Dermatology

Psoriasis management in children involves attention not only to treatment of the physical condition but also psychosocial wellness and quality of life, according to a new clinical guideline on the management of pediatric psoriasis from the American Academy of Dermatology and the National Psoriasis Foundation.

Psoriasis affects approximately 1% of children, either alone or associated with comorbid conditions such as psoriatic arthritis (PsA), wrote Alan Menter, MD, of Baylor University Medical Center, Dallas, and coauthors of the guideline.

In the guideline, published in the Journal of the American Academy of Dermatology, the multidisciplinary work group identified screening tools to measure disease severity, strategies for management of comorbidities, and the safety and effectiveness of topical, systemic, and phototherapy treatments.

To assess disease severity, the work group recommended not only the use of body surface area (BSA), similar to measurement of severity in adults, but also the use of the Children’s Dermatology Life Quality Index, a 10-question quality of life survey, as BSA alone does not account for the potential negative impact of the disease on quality of life in terms of physical, emotional, social, and psychological function.

“For example, a child with psoriasis limited to the face or the entire scalp does not have severe disease based on BSA definitions, but if this involvement causes shame, social withdrawal, or bullying, it satisfies criteria for severe disease based on impact beyond the skin,” they said.

The work group stated that a variety of conditions may trigger or exacerbate psoriasis in children, including infections, cutaneous trauma, or physiological, emotional, and environmental stressors.

The majority of children with PsA develop joint inflammation before skin disease, the work group wrote. In addition, children with psoriasis are at increased risk for rheumatoid arthritis, so clinicians may need to distinguish between a combination of psoriasis and musculoskeletal issues and cases of either psoriatic or rheumatoid arthritis in young patients.

The cardiovascular risk factors associated with metabolic syndrome are greater in children with psoriasis, compared with children without psoriasis, the work group noted. In addition, pediatric psoriasis patients have a higher prevalence of obesity than children without psoriasis, and they recommended that children with psoriasis be monitored for the development of obesity, and that obese children with psoriasis should be referred for weight management.

The work group noted that data are insufficient in children to support the link between psoriasis and cardiovascular disease that has been documented in adults with psoriasis. However, “patients with pediatric psoriasis should have American Academy of Pediatrics (AAP)–recommended age-related cardiovascular screening regardless of the presence of signs or symptoms,” they said.

The guideline also recommends screening for dyslipidemia and hypertension according to AAP guidelines and educating pediatric psoriasis patients about the risk of diabetes and regularly screening for diabetes and insulin resistance in those who are obese. Overweight children with psoriasis may be screened at the provider’s discretion, they wrote. Patients with signs of inflammatory bowel disease, which also is associated with psoriasis in adults, should be considered for referral to a gastroenterologist, they noted.

Children with psoriasis should be screened regularly for mental health conditions regardless of age, and they should be asked about substance abuse, according to the guideline, and those with concerns should be referred for additional assessment and management.

The guideline divides treatment of psoriasis in children into three categories: topical, phototherapy and photochemotherapy, and systemic treatments (nonbiologic or biologic).

For topicals, the guideline recommendations include corticosteroids as an off-label therapy, as well as ultra-high-potency topical corticosteroids as monotherapy. Overall, “selection of a therapeutic routine (potency, delivery vehicle, frequency of application) should take into account sites of involvement, type and thickness of psoriasis, age of the patient, total BSA of application, anticipated occlusion, and disease acuity, among other patient-, disease-, and drug-related factors,” the authors wrote. Other topical options included in the recommendations: calcineurin inhibitors, topical vitamin D analogues, tazarotene (off label), anthralin, and coal tar.

Phototherapy has a history of use in psoriasis treatment and remains part of the current recommendations, although data in children are limited, and data on the use of phototherapy for pustular psoriasis in children are insufficient to make specific treatment and dosing recommendations, the work group noted. The researchers also noted that in-office phototherapy may not be feasible for many patients, but that in-home ultraviolet light equipment or natural sunlight in moderation could be recommended as an alternative.

The use of systemic, nonbiologic treatments for pediatric psoriasis should be “based on baseline severity of disease, subtype of psoriasis, speed of disease progression, lack of response to more conservative therapies such as topical agents and phototherapy (when appropriate), impaired physical or psychological functioning or [quality of life] due to disease extent, and the presence of comorbidities such as PsA,” the workgroup said.

Options for systemic treatment include methotrexate, cyclosporine (notably for pustular as well as plaque and erythrodermic psoriasis), and systemic retinoids. In addition, fumaric acid esters may be an option for children with moderate to severe psoriasis, with recommended clinical and laboratory monitoring.

The increasing safety and efficacy data on biologics in pediatric psoriasis patients support their consideration among first-line systemic treatments, the work group suggested. “Etanercept and ustekinumab are now [Food and Drug Administration] approved for patients with psoriasis 4 years and older and 12 years and older, respectively,” they said, and infliximab and adalimumab have been used off label in children.

The work group concluded that research and knowledge gaps about pediatric psoriasis persist and include mechanism of disease onset, development of comorbidities, and identification of ideal dosing for various treatments.

Finally, the work group emphasized the importance of collaboration between dermatologists and primary care providers for managing psoriasis in children, as well as the importance of patient education.

“Dermatologists should be mindful of the unique aspects of the emotional development of children and the social dynamics of having a visible difference,” they wrote. “Shared decision making with the patient