challenges with other physically demanding occupations, such as the police force and firefighters.

Prevention Focus
Prevention of flares is key for patients with HS; secondary prevention aims to reduce impact of the disease or injury that has already occurred,^10,11 which includes prevention of the infundibulofolliculitis from becoming a deep folliculitis, nodule, or fistula, as well as Hurley stage progression. Prompt diagnosis with appropriate treatment can decrease the severity of lesions, pain, and scarring. Globally, HS patients continue to experience considerable diagnostic delays of 8 to 12 years after onset of initial symptoms.^11,12 Earlier accurate diagnosis and initiation of treatment from the primary care provider or general medical officer is imperative. Initial accurate management may help keep symptoms from progressing to more severe painful lesions. Similarly, patients should be educated on how to prevent HS flares. Patients should avoid known triggers, including smoking, obesity, sweating, mechanical irritation, stress, and poor hygiene.¹¹

Shaving for hair reduction creates ingrown hair shafts, which may lead to folliculitis in mechanically stressed areas in skin folds, thus initiating the inflammatory cascade of HS.^11,13 Therefore, shaving along with any other mechanical stress should be avoided in patients with HS. Laser hair removal has been shown to be quite helpful in both the prevention and treatment of HS. In one study, 22 patients with Hurley stage 2 to 3 disease were treated with an Nd:YAG laser once monthly. Results demonstrated a 65% decrease in disease severity after 3 monthly treatments.¹¹ Similarly, other lasers have been used with success in several small case series; an 800-nm diode laser, intense pulsed light therapy, and a ruby laser have each demonstrated efficacy.¹⁴ Given these results, hair removal should be recommended to patients with HS. Military servicemembers (SMs) with certain conditions, such as polycystic ovary syndrome, pseudofolliculitis barbae, and HS, are eligible for laser hair removal when available at local military treatment facilities. Primary care providers for military SMs must have a working understanding of the disease process of HS and awareness of what resources are available for treatment, which allows for more streamlined care and improved outcomes.

Treatment Options
Treatment options are diverse and depend on the severity of HS. Typically, treatment begins with medical therapy followed by escalation to surgical intervention. Medical therapies often include antibiotics, acne treatments, antiandrogen therapy, immunosuppressive agents, and biologic therapy.^15,16 If first-line medical interventions fail to control HS, surgical interventions should be considered. Surgical intervention in conjunction with medical therapy decreases the chance for recurrence.^3,15,16

Although HS is internationally recognized as an inflammatory disease and not an infectious process, topical antibiotics can help to prevent and improve formation of abscesses, nodules, and pustules.¹¹ Agents such as clindamycin and chlorhexidine wash have proven effective in preventing flares.^11,16 Other antibiotics used alone or in combination also are efficacious. Tetracyclines are recommended as monotherapy for mild stages of HS.^17-19 Doxycycline is the most commonly used tetracycline in HS patients and has been demonstrated to penetrate Staphylococcus aureus biofilm in high enough concentrations to maintain its antibacterial activity.²⁰ Moreover, doxycycline, as with other tetracyclines, has a multitude of anti-inflammatory and immunomodulatory properties²¹ and can reduce the production of IL-1, IL-6, tumor necrosis factor α, and IL-8; downregulate chemotaxis; and promote lipo-oxygenase, matrix metalloproteinase, and nuclear factor κB (NF-κB) signaling inhibition.¹⁷

Clindamycin is the only known agent that has been studied for topical treatment and utilization in milder cases of HS.^17,22 Systemic combination of clindamycin and rifampicin is the most studied, with well-established efficacy in managing HS.^17,23,24 Clindamycin has bacteriostatic activity toward both aerobic and anaerobic gram-positive bacteria by binding irreversibly to the 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis. Rifampicin binds to the beta subunit of DNA-dependent RNA polymerase, inhibiting bacterial DNA-dependent RNA synthesis. Rifampicin has broad-spectrum activity, mostly against gram-positive as well as some gram-negative bacteria. Moreover, rifampicin has anti-inflammatory and immunomodulatory properties, including evidence that it inhibits excessive helper T cell (T_H17) responses by reducing inducible nitric oxide synthase transcription and NF-κB activity.^25,26

Metronidazole, moxifloxacin, and rifampicin as triple combination therapy has been shown to be effective in reducing HS activity in moderate to severe cases that were refractory to other treatments.²⁷ Research suggests that moxifloxacin has anti-inflammatory properties, mainly by reducing IL-1β, IL-8, and tumor necrosis factor α; stabilizing IXb protein; suppressing NF-κB signaling; and reducing IL-17A.^28,29

Ertapenem can be utilized as a single 6-week antibiotic course during surgical planning or rescue therapy.¹⁸ Moreover, ertapenem can be used to treat complicated skin and soft tissue infections and has been shown to substantially improve clinical aspects of severe HS.^17,27

Disease-modifying antirheumatic drugs are effective in the treatment of moderate to severe HS.^17-19 In 2 phase 3 trials (PIONEER I and II), adalimumab was used as monotherapy or in conjunction with antibiotics in patients with moderate to severe HS compared to placebo.³⁰ Results demonstrated a disease burden reduction of greater than 50%. Antibiotic dual therapy was not noted to significantly affect disease burden.³⁰ Of note, use of immunosuppressants in the military affects an SM’s availability for worldwide deployment and duty station assignment.

Antiandrogen therapies have demonstrated some reduction in HS flares. Although recommendations for use in HS is based on limited evidence, one randomized controlled trial compared ethinyl estradiol–norgestrel to ethinyl estradiol and cyproterone acetate. Both therapies resulted in similar efficacy, with 12 of 24 (50%) patients reporting HS symptoms improving or completely resolved.³¹ In another retrospective study of women treated with antiandrogen therapies, including ethinyl estriol, cyproterone acetate, and spironolactone, 16 of 29 (55%) patients reported improvement.³² In another study, daily doses of 100 to 150 mg of spironolactone resulted in improvement in 17 of 20 (85%) patients, including complete remission in 11 of 20 (55%) patients. Of the 3 patients with severe HS, none had complete clearing of disease burden.³³ Patients with polycystic ovary syndrome or HS flares that occur around menstruation are more likely to benefit from treatment with spironolactone.^18,32,34

Retinoids frequently have been utilized in the management of HS. In some retrospective studies and other prospective studies with 5 or more patients, isotretinoin monotherapy was utilized for a 4- to 10-month period.^18,35-38 In the Alikhan et al¹⁸ study, 85 of 207 patients demonstrated improvement of HS symptoms, with more remarkable improvements in milder cases. Isotretinoin for management of patients with HS who have concomitant nodulocystic acne would have two-fold benefits.¹⁸

Wound Care
Given the purulent nodular formation in HS, adequate wound care management is vital. There is an abundance of HS wound care management strategies utilized by clinicians and patients. When selecting the appropriate dressing, consideration for the type of HS wound, cost, ease of application, patient comfort, absorbency, and odor management is important.³ However, living arrangements for military SMs can create difficulties applying and maintaining HS dressings, especially if deployed or in a field setting. Active-duty SMs often find themselves in austere living conditions in the field, aboard ships, or in other scenarios where they may or may not have running water or showers. Maintaining adequate hygiene may be difficult, and additional education about how to keep wounds clean must be imparted. Ideal dressings for HS should be highly absorbent, comfortable when applied to the anatomic locations of the HS lesions, and easily self-applied. Ideally, dressings would have atraumatic adhesion and antimicrobial properties.³ Cost-effective dressing options that have good absorption capability include sanitary napkins, adult briefs, infant diapers, and gauze.³ These dressings help to wick moisture, thus protecting the wound from maceration, which is a common patient concern. Although gauze dressings are easier to obtain, they are not as absorbent. Abdominal pads can be utilized, but they are moderately absorbent, bulky, and more challenging to obtain over-the-counter. Hydrofiber and calcium alginate dressings with silver are not accessible to the common consumer and are more expensive than the aforementioned dressings, but they do have some antimicrobial activity. Silver-impregnated foam dressings are moldable to intertriginous areas, easy to self-apply, and have moderate-heavy absorption abilities.

Final Thoughts

Hidradenitis suppurativa poses cumbersome and uncomfortable symptoms for all patients and may pose additional hardships for military SMs or those with physically demanding occupations who work in austere environments. Severe HS can restrict a military SM from certain duty stations, positions, or deployments. Early identification of HS can help reduce HS flares, disfigurement, and placement on limited duty status, therefore rendering the SM more able to engage in his/her operational responsibilities. Hidradenitis suppurativa should be discussed with the patient, with the goal to prevent flares for SMs that will be in the field, placed in austere environments, or be deployed. Use of immunosuppressants in active-duty SMs may affect their deployability, duty assignment, and retention.

For a military SM with HS, all aspects of prevention and treatment need to be balanced with his/her ability to remain deployable and complete his/her daily duties. Military SMs are not guaranteed the ideal scenario for treatment and prevention of HS. Unsanitary environments and occlusive uniforms undoubtedly contribute to disease process and make treatment more challenging. If a military SM is in a field setting or deployed, frequent daily dressing changes should still be attempted.

Case Report

A 19-year-old female marine with a 10-year history of hidradenitis suppurativa (HS) presented with hyperpigmented nodules in the inguinal folds and a recurrent cyst in the right groin area of 2 to 3 weeks’ duration. She denied axillary or inframammary involvement. She underwent several incision and drainage procedures 1 year prior to her enlistment in the US Marine Corps at 18 years of age. She previously had been treated by dermatology with doxycycline 100-mg tablets twice daily, benzoyl peroxide wash 5% applied to affected areas and rinsed daily, and clindamycin solution 1% with minimal improvement. She denied smoking or alcohol intake and said she typically wore a loose-fitting uniform to work. As a marine, she was expected to participate in daily physical training and exercises with her military unit, during which she wore a standardized physical training uniform, including nylon shorts and a cotton T-shirt. She requested light duty—military duty status with physical limitations or restrictions—to avoid physical training that would cause further friction and irritation to the inguinal region.

Physical examination demonstrated a woman with Fitzpatrick skin type III and normal body mass index. There were hyperpigmented nodules and scarring in the inguinal folds, most consistent with Hurley stage 2. A single, 0.5-cm, draining lesion was visualized. No hyperhidrosis was noted. The patient was placed on light duty for 7 days, with physical training only at her own pace and discretion. Moreover, she was restricted from field training, rifle range training, and other situations where she may excessively sweat or not be able to adequately maintain personal hygiene. She was encouraged to continue clindamycin solution 1% to the affected area twice daily and was prescribed chlorhexidine solution 4% to use when washing affected areas in the shower. The patient also was referred to the dermatology department at the Naval Hospital Camp Pendleton (Oceanside, California), where she was treated with laser hair removal in the inguinal region, thus avoiding waxing and further aggravation of HS flares. Due to the combination of topical therapies along with laser hair removal and duty restrictions, the patient had a dramatic decrease in development of severe nodular lesions.

Comment

Presentation
Historically, the incidence of HS is estimated at 0.5% to 4% of the general population with female predominance.¹ Predisposing factors include obesity, smoking, genetic predisposition to acne, apocrine duct obstruction, and secondary bacterial infection.² During acute flares, patients generally present with tender subcutaneous nodules that drain malodorous purulent material.^3,4 Acute flares are unpredictable, and patients deal with chronic, recurrent, draining wounds, leading to a poor quality of life with resulting physical, psychological, financial, social, and emotional distress.^3-5 The negative impact of HS on a patient’s quality of life has been reported to be greater than other dermatologic conditions.⁶ Lesions can be particularly painful and can cause disfiguration to the surface of the skin.⁷ Lesion severity is described using the Hurley staging system. Patient quality of life is directly correlated with disease severity and Hurley stage. In stage 1, abscesses develop, but no sinus tracts or cicatrization is present. In stage 2, recurrent abscesses will form tracts and cicatrization. In stage 3, the abscesses become diffuse or near diffuse, with multiple interconnected tracts and abscesses across the entire area of the body.^8,9

Severe or refractory HS within the physically active military population may require consideration of light or limited duty or even separation from service. Similarly, severe HS may pose challenges with other physically demanding occupations, such as the police force and firefighters.

Prevention Focus
Prevention of flares is key for patients with HS; secondary prevention aims to reduce impact of the disease or injury that has already occurred,^10,11 which includes prevention of the infundibulofolliculitis from becoming a deep folliculitis, nodule, or fistula, as well as Hurley stage progression. Prompt diagnosis with appropriate treatment can decrease the severity of lesions, pain, and scarring. Globally, HS patients continue to experience considerable diagnostic delays of 8 to 12 years after onset of initial symptoms.^11,12 Earlier accurate diagnosis and initiation of treatment from the primary care provider or general medical officer is imperative. Initial accurate management may help keep symptoms from progressing to more severe painful lesions. Similarly, patients should be educated on how to prevent HS flares. Patients should avoid known triggers, including smoking, obesity, sweating, mechanical irritation, stress, and poor hygiene.¹¹

Shaving for hair reduction creates ingrown hair shafts, which may lead to folliculitis in mechanically stressed areas in skin folds, thus initiating the inflammatory cascade of HS.^11,13 Therefore, shaving along with any other mechanical stress should be avoided in patients with HS. Laser hair removal has been shown to be quite helpful in both the prevention and treatment of HS. In one study, 22 patients with Hurley stage 2 to 3 disease were treated with an Nd:YAG laser once monthly. Results demonstrated a 65% decrease in disease severity after 3 monthly treatments.¹¹ Similarly, other lasers have been used with success in several small case series; an 800-nm diode laser, intense pulsed light therapy, and a ruby laser have each demonstrated efficacy.¹⁴ Given these results, hair removal should be recommended to patients with HS. Military servicemembers (SMs) with certain conditions, such as polycystic ovary syndrome, pseudofolliculitis barbae, and HS, are eligible for laser hair removal when available at local military treatment facilities. Primary care providers for military SMs must have a working understanding of the disease process of HS and awareness of what resources are available for treatment, which allows for more streamlined care and improved outcomes.

Treatment Options
Treatment options are diverse and depend on the severity of HS. Typically, treatment begins with medical therapy followed by escalation to surgical intervention. Medical therapies often include antibiotics, acne treatments, antiandrogen therapy, immunosuppressive agents, and biologic therapy.^15,16 If first-line medical interventions fail to control HS, surgical interventions should be considered. Surgical intervention in conjunction with medical therapy decreases the chance for recurrence.^3,15,16

Although HS is internationally recognized as an inflammatory disease and not an infectious process, topical antibiotics can help to prevent and improve formation of abscesses, nodules, and pustules.¹¹ Agents such as clindamycin and chlorhexidine wash have proven effective in preventing flares.^11,16 Other antibiotics used alone or in combination also are efficacious. Tetracyclines are recommended as monotherapy for mild stages of HS.^17-19 Doxycycline is the most commonly used tetracycline in HS patients and has been demonstrated to penetrate Staphylococcus aureus biofilm in high enough concentrations to maintain its antibacterial activity.²⁰ Moreover, doxycycline, as with other tetracyclines, has a multitude of anti-inflammatory and immunomodulatory properties²¹ and can reduce the production of IL-1, IL-6, tumor necrosis factor α, and IL-8; downregulate chemotaxis; and promote lipo-oxygenase, matrix metalloproteinase, and nuclear factor κB (NF-κB) signaling inhibition.¹⁷

Clindamycin is the only known agent that has been studied for topical treatment and utilization in milder cases of HS.^17,22 Systemic combination of clindamycin and rifampicin is the most studied, with well-established efficacy in managing HS.^17,23,24 Clindamycin has bacteriostatic activity toward both aerobic and anaerobic gram-positive bacteria by binding irreversibly to the 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis. Rifampicin binds to the beta subunit of DNA-dependent RNA polymerase, inhibiting bacterial DNA-dependent RNA synthesis. Rifampicin has broad-spectrum activity, mostly against gram-positive as well as some gram-negative bacteria. Moreover, rifampicin has anti-inflammatory and immunomodulatory properties, including evidence that it inhibits excessive helper T cell (T_H17) responses by reducing inducible nitric oxide synthase transcription and NF-κB activity.^25,26

Metronidazole, moxifloxacin, and rifampicin as triple combination therapy has been shown to be effective in reducing HS activity in moderate to severe cases that were refractory to other treatments.²⁷ Research suggests that moxifloxacin has anti-inflammatory properties, mainly by reducing IL-1β, IL-8, and tumor necrosis factor α; stabilizing IXb protein; suppressing NF-κB signaling; and reducing IL-17A.^28,29

Ertapenem can be utilized as a single 6-week antibiotic course during surgical planning or rescue therapy.¹⁸ Moreover, ertapenem can be used to treat complicated skin and soft tissue infections and has been shown to substantially improve clinical aspects of severe HS.^17,27

Disease-modifying antirheumatic drugs are effective in the treatment of moderate to severe HS.^17-19 In 2 phase 3 trials (PIONEER I and II), adalimumab was used as monotherapy or in conjunction with antibiotics in patients with moderate to severe HS compared to placebo.³⁰ Results demonstrated a disease burden reduction of greater than 50%. Antibiotic dual therapy was not noted to significantly affect disease burden.³⁰ Of note, use of immunosuppressants in the military affects an SM’s availability for worldwide deployment and duty station assignment.

Antiandrogen therapies have demonstrated some reduction in HS flares. Although recommendations for use in HS is based on limited evidence, one randomized controlled trial compared ethinyl estradiol–norgestrel to ethinyl estradiol and cyproterone acetate. Both therapies resulted in similar efficacy, with 12 of 24 (50%) patients reporting HS symptoms improving or completely resolved.³¹ In another retrospective study of women treated with antiandrogen therapies, including ethinyl estriol, cyproterone acetate, and spironolactone, 16 of 29 (55%) patients reported improvement.³² In another study, daily doses of 100 to 150 mg of spironolactone resulted in improvement in 17 of 20 (85%) patients, including complete remission in 11 of 20 (55%) patients. Of the 3 patients with severe HS, none had complete clearing of disease burden.³³ Patients with polycystic ovary syndrome or HS flares that occur around menstruation are more likely to benefit from treatment with spironolactone.^18,32,34

Retinoids frequently have been utilized in the management of HS. In some retrospective studies and other prospective studies with 5 or more patients, isotretinoin monotherapy was utilized for a 4- to 10-month period.^18,35-38 In the Alikhan et al¹⁸ study, 85 of 207 patients demonstrated improvement of HS symptoms, with more remarkable improvements in milder cases. Isotretinoin for management of patients with HS who have concomitant nodulocystic acne would have two-fold benefits.¹⁸

Wound Care
Given the purulent nodular formation in HS, adequate wound care management is vital. There is an abundance of HS wound care management strategies utilized by clinicians and patients. When selecting the appropriate dressing, consideration for the type of HS wound, cost, ease of application, patient comfort, absorbency, and odor management is important.³ However, living arrangements for military SMs can create difficulties applying and maintaining HS dressings, especially if deployed or in a field setting. Active-duty SMs often find themselves in austere living conditions in the field, aboard ships, or in other scenarios where they may or may not have running water or showers. Maintaining adequate hygiene may be difficult, and additional education about how to keep wounds clean must be imparted. Ideal dressings for HS should be highly absorbent, comfortable when applied to the anatomic locations of the HS lesions, and easily self-applied. Ideally, dressings would have atraumatic adhesion and antimicrobial properties.³ Cost-effective dressing options that have good absorption capability include sanitary napkins, adult briefs, infant diapers, and gauze.³ These dressings help to wick moisture, thus protecting the wound from maceration, which is a common patient concern. Although gauze dressings are easier to obtain, they are not as absorbent. Abdominal pads can be utilized, but they are moderately absorbent, bulky, and more challenging to obtain over-the-counter. Hydrofiber and calcium alginate dressings with silver are not accessible to the common consumer and are more expensive than the aforementioned dressings, but they do have some antimicrobial activity. Silver-impregnated foam dressings are moldable to intertriginous areas, easy to self-apply, and have moderate-heavy absorption abilities.

Final Thoughts

Hidradenitis suppurativa poses cumbersome and uncomfortable symptoms for all patients and may pose additional hardships for military SMs or those with physically demanding occupations who work in austere environments. Severe HS can restrict a military SM from certain duty stations, positions, or deployments. Early identification of HS can help reduce HS flares, disfigurement, and placement on limited duty status, therefore rendering the SM more able to engage in his/her operational responsibilities. Hidradenitis suppurativa should be discussed with the patient, with the goal to prevent flares for SMs that will be in the field, placed in austere environments, or be deployed. Use of immunosuppressants in active-duty SMs may affect their deployability, duty assignment, and retention.

For a military SM with HS, all aspects of prevention and treatment need to be balanced with his/her ability to remain deployable and complete his/her daily duties. Military SMs are not guaranteed the ideal scenario for treatment and prevention of HS. Unsanitary environments and occlusive uniforms undoubtedly contribute to disease process and make treatment more challenging. If a military SM is in a field setting or deployed, frequent daily dressing changes should still be attempted.

Case Report

A 19-year-old female marine with a 10-year history of hidradenitis suppurativa (HS) presented with hyperpigmented nodules in the inguinal folds and a recurrent cyst in the right groin area of 2 to 3 weeks’ duration. She denied axillary or inframammary involvement. She underwent several incision and drainage procedures 1 year prior to her enlistment in the US Marine Corps at 18 years of age. She previously had been treated by dermatology with doxycycline 100-mg tablets twice daily, benzoyl peroxide wash 5% applied to affected areas and rinsed daily, and clindamycin solution 1% with minimal improvement. She denied smoking or alcohol intake and said she typically wore a loose-fitting uniform to work. As a marine, she was expected to participate in daily physical training and exercises with her military unit, during which she wore a standardized physical training uniform, including nylon shorts and a cotton T-shirt. She requested light duty—military duty status with physical limitations or restrictions—to avoid physical training that would cause further friction and irritation to the inguinal region.

Physical examination demonstrated a woman with Fitzpatrick skin type III and normal body mass index. There were hyperpigmented nodules and scarring in the inguinal folds, most consistent with Hurley stage 2. A single, 0.5-cm, draining lesion was visualized. No hyperhidrosis was noted. The patient was placed on light duty for 7 days, with physical training only at her own pace and discretion. Moreover, she was restricted from field training, rifle range training, and other situations where she may excessively sweat or not be able to adequately maintain personal hygiene. She was encouraged to continue clindamycin solution 1% to the affected area twice daily and was prescribed chlorhexidine solution 4% to use when washing affected areas in the shower. The patient also was referred to the dermatology department at the Naval Hospital Camp Pendleton (Oceanside, California), where she was treated with laser hair removal in the inguinal region, thus avoiding waxing and further aggravation of HS flares. Due to the combination of topical therapies along with laser hair removal and duty restrictions, the patient had a dramatic decrease in development of severe nodular lesions.

Comment

Presentation
Historically, the incidence of HS is estimated at 0.5% to 4% of the general population with female predominance.¹ Predisposing factors include obesity, smoking, genetic predisposition to acne, apocrine duct obstruction, and secondary bacterial infection.² During acute flares, patients generally present with tender subcutaneous nodules that drain malodorous purulent material.^3,4 Acute flares are unpredictable, and patients deal with chronic, recurrent, draining wounds, leading to a poor quality of life with resulting physical, psychological, financial, social, and emotional distress.^3-5 The negative impact of HS on a patient’s quality of life has been reported to be greater than other dermatologic conditions.⁶ Lesions can be particularly painful and can cause disfiguration to the surface of the skin.⁷ Lesion severity is described using the Hurley staging system. Patient quality of life is directly correlated with disease severity and Hurley stage. In stage 1, abscesses develop, but no sinus tracts or cicatrization is present. In stage 2, recurrent abscesses will form tracts and cicatrization. In stage 3, the abscesses become diffuse or near diffuse, with multiple interconnected tracts and abscesses across the entire area of the body.^8,9

Severe or refractory HS within the physically active military population may require consideration of light or limited duty or even separation from service. Similarly, severe HS may pose challenges with other physically demanding occupations, such as the police force and firefighters.

Prevention Focus
Prevention of flares is key for patients with HS; secondary prevention aims to reduce impact of the disease or injury that has already occurred,^10,11 which includes prevention of the infundibulofolliculitis from becoming a deep folliculitis, nodule, or fistula, as well as Hurley stage progression. Prompt diagnosis with appropriate treatment can decrease the severity of lesions, pain, and scarring. Globally, HS patients continue to experience considerable diagnostic delays of 8 to 12 years after onset of initial symptoms.^11,12 Earlier accurate diagnosis and initiation of treatment from the primary care provider or general medical officer is imperative. Initial accurate management may help keep symptoms from progressing to more severe painful lesions. Similarly, patients should be educated on how to prevent HS flares. Patients should avoid known triggers, including smoking, obesity, sweating, mechanical irritation, stress, and poor hygiene.¹¹

Shaving for hair reduction creates ingrown hair shafts, which may lead to folliculitis in mechanically stressed areas in skin folds, thus initiating the inflammatory cascade of HS.^11,13 Therefore, shaving along with any other mechanical stress should be avoided in patients with HS. Laser hair removal has been shown to be quite helpful in both the prevention and treatment of HS. In one study, 22 patients with Hurley stage 2 to 3 disease were treated with an Nd:YAG laser once monthly. Results demonstrated a 65% decrease in disease severity after 3 monthly treatments.¹¹ Similarly, other lasers have been used with success in several small case series; an 800-nm diode laser, intense pulsed light therapy, and a ruby laser have each demonstrated efficacy.¹⁴ Given these results, hair removal should be recommended to patients with HS. Military servicemembers (SMs) with certain conditions, such as polycystic ovary syndrome, pseudofolliculitis barbae, and HS, are eligible for laser hair removal when available at local military treatment facilities. Primary care providers for military SMs must have a working understanding of the disease process of HS and awareness of what resources are available for treatment, which allows for more streamlined care and improved outcomes.

Treatment Options
Treatment options are diverse and depend on the severity of HS. Typically, treatment begins with medical therapy followed by escalation to surgical intervention. Medical therapies often include antibiotics, acne treatments, antiandrogen therapy, immunosuppressive agents, and biologic therapy.^15,16 If first-line medical interventions fail to control HS, surgical interventions should be considered. Surgical intervention in conjunction with medical therapy decreases the chance for recurrence.^3,15,16

Although HS is internationally recognized as an inflammatory disease and not an infectious process, topical antibiotics can help to prevent and improve formation of abscesses, nodules, and pustules.¹¹ Agents such as clindamycin and chlorhexidine wash have proven effective in preventing flares.^11,16 Other antibiotics used alone or in combination also are efficacious. Tetracyclines are recommended as monotherapy for mild stages of HS.^17-19 Doxycycline is the most commonly used tetracycline in HS patients and has been demonstrated to penetrate Staphylococcus aureus biofilm in high enough concentrations to maintain its antibacterial activity.²⁰ Moreover, doxycycline, as with other tetracyclines, has a multitude of anti-inflammatory and immunomodulatory properties²¹ and can reduce the production of IL-1, IL-6, tumor necrosis factor α, and IL-8; downregulate chemotaxis; and promote lipo-oxygenase, matrix metalloproteinase, and nuclear factor κB (NF-κB) signaling inhibition.¹⁷

Clindamycin is the only known agent that has been studied for topical treatment and utilization in milder cases of HS.^17,22 Systemic combination of clindamycin and rifampicin is the most studied, with well-established efficacy in managing HS.^17,23,24 Clindamycin has bacteriostatic activity toward both aerobic and anaerobic gram-positive bacteria by binding irreversibly to the 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis. Rifampicin binds to the beta subunit of DNA-dependent RNA polymerase, inhibiting bacterial DNA-dependent RNA synthesis. Rifampicin has broad-spectrum activity, mostly against gram-positive as well as some gram-negative bacteria. Moreover, rifampicin has anti-inflammatory and immunomodulatory properties, including evidence that it inhibits excessive helper T cell (T_H17) responses by reducing inducible nitric oxide synthase transcription and NF-κB activity.^25,26

Metronidazole, moxifloxacin, and rifampicin as triple combination therapy has been shown to be effective in reducing HS activity in moderate to severe cases that were refractory to other treatments.²⁷ Research suggests that moxifloxacin has anti-inflammatory properties, mainly by reducing IL-1β, IL-8, and tumor necrosis factor α; stabilizing IXb protein; suppressing NF-κB signaling; and reducing IL-17A.^28,29

Ertapenem can be utilized as a single 6-week antibiotic course during surgical planning or rescue therapy.¹⁸ Moreover, ertapenem can be used to treat complicated skin and soft tissue infections and has been shown to substantially improve clinical aspects of severe HS.^17,27

Disease-modifying antirheumatic drugs are effective in the treatment of moderate to severe HS.^17-19 In 2 phase 3 trials (PIONEER I and II), adalimumab was used as monotherapy or in conjunction with antibiotics in patients with moderate to severe HS compared to placebo.³⁰ Results demonstrated a disease burden reduction of greater than 50%. Antibiotic dual therapy was not noted to significantly affect disease burden.³⁰ Of note, use of immunosuppressants in the military affects an SM’s availability for worldwide deployment and duty station assignment.

Antiandrogen therapies have demonstrated some reduction in HS flares. Although recommendations for use in HS is based on limited evidence, one randomized controlled trial compared ethinyl estradiol–norgestrel to ethinyl estradiol and cyproterone acetate. Both therapies resulted in similar efficacy, with 12 of 24 (50%) patients reporting HS symptoms improving or completely resolved.³¹ In another retrospective study of women treated with antiandrogen therapies, including ethinyl estriol, cyproterone acetate, and spironolactone, 16 of 29 (55%) patients reported improvement.³² In another study, daily doses of 100 to 150 mg of spironolactone resulted in improvement in 17 of 20 (85%) patients, including complete remission in 11 of 20 (55%) patients. Of the 3 patients with severe HS, none had complete clearing of disease burden.³³ Patients with polycystic ovary syndrome or HS flares that occur around menstruation are more likely to benefit from treatment with spironolactone.^18,32,34

Retinoids frequently have been utilized in the management of HS. In some retrospective studies and other prospective studies with 5 or more patients, isotretinoin monotherapy was utilized for a 4- to 10-month period.^18,35-38 In the Alikhan et al¹⁸ study, 85 of 207 patients demonstrated improvement of HS symptoms, with more remarkable improvements in milder cases. Isotretinoin for management of patients with HS who have concomitant nodulocystic acne would have two-fold benefits.¹⁸

Wound Care
Given the purulent nodular formation in HS, adequate wound care management is vital. There is an abundance of HS wound care management strategies utilized by clinicians and patients. When selecting the appropriate dressing, consideration for the type of HS wound, cost, ease of application, patient comfort, absorbency, and odor management is important.³ However, living arrangements for military SMs can create difficulties applying and maintaining HS dressings, especially if deployed or in a field setting. Active-duty SMs often find themselves in austere living conditions in the field, aboard ships, or in other scenarios where they may or may not have running water or showers. Maintaining adequate hygiene may be difficult, and additional education about how to keep wounds clean must be imparted. Ideal dressings for HS should be highly absorbent, comfortable when applied to the anatomic locations of the HS lesions, and easily self-applied. Ideally, dressings would have atraumatic adhesion and antimicrobial properties.³ Cost-effective dressing options that have good absorption capability include sanitary napkins, adult briefs, infant diapers, and gauze.³ These dressings help to wick moisture, thus protecting the wound from maceration, which is a common patient concern. Although gauze dressings are easier to obtain, they are not as absorbent. Abdominal pads can be utilized, but they are moderately absorbent, bulky, and more challenging to obtain over-the-counter. Hydrofiber and calcium alginate dressings with silver are not accessible to the common consumer and are more expensive than the aforementioned dressings, but they do have some antimicrobial activity. Silver-impregnated foam dressings are moldable to intertriginous areas, easy to self-apply, and have moderate-heavy absorption abilities.

Final Thoughts

Hidradenitis suppurativa poses cumbersome and uncomfortable symptoms for all patients and may pose additional hardships for military SMs or those with physically demanding occupations who work in austere environments. Severe HS can restrict a military SM from certain duty stations, positions, or deployments. Early identification of HS can help reduce HS flares, disfigurement, and placement on limited duty status, therefore rendering the SM more able to engage in his/her operational responsibilities. Hidradenitis suppurativa should be discussed with the patient, with the goal to prevent flares for SMs that will be in the field, placed in austere environments, or be deployed. Use of immunosuppressants in active-duty SMs may affect their deployability, duty assignment, and retention.

For a military SM with HS, all aspects of prevention and treatment need to be balanced with his/her ability to remain deployable and complete his/her daily duties. Military SMs are not guaranteed the ideal scenario for treatment and prevention of HS. Unsanitary environments and occlusive uniforms undoubtedly contribute to disease process and make treatment more challenging. If a military SM is in a field setting or deployed, frequent daily dressing changes should still be attempted.

Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited disorder that is estimated to occur in 1:2500 births and to have a prevalence of 1:2000 to 1:4000.^1,2 It was first described in 1882 by Friedrich Daniel Von Recklinghausen, who identified patients and their relatives with signs of neuroectodermal abnormalities (café-au-lait macules [CALMs], axillary and inguinal freckling, and neurofibromas).

NF1 may begin insidiously in childhood and evolves as the patient ages. It is associated with intracranial, intraspinal, and intraorbital neoplasms, although other organs and tissues can also be involved.

The family physician might be the first one to recognize the signs of this condition during a well-child exam and is in a unique position to coordinate a multidisciplinary approach to care.

A mutated allele and early manifestations on the skin

NF1 has been attributed to genetic mosaicism and is classified as segmental, generalized, or (less frequently) gonadal. The disorder results from germline mutations in the NF1 tumor-suppressor gene on chromosome 17, known to codify the cytoplasmic protein called neurofibromin.³ The penetrance of NF1 is complete, which means that 100% of patients with the mutated allele will develop the disease.

Patients typically have symptoms by the third decade of life, although many will show signs of the disease in early childhood. CALMs are the earliest expression of NF1. They manifest in the first 2 years of life and are found in almost all affected patients. The lesions are well defined and measure 10 to 40 mm. They are typically light brown, although they may darken with sun exposure.

Histologically, the lesions will show macromelanosomes and high concentrations of melanin but do not represent an increased risk for malignancy.⁴ Not all isolated CALMs are a sign of NF1. While children younger than 29 months with 6 or more CALMs have a high risk for NF1 (80.4%; 95% confidence interval [CI], 74.6% to 86.2%), those who are older than 29 months with at least 1 atypical CALM or fewer than 6 CALMs have just a 0.9% (95% CI, 0% to 2.6%) risk for constitutional NF1.⁵

Freckles are also observed in 90% of patients with NF1; these tend to develop after the third year of life. The breast and trunk are the most commonly affected areas in adults. The pathophysiology is unknown, but this freckling is believed to be related to skin friction, high humidity, and ambient temperature.⁶

Continue to: Neurofibromas are benign...

Some patients show disfiguration when hundreds of neurofibromas are present.

Neurofibromas are benign subcutaneous palpable lesions that grow within peripheral nerve tissue, including spinal, subcutaneous, plexiform, or dermal encapsulated nerves. Originating in Schwann cells, they are composed of fibroblasts, mast cells, macrophages, endothelial cells, and other perineural cells. Some patients show disfiguration when hundreds of these masses are present (FIGURE). These tumors increase in number as the patient ages or during pregnancy, which is thought to be secondary to hormonal changes.⁷ They are sometimes painful and can be pruritic. Their appearance can also cause patient distress.

The diagnosis is a clinical one

Suspicion for NF1 should be high in patients presenting with the dermatologic findings described, although CALMs and freckling are not exclusive to NF1. Diagnostic criteria for NF1, which distinguish it from other conditions, were first outlined in a National Institutes of Health Consensus Development Conference Statement in 1987.⁸ The list of criteria has subsequently been expanded.

While the presence of at least 2 criteria is required for diagnosis,² NF1 should be suspected in individuals who have any of the following findings^8,9:

• the presence of at least 6 CALMs that are > 5 mm in prepubertal children and > 15 mm in adults
• 2 or more neurofibromas of any type, or at least one plexiform neurofibroma
• axillary or groin freckling
• optic pathway glioma
• 2 or more Lisch nodules (iris hamartomas seen on slit-lamp examination)
• bony dysplasia (sphenoid wing dysplasia, bowing of long bone ± pseudarthrosis)
• first-degree relative with NF1.

What you’ll see as the disease progresses

NF1 can affect a variety of systems, and potential complications of the disease are numerous and varied (see TABLE⁹). Here is some of what you may see as the patient’s disease progresses to various organ systems:

Learning disabilities and other cognitive and behavioral problems, such as attention-deficit/hyperactivity disorder, may affect up to 70% of children with NF1. Additionally, children with NF1 have visual/spatial problems, impaired visual motor integration, and language deficits.¹⁰ The etiology of cognitive impairment in NF1 is unknown.¹¹  

Continue to: Hypertension

Hypertension is common and may contribute to premature death in patients with NF1. Up to 27% of patients will have significant cardiovascular anomalies, including pulmonary valve stenosis, hypertrophic cardiomyopathy in patients with complete deletions of the NF1 gene, intracardiac neurofibromas, renal artery stenosis, coarctation of the aorta, and cerebral infarctions.¹² Renal artery stenosis occurs in approximately 2% of the NF1 population, and the diagnosis should be considered in hypertensive children, young adults, pregnant women, older individuals with refractory hypertension, and those with an abdominal bruit.¹³

Psychological issues. The disfigurement caused by neurofibromas and the uncertainty of an unpredictable disease course can cause psychological manifestations for patients with NF1. Anxiety and depression are common. Not surprisingly, patients with more severe disease report more adverse psychological effects.

Orthopedic deformities. Spinal deformities are the most common skeletal manifestation of NF1, with an incidence estimated from 10% to 25% in various studies. Bone mineral density, as measured by age- and gender-adjusted Z-scores, is significantly lower in NF1 patients than in the general population.¹⁴ Children may develop bowing of the long bones, particularly the tibia, and pseudarthrosis, a false joint in a long bone. Children with NF1 need yearly assessment of the spine. Patients with clinical evidence of scoliosis should be referred to Orthopedics for further evaluation.

Eye issues. A majority of adult patients develop neurofibroma-like nodules in the iris known as Lisch nodules. The nodules are not thought to cause any ophthalmologic complications. Patients may also develop palpebral neurofibroma, which may become large and sporadically show malignant transformation. Optic nerve glioma may cause strabismus and proptosis, and a large number of patients will also develop glaucoma and globe enlargement.¹⁵

Gastrointestinal lesions and cancer. Neurofibromas can grow in the stomach, liver, mesentery, retroperitoneum, and bowel. Adenocarcinoma developed in 23% of patients.¹⁶ Gastrointestinal tract bleeding, pseudo-obstruction, and protein-losing enteropathy also may occur.¹⁷

Continue to: Central nervous system manifestations

Central nervous system manifestations. Neurological manifestations have been observed in 55% of patients with NF1.¹⁸ These include headache, hydrocephalus, epilepsy, lacunar stroke, white matter disease, intraspinal neurofibroma, facial palsy, radiculopathy, and polyneuropathy. Tumors include optic pathway tumors, meningioma, and cerebral glioma. Glioma is the predominant tumor type in NF1 and occurs in all parts of the nervous system, with a predilection for the optic pathways, brainstem, and cerebellum.¹⁸

Malignant peripheral nerve sheath tumors. There is an 8% to 13% lifetime risk for malignant peripheral nerve sheath tumors (MPNST), predominantly in individuals between the ages of 20 and 35.^19,20 Any change in neurofibroma from soft to hard, or a rapid increase in the size, is suspicious for MPNST. Other symptoms include persistent pain lasting for longer than a month, pain that disturbs sleep, and new neurological deficits. These cancers can be hard to detect, leading to poor prognosis secondary to metastasis.^19,20 The greatest risk factors for MPNST are pain associated with a mass and the presence of cutaneous and subcutaneous neurofibromas.²¹

Treatment is symptom based, but there is a new option

Treatment is individualized to the patient’s symptoms. Neurofibromas that are disfiguring, disruptive, or malignant may be surgically removed.

In April 2020, the US Food and Drug Administration (FDA) approved selumetinib (Koselugo) for the treatment of pediatric patients (ages ≥ 2 years) with NF1 who have symptomatic, inoperable plexiform neurofibromas (PNs).²² In a clinical trial, patients received selumetinib 25 mg/m² orally twice a day until they demonstrated disease progression or experienced “unacceptable” adverse events.^22,23 The overall response rate was 66%, defined as “the percentage of patients with a complete response and those who experienced more than a 20% reduction in PN volume on MRI that was confirmed on a subsequent MRI within 3 to 6 months.”²²

In light of the condition’s heterogeneity, the goals of care include early recognition and treatment of complications, especially neoplasms.

Of note, all patients had a partial, not complete, response. Common adverse effects included vomiting, rash, abdominal pain, diarrhea, and nausea.²³ Selumetinib may also cause more serious adverse effects, including cardiomyopathy and ocular toxicity. Prior to treatment initiation and at regular intervals during treatment, patients should undergo cardiac and ophthalmic evaluation.^22,23 Selumetinib was granted priority review and orphan drug status by the FDA.²²

Continue to: You play a key role in ongoing monitoring

 

 

You play a key role in ongoing monitoring

In light of the condition’s heterogeneity, the goals of care include early recognition and treatment of complications, especially neoplasms; optimization of quality of life; and identification and treatment of comorbidities. Family physicians are well positioned to monitor patients with NF1 for age-specific disease manifestations and potential complications.⁹ All patients require:

• an annual physical examination by a physician who is familiar with the individual and with the disease
• annual ophthalmologic examination in early childhood; less frequent examination in older children and adults
• regular blood pressure monitoring
• other studies (eg, MRI) only as indicated on the basis of clinically apparent signs or symptoms
• monitoring by an appropriate specialist if there are abnormalities of the central nervous, skeletal, or cardiovascular systems
• referral to a neurologist for any unexplained neurological signs and symptoms. Referral should be urgent if there are acute symptoms of progressive sensory disturbance, motor deficit and incoordination, or sphincter disturbances since these might indicate an intracranial lesion or spinal cord compression. Headaches on waking, morning vomiting, and altered consciousness are suggestive of raised intracranial pressure.

Children with NF1 benefit from coordinated care between the FP and a pediatrician or other specialist familiar with the disease. In addition to providing usual well care, perform regular assessment of development and school performance. Pay careful attention to the cardiovascular system (particularly blood pressure) and evaluate for scoliosis.

Young adults should be continually monitored for all complications, especially hypertension. This population requires continued education about NF1 and its possible complications and may benefit from counseling about disease inheritance. Screen for anxiety and depression; offer psychological support.

Provide adult patients with education about complications, especially malignant peripheral nerve sheath tumors and spinal cord compression.

Adults require monitoring based on patient preference and disease severity. For this population, blood pressure should be measured annually, or more frequently if the patient’s values indicate borderline hypertension. Provide education about complications, especially MPNSTs and spinal cord compression. Patients who have abnormalities of the central nervous, skeletal, or cardiovascular systems should be monitored by an appropriate specialist. If desired, the patient may be referred to a geneticist, especially if he or she expresses concern about inheritance. Cutaneous neurofibromas can be removed if they cause discomfort, although removal occasionally results in neurological deficit.

CORRESPONDENCE
T. Grant Phillips, MD, Associate Director, UPMC Altoona Family Physicians Residency, 501 Howard Avenue, Altoona, PA 16601-4899; phillipstg2@upmc.edu

Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited disorder that is estimated to occur in 1:2500 births and to have a prevalence of 1:2000 to 1:4000.^1,2 It was first described in 1882 by Friedrich Daniel Von Recklinghausen, who identified patients and their relatives with signs of neuroectodermal abnormalities (café-au-lait macules [CALMs], axillary and inguinal freckling, and neurofibromas).

NF1 may begin insidiously in childhood and evolves as the patient ages. It is associated with intracranial, intraspinal, and intraorbital neoplasms, although other organs and tissues can also be involved.

The family physician might be the first one to recognize the signs of this condition during a well-child exam and is in a unique position to coordinate a multidisciplinary approach to care.

A mutated allele and early manifestations on the skin

NF1 has been attributed to genetic mosaicism and is classified as segmental, generalized, or (less frequently) gonadal. The disorder results from germline mutations in the NF1 tumor-suppressor gene on chromosome 17, known to codify the cytoplasmic protein called neurofibromin.³ The penetrance of NF1 is complete, which means that 100% of patients with the mutated allele will develop the disease.

Patients typically have symptoms by the third decade of life, although many will show signs of the disease in early childhood. CALMs are the earliest expression of NF1. They manifest in the first 2 years of life and are found in almost all affected patients. The lesions are well defined and measure 10 to 40 mm. They are typically light brown, although they may darken with sun exposure.

Histologically, the lesions will show macromelanosomes and high concentrations of melanin but do not represent an increased risk for malignancy.⁴ Not all isolated CALMs are a sign of NF1. While children younger than 29 months with 6 or more CALMs have a high risk for NF1 (80.4%; 95% confidence interval [CI], 74.6% to 86.2%), those who are older than 29 months with at least 1 atypical CALM or fewer than 6 CALMs have just a 0.9% (95% CI, 0% to 2.6%) risk for constitutional NF1.⁵

Freckles are also observed in 90% of patients with NF1; these tend to develop after the third year of life. The breast and trunk are the most commonly affected areas in adults. The pathophysiology is unknown, but this freckling is believed to be related to skin friction, high humidity, and ambient temperature.⁶

Continue to: Neurofibromas are benign...

Some patients show disfiguration when hundreds of neurofibromas are present.

Neurofibromas are benign subcutaneous palpable lesions that grow within peripheral nerve tissue, including spinal, subcutaneous, plexiform, or dermal encapsulated nerves. Originating in Schwann cells, they are composed of fibroblasts, mast cells, macrophages, endothelial cells, and other perineural cells. Some patients show disfiguration when hundreds of these masses are present (FIGURE). These tumors increase in number as the patient ages or during pregnancy, which is thought to be secondary to hormonal changes.⁷ They are sometimes painful and can be pruritic. Their appearance can also cause patient distress.

The diagnosis is a clinical one

Suspicion for NF1 should be high in patients presenting with the dermatologic findings described, although CALMs and freckling are not exclusive to NF1. Diagnostic criteria for NF1, which distinguish it from other conditions, were first outlined in a National Institutes of Health Consensus Development Conference Statement in 1987.⁸ The list of criteria has subsequently been expanded.

While the presence of at least 2 criteria is required for diagnosis,² NF1 should be suspected in individuals who have any of the following findings^8,9:

• the presence of at least 6 CALMs that are > 5 mm in prepubertal children and > 15 mm in adults
• 2 or more neurofibromas of any type, or at least one plexiform neurofibroma
• axillary or groin freckling
• optic pathway glioma
• 2 or more Lisch nodules (iris hamartomas seen on slit-lamp examination)
• bony dysplasia (sphenoid wing dysplasia, bowing of long bone ± pseudarthrosis)
• first-degree relative with NF1.

What you’ll see as the disease progresses

NF1 can affect a variety of systems, and potential complications of the disease are numerous and varied (see TABLE⁹). Here is some of what you may see as the patient’s disease progresses to various organ systems:

Learning disabilities and other cognitive and behavioral problems, such as attention-deficit/hyperactivity disorder, may affect up to 70% of children with NF1. Additionally, children with NF1 have visual/spatial problems, impaired visual motor integration, and language deficits.¹⁰ The etiology of cognitive impairment in NF1 is unknown.¹¹  

Continue to: Hypertension

Hypertension is common and may contribute to premature death in patients with NF1. Up to 27% of patients will have significant cardiovascular anomalies, including pulmonary valve stenosis, hypertrophic cardiomyopathy in patients with complete deletions of the NF1 gene, intracardiac neurofibromas, renal artery stenosis, coarctation of the aorta, and cerebral infarctions.¹² Renal artery stenosis occurs in approximately 2% of the NF1 population, and the diagnosis should be considered in hypertensive children, young adults, pregnant women, older individuals with refractory hypertension, and those with an abdominal bruit.¹³

Psychological issues. The disfigurement caused by neurofibromas and the uncertainty of an unpredictable disease course can cause psychological manifestations for patients with NF1. Anxiety and depression are common. Not surprisingly, patients with more severe disease report more adverse psychological effects.

Orthopedic deformities. Spinal deformities are the most common skeletal manifestation of NF1, with an incidence estimated from 10% to 25% in various studies. Bone mineral density, as measured by age- and gender-adjusted Z-scores, is significantly lower in NF1 patients than in the general population.¹⁴ Children may develop bowing of the long bones, particularly the tibia, and pseudarthrosis, a false joint in a long bone. Children with NF1 need yearly assessment of the spine. Patients with clinical evidence of scoliosis should be referred to Orthopedics for further evaluation.

Eye issues. A majority of adult patients develop neurofibroma-like nodules in the iris known as Lisch nodules. The nodules are not thought to cause any ophthalmologic complications. Patients may also develop palpebral neurofibroma, which may become large and sporadically show malignant transformation. Optic nerve glioma may cause strabismus and proptosis, and a large number of patients will also develop glaucoma and globe enlargement.¹⁵

Gastrointestinal lesions and cancer. Neurofibromas can grow in the stomach, liver, mesentery, retroperitoneum, and bowel. Adenocarcinoma developed in 23% of patients.¹⁶ Gastrointestinal tract bleeding, pseudo-obstruction, and protein-losing enteropathy also may occur.¹⁷

Continue to: Central nervous system manifestations

Central nervous system manifestations. Neurological manifestations have been observed in 55% of patients with NF1.¹⁸ These include headache, hydrocephalus, epilepsy, lacunar stroke, white matter disease, intraspinal neurofibroma, facial palsy, radiculopathy, and polyneuropathy. Tumors include optic pathway tumors, meningioma, and cerebral glioma. Glioma is the predominant tumor type in NF1 and occurs in all parts of the nervous system, with a predilection for the optic pathways, brainstem, and cerebellum.¹⁸

Malignant peripheral nerve sheath tumors. There is an 8% to 13% lifetime risk for malignant peripheral nerve sheath tumors (MPNST), predominantly in individuals between the ages of 20 and 35.^19,20 Any change in neurofibroma from soft to hard, or a rapid increase in the size, is suspicious for MPNST. Other symptoms include persistent pain lasting for longer than a month, pain that disturbs sleep, and new neurological deficits. These cancers can be hard to detect, leading to poor prognosis secondary to metastasis.^19,20 The greatest risk factors for MPNST are pain associated with a mass and the presence of cutaneous and subcutaneous neurofibromas.²¹

Treatment is symptom based, but there is a new option

Treatment is individualized to the patient’s symptoms. Neurofibromas that are disfiguring, disruptive, or malignant may be surgically removed.

In April 2020, the US Food and Drug Administration (FDA) approved selumetinib (Koselugo) for the treatment of pediatric patients (ages ≥ 2 years) with NF1 who have symptomatic, inoperable plexiform neurofibromas (PNs).²² In a clinical trial, patients received selumetinib 25 mg/m² orally twice a day until they demonstrated disease progression or experienced “unacceptable” adverse events.^22,23 The overall response rate was 66%, defined as “the percentage of patients with a complete response and those who experienced more than a 20% reduction in PN volume on MRI that was confirmed on a subsequent MRI within 3 to 6 months.”²²

In light of the condition’s heterogeneity, the goals of care include early recognition and treatment of complications, especially neoplasms.

Of note, all patients had a partial, not complete, response. Common adverse effects included vomiting, rash, abdominal pain, diarrhea, and nausea.²³ Selumetinib may also cause more serious adverse effects, including cardiomyopathy and ocular toxicity. Prior to treatment initiation and at regular intervals during treatment, patients should undergo cardiac and ophthalmic evaluation.^22,23 Selumetinib was granted priority review and orphan drug status by the FDA.²²

Continue to: You play a key role in ongoing monitoring

 

 

You play a key role in ongoing monitoring

In light of the condition’s heterogeneity, the goals of care include early recognition and treatment of complications, especially neoplasms; optimization of quality of life; and identification and treatment of comorbidities. Family physicians are well positioned to monitor patients with NF1 for age-specific disease manifestations and potential complications.⁹ All patients require:

• an annual physical examination by a physician who is familiar with the individual and with the disease
• annual ophthalmologic examination in early childhood; less frequent examination in older children and adults
• regular blood pressure monitoring
• other studies (eg, MRI) only as indicated on the basis of clinically apparent signs or symptoms
• monitoring by an appropriate specialist if there are abnormalities of the central nervous, skeletal, or cardiovascular systems
• referral to a neurologist for any unexplained neurological signs and symptoms. Referral should be urgent if there are acute symptoms of progressive sensory disturbance, motor deficit and incoordination, or sphincter disturbances since these might indicate an intracranial lesion or spinal cord compression. Headaches on waking, morning vomiting, and altered consciousness are suggestive of raised intracranial pressure.

Children with NF1 benefit from coordinated care between the FP and a pediatrician or other specialist familiar with the disease. In addition to providing usual well care, perform regular assessment of development and school performance. Pay careful attention to the cardiovascular system (particularly blood pressure) and evaluate for scoliosis.

Young adults should be continually monitored for all complications, especially hypertension. This population requires continued education about NF1 and its possible complications and may benefit from counseling about disease inheritance. Screen for anxiety and depression; offer psychological support.

Provide adult patients with education about complications, especially malignant peripheral nerve sheath tumors and spinal cord compression.

Adults require monitoring based on patient preference and disease severity. For this population, blood pressure should be measured annually, or more frequently if the patient’s values indicate borderline hypertension. Provide education about complications, especially MPNSTs and spinal cord compression. Patients who have abnormalities of the central nervous, skeletal, or cardiovascular systems should be monitored by an appropriate specialist. If desired, the patient may be referred to a geneticist, especially if he or she expresses concern about inheritance. Cutaneous neurofibromas can be removed if they cause discomfort, although removal occasionally results in neurological deficit.

CORRESPONDENCE
T. Grant Phillips, MD, Associate Director, UPMC Altoona Family Physicians Residency, 501 Howard Avenue, Altoona, PA 16601-4899; phillipstg2@upmc.edu

Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited disorder that is estimated to occur in 1:2500 births and to have a prevalence of 1:2000 to 1:4000.^1,2 It was first described in 1882 by Friedrich Daniel Von Recklinghausen, who identified patients and their relatives with signs of neuroectodermal abnormalities (café-au-lait macules [CALMs], axillary and inguinal freckling, and neurofibromas).

NF1 may begin insidiously in childhood and evolves as the patient ages. It is associated with intracranial, intraspinal, and intraorbital neoplasms, although other organs and tissues can also be involved.

The family physician might be the first one to recognize the signs of this condition during a well-child exam and is in a unique position to coordinate a multidisciplinary approach to care.

A mutated allele and early manifestations on the skin

NF1 has been attributed to genetic mosaicism and is classified as segmental, generalized, or (less frequently) gonadal. The disorder results from germline mutations in the NF1 tumor-suppressor gene on chromosome 17, known to codify the cytoplasmic protein called neurofibromin.³ The penetrance of NF1 is complete, which means that 100% of patients with the mutated allele will develop the disease.

Patients typically have symptoms by the third decade of life, although many will show signs of the disease in early childhood. CALMs are the earliest expression of NF1. They manifest in the first 2 years of life and are found in almost all affected patients. The lesions are well defined and measure 10 to 40 mm. They are typically light brown, although they may darken with sun exposure.

Histologically, the lesions will show macromelanosomes and high concentrations of melanin but do not represent an increased risk for malignancy.⁴ Not all isolated CALMs are a sign of NF1. While children younger than 29 months with 6 or more CALMs have a high risk for NF1 (80.4%; 95% confidence interval [CI], 74.6% to 86.2%), those who are older than 29 months with at least 1 atypical CALM or fewer than 6 CALMs have just a 0.9% (95% CI, 0% to 2.6%) risk for constitutional NF1.⁵

Freckles are also observed in 90% of patients with NF1; these tend to develop after the third year of life. The breast and trunk are the most commonly affected areas in adults. The pathophysiology is unknown, but this freckling is believed to be related to skin friction, high humidity, and ambient temperature.⁶

Continue to: Neurofibromas are benign...

Some patients show disfiguration when hundreds of neurofibromas are present.

Neurofibromas are benign subcutaneous palpable lesions that grow within peripheral nerve tissue, including spinal, subcutaneous, plexiform, or dermal encapsulated nerves. Originating in Schwann cells, they are composed of fibroblasts, mast cells, macrophages, endothelial cells, and other perineural cells. Some patients show disfiguration when hundreds of these masses are present (FIGURE). These tumors increase in number as the patient ages or during pregnancy, which is thought to be secondary to hormonal changes.⁷ They are sometimes painful and can be pruritic. Their appearance can also cause patient distress.

The diagnosis is a clinical one

Suspicion for NF1 should be high in patients presenting with the dermatologic findings described, although CALMs and freckling are not exclusive to NF1. Diagnostic criteria for NF1, which distinguish it from other conditions, were first outlined in a National Institutes of Health Consensus Development Conference Statement in 1987.⁸ The list of criteria has subsequently been expanded.

While the presence of at least 2 criteria is required for diagnosis,² NF1 should be suspected in individuals who have any of the following findings^8,9:

• the presence of at least 6 CALMs that are > 5 mm in prepubertal children and > 15 mm in adults
• 2 or more neurofibromas of any type, or at least one plexiform neurofibroma
• axillary or groin freckling
• optic pathway glioma
• 2 or more Lisch nodules (iris hamartomas seen on slit-lamp examination)
• bony dysplasia (sphenoid wing dysplasia, bowing of long bone ± pseudarthrosis)
• first-degree relative with NF1.

What you’ll see as the disease progresses

NF1 can affect a variety of systems, and potential complications of the disease are numerous and varied (see TABLE⁹). Here is some of what you may see as the patient’s disease progresses to various organ systems:

Learning disabilities and other cognitive and behavioral problems, such as attention-deficit/hyperactivity disorder, may affect up to 70% of children with NF1. Additionally, children with NF1 have visual/spatial problems, impaired visual motor integration, and language deficits.¹⁰ The etiology of cognitive impairment in NF1 is unknown.¹¹  

Continue to: Hypertension

Hypertension is common and may contribute to premature death in patients with NF1. Up to 27% of patients will have significant cardiovascular anomalies, including pulmonary valve stenosis, hypertrophic cardiomyopathy in patients with complete deletions of the NF1 gene, intracardiac neurofibromas, renal artery stenosis, coarctation of the aorta, and cerebral infarctions.¹² Renal artery stenosis occurs in approximately 2% of the NF1 population, and the diagnosis should be considered in hypertensive children, young adults, pregnant women, older individuals with refractory hypertension, and those with an abdominal bruit.¹³

Psychological issues. The disfigurement caused by neurofibromas and the uncertainty of an unpredictable disease course can cause psychological manifestations for patients with NF1. Anxiety and depression are common. Not surprisingly, patients with more severe disease report more adverse psychological effects.

Orthopedic deformities. Spinal deformities are the most common skeletal manifestation of NF1, with an incidence estimated from 10% to 25% in various studies. Bone mineral density, as measured by age- and gender-adjusted Z-scores, is significantly lower in NF1 patients than in the general population.¹⁴ Children may develop bowing of the long bones, particularly the tibia, and pseudarthrosis, a false joint in a long bone. Children with NF1 need yearly assessment of the spine. Patients with clinical evidence of scoliosis should be referred to Orthopedics for further evaluation.

Eye issues. A majority of adult patients develop neurofibroma-like nodules in the iris known as Lisch nodules. The nodules are not thought to cause any ophthalmologic complications. Patients may also develop palpebral neurofibroma, which may become large and sporadically show malignant transformation. Optic nerve glioma may cause strabismus and proptosis, and a large number of patients will also develop glaucoma and globe enlargement.¹⁵

Gastrointestinal lesions and cancer. Neurofibromas can grow in the stomach, liver, mesentery, retroperitoneum, and bowel. Adenocarcinoma developed in 23% of patients.¹⁶ Gastrointestinal tract bleeding, pseudo-obstruction, and protein-losing enteropathy also may occur.¹⁷

Continue to: Central nervous system manifestations

Central nervous system manifestations. Neurological manifestations have been observed in 55% of patients with NF1.¹⁸ These include headache, hydrocephalus, epilepsy, lacunar stroke, white matter disease, intraspinal neurofibroma, facial palsy, radiculopathy, and polyneuropathy. Tumors include optic pathway tumors, meningioma, and cerebral glioma. Glioma is the predominant tumor type in NF1 and occurs in all parts of the nervous system, with a predilection for the optic pathways, brainstem, and cerebellum.¹⁸

Malignant peripheral nerve sheath tumors. There is an 8% to 13% lifetime risk for malignant peripheral nerve sheath tumors (MPNST), predominantly in individuals between the ages of 20 and 35.^19,20 Any change in neurofibroma from soft to hard, or a rapid increase in the size, is suspicious for MPNST. Other symptoms include persistent pain lasting for longer than a month, pain that disturbs sleep, and new neurological deficits. These cancers can be hard to detect, leading to poor prognosis secondary to metastasis.^19,20 The greatest risk factors for MPNST are pain associated with a mass and the presence of cutaneous and subcutaneous neurofibromas.²¹

Treatment is symptom based, but there is a new option

Treatment is individualized to the patient’s symptoms. Neurofibromas that are disfiguring, disruptive, or malignant may be surgically removed.

In April 2020, the US Food and Drug Administration (FDA) approved selumetinib (Koselugo) for the treatment of pediatric patients (ages ≥ 2 years) with NF1 who have symptomatic, inoperable plexiform neurofibromas (PNs).²² In a clinical trial, patients received selumetinib 25 mg/m² orally twice a day until they demonstrated disease progression or experienced “unacceptable” adverse events.^22,23 The overall response rate was 66%, defined as “the percentage of patients with a complete response and those who experienced more than a 20% reduction in PN volume on MRI that was confirmed on a subsequent MRI within 3 to 6 months.”²²

In light of the condition’s heterogeneity, the goals of care include early recognition and treatment of complications, especially neoplasms.

Of note, all patients had a partial, not complete, response. Common adverse effects included vomiting, rash, abdominal pain, diarrhea, and nausea.²³ Selumetinib may also cause more serious adverse effects, including cardiomyopathy and ocular toxicity. Prior to treatment initiation and at regular intervals during treatment, patients should undergo cardiac and ophthalmic evaluation.^22,23 Selumetinib was granted priority review and orphan drug status by the FDA.²²

Continue to: You play a key role in ongoing monitoring

 

 

You play a key role in ongoing monitoring

In light of the condition’s heterogeneity, the goals of care include early recognition and treatment of complications, especially neoplasms; optimization of quality of life; and identification and treatment of comorbidities. Family physicians are well positioned to monitor patients with NF1 for age-specific disease manifestations and potential complications.⁹ All patients require:

• an annual physical examination by a physician who is familiar with the individual and with the disease
• annual ophthalmologic examination in early childhood; less frequent examination in older children and adults
• regular blood pressure monitoring
• other studies (eg, MRI) only as indicated on the basis of clinically apparent signs or symptoms
• monitoring by an appropriate specialist if there are abnormalities of the central nervous, skeletal, or cardiovascular systems
• referral to a neurologist for any unexplained neurological signs and symptoms. Referral should be urgent if there are acute symptoms of progressive sensory disturbance, motor deficit and incoordination, or sphincter disturbances since these might indicate an intracranial lesion or spinal cord compression. Headaches on waking, morning vomiting, and altered consciousness are suggestive of raised intracranial pressure.

Children with NF1 benefit from coordinated care between the FP and a pediatrician or other specialist familiar with the disease. In addition to providing usual well care, perform regular assessment of development and school performance. Pay careful attention to the cardiovascular system (particularly blood pressure) and evaluate for scoliosis.

Young adults should be continually monitored for all complications, especially hypertension. This population requires continued education about NF1 and its possible complications and may benefit from counseling about disease inheritance. Screen for anxiety and depression; offer psychological support.

Provide adult patients with education about complications, especially malignant peripheral nerve sheath tumors and spinal cord compression.

Adults require monitoring based on patient preference and disease severity. For this population, blood pressure should be measured annually, or more frequently if the patient’s values indicate borderline hypertension. Provide education about complications, especially MPNSTs and spinal cord compression. Patients who have abnormalities of the central nervous, skeletal, or cardiovascular systems should be monitored by an appropriate specialist. If desired, the patient may be referred to a geneticist, especially if he or she expresses concern about inheritance. Cutaneous neurofibromas can be removed if they cause discomfort, although removal occasionally results in neurological deficit.

CORRESPONDENCE
T. Grant Phillips, MD, Associate Director, UPMC Altoona Family Physicians Residency, 501 Howard Avenue, Altoona, PA 16601-4899; phillipstg2@upmc.edu

Prurigo pigmentosa is an inflammatory disorder of uncertain etiology characterized by the eruption of erythematous, markedly pruritic, urticaria-like papules and vesicles on the posterior neck, mid- to upper back, and chest. Crops of papules appear rapidly and then involute within days, leaving behind postinflammatory hyperpigmentation in a netlike configuration. New papules may appear prior to resolution of hyperpigmented macules, resulting in a mixed presentation of erythematous papules overlying reticulated hyperpigmentation.¹

The condition was initially described in Japanese individuals, and to date, most cases have occurred in this population.² However, the incidence of prurigo pigmentosa is increasing worldwide, including in the United States, which has led to the identification of several metabolic risk factors including diabetes mellitus, fasting, and dieting, with the common etiologic endpoint of ketosis.³With the increasing popularity of diets with strict carbohydrate limits, often with the goal of ketosis, dermatologists should be aware of the clinical appearance and common history of this rash to facilitate prompt diagnosis and treatment.

Clinical exam with appropriate history is usually sufficient for diagnosis. However, biopsy with histopathologic analysis can be utilized to confirm atypical cases. Histopathologic findings depend on the stage of the lesion biopsied. The earliest finding is a shallow perivascular neutrophilic infiltrate, neutrophil exocytosis, and epidermal and superficial dermal edema. As lesions progress, the prominent findings include epidermal vesiculation with necrotic keratinocytes and a lichenoid infiltrate dominated by lymphocytes and eosinophils. In the final stages, lesions demonstrate variable parakeratosis and acanthosis, as well as prominent dermal melanophagia.¹

Treatment of prurigo pigmentosa includes modification of the patient’s underlying health issues to avoid ketosis, and in the case of diet-induced ketosis, reinstitution of a more balanced diet with sufficient carbohydrates. In the case of the patient presented here, rash resolved 1 week following instruction to include more carbohydrates in his diet. For recalcitrant cases or those without a clear precipitating factor, the addition of oral antibiotics is often helpful. Tetracyclines or dapsone are typically employed, usually in courses of 1-2 months.^3,4
 

Dr. Johnson is a PGY-4 dermatology resident at Carilion Clinic in Roanoke, Va. He provided the case and photos. Donna Bilu Martin, MD, is the editor of the column.

References

1. Boer A et al. Am J Dermatopathol. 2003 Apr;25(2):117-292.

2. Satter E et al. J Cutan Pathol. 2016 Oct;43(10):809-14.

3. Alshaya M et al. JAAD Case Rep. 2019 Jun 8;5(6):504-7.

4. Hartman M et al. Cutis. 2019 Mar;103(3):E10-3.

Prurigo pigmentosa is an inflammatory disorder of uncertain etiology characterized by the eruption of erythematous, markedly pruritic, urticaria-like papules and vesicles on the posterior neck, mid- to upper back, and chest. Crops of papules appear rapidly and then involute within days, leaving behind postinflammatory hyperpigmentation in a netlike configuration. New papules may appear prior to resolution of hyperpigmented macules, resulting in a mixed presentation of erythematous papules overlying reticulated hyperpigmentation.¹

The condition was initially described in Japanese individuals, and to date, most cases have occurred in this population.² However, the incidence of prurigo pigmentosa is increasing worldwide, including in the United States, which has led to the identification of several metabolic risk factors including diabetes mellitus, fasting, and dieting, with the common etiologic endpoint of ketosis.³With the increasing popularity of diets with strict carbohydrate limits, often with the goal of ketosis, dermatologists should be aware of the clinical appearance and common history of this rash to facilitate prompt diagnosis and treatment.

Clinical exam with appropriate history is usually sufficient for diagnosis. However, biopsy with histopathologic analysis can be utilized to confirm atypical cases. Histopathologic findings depend on the stage of the lesion biopsied. The earliest finding is a shallow perivascular neutrophilic infiltrate, neutrophil exocytosis, and epidermal and superficial dermal edema. As lesions progress, the prominent findings include epidermal vesiculation with necrotic keratinocytes and a lichenoid infiltrate dominated by lymphocytes and eosinophils. In the final stages, lesions demonstrate variable parakeratosis and acanthosis, as well as prominent dermal melanophagia.¹

Treatment of prurigo pigmentosa includes modification of the patient’s underlying health issues to avoid ketosis, and in the case of diet-induced ketosis, reinstitution of a more balanced diet with sufficient carbohydrates. In the case of the patient presented here, rash resolved 1 week following instruction to include more carbohydrates in his diet. For recalcitrant cases or those without a clear precipitating factor, the addition of oral antibiotics is often helpful. Tetracyclines or dapsone are typically employed, usually in courses of 1-2 months.^3,4
 

Dr. Johnson is a PGY-4 dermatology resident at Carilion Clinic in Roanoke, Va. He provided the case and photos. Donna Bilu Martin, MD, is the editor of the column.

References

1. Boer A et al. Am J Dermatopathol. 2003 Apr;25(2):117-292.

2. Satter E et al. J Cutan Pathol. 2016 Oct;43(10):809-14.

3. Alshaya M et al. JAAD Case Rep. 2019 Jun 8;5(6):504-7.

4. Hartman M et al. Cutis. 2019 Mar;103(3):E10-3.

Prurigo pigmentosa is an inflammatory disorder of uncertain etiology characterized by the eruption of erythematous, markedly pruritic, urticaria-like papules and vesicles on the posterior neck, mid- to upper back, and chest. Crops of papules appear rapidly and then involute within days, leaving behind postinflammatory hyperpigmentation in a netlike configuration. New papules may appear prior to resolution of hyperpigmented macules, resulting in a mixed presentation of erythematous papules overlying reticulated hyperpigmentation.¹

The condition was initially described in Japanese individuals, and to date, most cases have occurred in this population.² However, the incidence of prurigo pigmentosa is increasing worldwide, including in the United States, which has led to the identification of several metabolic risk factors including diabetes mellitus, fasting, and dieting, with the common etiologic endpoint of ketosis.³With the increasing popularity of diets with strict carbohydrate limits, often with the goal of ketosis, dermatologists should be aware of the clinical appearance and common history of this rash to facilitate prompt diagnosis and treatment.

Clinical exam with appropriate history is usually sufficient for diagnosis. However, biopsy with histopathologic analysis can be utilized to confirm atypical cases. Histopathologic findings depend on the stage of the lesion biopsied. The earliest finding is a shallow perivascular neutrophilic infiltrate, neutrophil exocytosis, and epidermal and superficial dermal edema. As lesions progress, the prominent findings include epidermal vesiculation with necrotic keratinocytes and a lichenoid infiltrate dominated by lymphocytes and eosinophils. In the final stages, lesions demonstrate variable parakeratosis and acanthosis, as well as prominent dermal melanophagia.¹

Treatment of prurigo pigmentosa includes modification of the patient’s underlying health issues to avoid ketosis, and in the case of diet-induced ketosis, reinstitution of a more balanced diet with sufficient carbohydrates. In the case of the patient presented here, rash resolved 1 week following instruction to include more carbohydrates in his diet. For recalcitrant cases or those without a clear precipitating factor, the addition of oral antibiotics is often helpful. Tetracyclines or dapsone are typically employed, usually in courses of 1-2 months.^3,4
 

Dr. Johnson is a PGY-4 dermatology resident at Carilion Clinic in Roanoke, Va. He provided the case and photos. Donna Bilu Martin, MD, is the editor of the column.

References

1. Boer A et al. Am J Dermatopathol. 2003 Apr;25(2):117-292.

2. Satter E et al. J Cutan Pathol. 2016 Oct;43(10):809-14.

3. Alshaya M et al. JAAD Case Rep. 2019 Jun 8;5(6):504-7.

4. Hartman M et al. Cutis. 2019 Mar;103(3):E10-3.

An 80-year-old woman with a history of hypertension, hyperlipidemia, psoriasis vulgaris with associated pruritus, and well-controlled type 2 diabetes mellitus presented with a slowly enlarging ulceration on her left leg of 1 year’s duration. She noted that this lesion healed less rapidly than previous stasis leg ulcerations, despite using the same treatment approach that included dressings, elevation, and diuretics to decrease pedal edema.

Physical examination revealed plaques with white micaceous scaling over her extensor surfaces and scalp, as well as guttate lesions on the trunk, typical of psoriasis vulgaris. A 5.8 × 7.2-cm malodorous ulceration was superimposed on a large psoriatic plaque on her left anterior lower leg (FIGURE 1). A 4-mm punch biopsy was obtained from the peripheral margin.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Basal cell carcinoma

Histopathological examination revealed elongated strands of closely packed basaloid cells embedded in a dense fibrous stroma with overlying ulceration and crusting (FIGURE 2). Immunohistochemical staining with cytokeratin (CK) 5/6 decorated the cytoplasm of the tumor cells, which confirmed that the tumor was a keratinocyte cancer. CK 20 was negative, excluding the possibility of a Merkel cell carcinoma. Scout biopsies from 3 additional areas of ulceration confirmed that the entire ulceration was infiltrated by basal cell carcinoma (BCC).

IMAGE COURTESY OF ROBERT BRODELL, MD

A surprise hidden in a chronic ulcer

More than 6 million Americans have chronic ulcers and most occur on the legs.¹ The majority of these chronic ulcerations are etiologically related to venous stasis, arterial insufficiency, or neuropathy.²

Bacterial pyoderma, chronic infection caused by atypical acid-fast bacilli or deep fungal infection, pyoderma gangrenosum, cutaneous vasculitis, calciphylaxis, and venous ulceration were all considered to explain this patient’s nonhealing wound. A biopsy was required to fully assess these possibilities.

Don’t overlook the possibility of malignancy. In a cross-sectional, multicenter study by Senet et al,³ 144 patients with 154 total chronic leg ulcers were evaluated in tertiary care centers for malignancy, which was found to occur at a rate of 10.4%. Similarly, Ghasemi et al⁴ demonstrated a malignancy rate of 16.1% in 124 patients who underwent biopsy; the anterior shin was determined to be the most frequent location for malignancy. The most common skin cancer identified within the setting of chronic ulcers is squamous cell carcinoma.³ Although rare, there are reports of BCC identified in chronic wounds.^3-7

Morphological signs suggestive of malignancy in chronic ulcerations include hyperkeratosis, granulation tissue surrounded by a raised border, unusual pain or bleeding, and increased tissue friability. Our patient had none of these signs and symptoms. However, it is possible that she had a tumor that ulcerated and would not heal.

Continue to: Which came first?

Which came first? It’s difficult to know in this case whether a persistent BCC ulcerated, forming this lesion, or if scarring associated with a chronic ulceration led to the development of the BCC.⁶ Based on biopsies taken at an earlier date, Schnirring-Judge and Belpedio⁷ concluded that a chronic leg ulcer could, indeed, transform into a BCC; however, pre-existing BCC more commonly ulcerates and then does not heal.

Treatment options

While smaller, superficial BCCs can be treated with topical imiquimod, photodynamic therapy, or electrodesiccation and curettage, larger lesions should be treated with Mohs micrographic surgery and excisional surgery with grafting. Inoperable tumors may be treated with radiation therapy and vismodegib.

Our patient. Once the diagnosis of BCC was established, treatment options were discussed, including excision, local radiation therapy, and oral hedgehog inhibitor drug therapy.⁸ Our patient opted to undergo a wide local excision of the lesion followed by negative-pressure wound therapy, which led to complete healing.

CORRESPONDENCE
David Crasto, DO, William Carey University College of Osteopathic Medicine, 498 Tuscan Avenue, Hattiesburg, MS 39401; crastodave@gmail.com

An 80-year-old woman with a history of hypertension, hyperlipidemia, psoriasis vulgaris with associated pruritus, and well-controlled type 2 diabetes mellitus presented with a slowly enlarging ulceration on her left leg of 1 year’s duration. She noted that this lesion healed less rapidly than previous stasis leg ulcerations, despite using the same treatment approach that included dressings, elevation, and diuretics to decrease pedal edema.

Physical examination revealed plaques with white micaceous scaling over her extensor surfaces and scalp, as well as guttate lesions on the trunk, typical of psoriasis vulgaris. A 5.8 × 7.2-cm malodorous ulceration was superimposed on a large psoriatic plaque on her left anterior lower leg (FIGURE 1). A 4-mm punch biopsy was obtained from the peripheral margin.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Basal cell carcinoma

Histopathological examination revealed elongated strands of closely packed basaloid cells embedded in a dense fibrous stroma with overlying ulceration and crusting (FIGURE 2). Immunohistochemical staining with cytokeratin (CK) 5/6 decorated the cytoplasm of the tumor cells, which confirmed that the tumor was a keratinocyte cancer. CK 20 was negative, excluding the possibility of a Merkel cell carcinoma. Scout biopsies from 3 additional areas of ulceration confirmed that the entire ulceration was infiltrated by basal cell carcinoma (BCC).

IMAGE COURTESY OF ROBERT BRODELL, MD

A surprise hidden in a chronic ulcer

More than 6 million Americans have chronic ulcers and most occur on the legs.¹ The majority of these chronic ulcerations are etiologically related to venous stasis, arterial insufficiency, or neuropathy.²

Bacterial pyoderma, chronic infection caused by atypical acid-fast bacilli or deep fungal infection, pyoderma gangrenosum, cutaneous vasculitis, calciphylaxis, and venous ulceration were all considered to explain this patient’s nonhealing wound. A biopsy was required to fully assess these possibilities.

Don’t overlook the possibility of malignancy. In a cross-sectional, multicenter study by Senet et al,³ 144 patients with 154 total chronic leg ulcers were evaluated in tertiary care centers for malignancy, which was found to occur at a rate of 10.4%. Similarly, Ghasemi et al⁴ demonstrated a malignancy rate of 16.1% in 124 patients who underwent biopsy; the anterior shin was determined to be the most frequent location for malignancy. The most common skin cancer identified within the setting of chronic ulcers is squamous cell carcinoma.³ Although rare, there are reports of BCC identified in chronic wounds.^3-7

Morphological signs suggestive of malignancy in chronic ulcerations include hyperkeratosis, granulation tissue surrounded by a raised border, unusual pain or bleeding, and increased tissue friability. Our patient had none of these signs and symptoms. However, it is possible that she had a tumor that ulcerated and would not heal.

Continue to: Which came first?

Which came first? It’s difficult to know in this case whether a persistent BCC ulcerated, forming this lesion, or if scarring associated with a chronic ulceration led to the development of the BCC.⁶ Based on biopsies taken at an earlier date, Schnirring-Judge and Belpedio⁷ concluded that a chronic leg ulcer could, indeed, transform into a BCC; however, pre-existing BCC more commonly ulcerates and then does not heal.

Treatment options

While smaller, superficial BCCs can be treated with topical imiquimod, photodynamic therapy, or electrodesiccation and curettage, larger lesions should be treated with Mohs micrographic surgery and excisional surgery with grafting. Inoperable tumors may be treated with radiation therapy and vismodegib.

Our patient. Once the diagnosis of BCC was established, treatment options were discussed, including excision, local radiation therapy, and oral hedgehog inhibitor drug therapy.⁸ Our patient opted to undergo a wide local excision of the lesion followed by negative-pressure wound therapy, which led to complete healing.

CORRESPONDENCE
David Crasto, DO, William Carey University College of Osteopathic Medicine, 498 Tuscan Avenue, Hattiesburg, MS 39401; crastodave@gmail.com

An 80-year-old woman with a history of hypertension, hyperlipidemia, psoriasis vulgaris with associated pruritus, and well-controlled type 2 diabetes mellitus presented with a slowly enlarging ulceration on her left leg of 1 year’s duration. She noted that this lesion healed less rapidly than previous stasis leg ulcerations, despite using the same treatment approach that included dressings, elevation, and diuretics to decrease pedal edema.

Physical examination revealed plaques with white micaceous scaling over her extensor surfaces and scalp, as well as guttate lesions on the trunk, typical of psoriasis vulgaris. A 5.8 × 7.2-cm malodorous ulceration was superimposed on a large psoriatic plaque on her left anterior lower leg (FIGURE 1). A 4-mm punch biopsy was obtained from the peripheral margin.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Basal cell carcinoma

Histopathological examination revealed elongated strands of closely packed basaloid cells embedded in a dense fibrous stroma with overlying ulceration and crusting (FIGURE 2). Immunohistochemical staining with cytokeratin (CK) 5/6 decorated the cytoplasm of the tumor cells, which confirmed that the tumor was a keratinocyte cancer. CK 20 was negative, excluding the possibility of a Merkel cell carcinoma. Scout biopsies from 3 additional areas of ulceration confirmed that the entire ulceration was infiltrated by basal cell carcinoma (BCC).

IMAGE COURTESY OF ROBERT BRODELL, MD

A surprise hidden in a chronic ulcer

More than 6 million Americans have chronic ulcers and most occur on the legs.¹ The majority of these chronic ulcerations are etiologically related to venous stasis, arterial insufficiency, or neuropathy.²

Bacterial pyoderma, chronic infection caused by atypical acid-fast bacilli or deep fungal infection, pyoderma gangrenosum, cutaneous vasculitis, calciphylaxis, and venous ulceration were all considered to explain this patient’s nonhealing wound. A biopsy was required to fully assess these possibilities.

Don’t overlook the possibility of malignancy. In a cross-sectional, multicenter study by Senet et al,³ 144 patients with 154 total chronic leg ulcers were evaluated in tertiary care centers for malignancy, which was found to occur at a rate of 10.4%. Similarly, Ghasemi et al⁴ demonstrated a malignancy rate of 16.1% in 124 patients who underwent biopsy; the anterior shin was determined to be the most frequent location for malignancy. The most common skin cancer identified within the setting of chronic ulcers is squamous cell carcinoma.³ Although rare, there are reports of BCC identified in chronic wounds.^3-7

Morphological signs suggestive of malignancy in chronic ulcerations include hyperkeratosis, granulation tissue surrounded by a raised border, unusual pain or bleeding, and increased tissue friability. Our patient had none of these signs and symptoms. However, it is possible that she had a tumor that ulcerated and would not heal.

Continue to: Which came first?

Which came first? It’s difficult to know in this case whether a persistent BCC ulcerated, forming this lesion, or if scarring associated with a chronic ulceration led to the development of the BCC.⁶ Based on biopsies taken at an earlier date, Schnirring-Judge and Belpedio⁷ concluded that a chronic leg ulcer could, indeed, transform into a BCC; however, pre-existing BCC more commonly ulcerates and then does not heal.

Treatment options

While smaller, superficial BCCs can be treated with topical imiquimod, photodynamic therapy, or electrodesiccation and curettage, larger lesions should be treated with Mohs micrographic surgery and excisional surgery with grafting. Inoperable tumors may be treated with radiation therapy and vismodegib.

Our patient. Once the diagnosis of BCC was established, treatment options were discussed, including excision, local radiation therapy, and oral hedgehog inhibitor drug therapy.⁸ Our patient opted to undergo a wide local excision of the lesion followed by negative-pressure wound therapy, which led to complete healing.

CORRESPONDENCE
David Crasto, DO, William Carey University College of Osteopathic Medicine, 498 Tuscan Avenue, Hattiesburg, MS 39401; crastodave@gmail.com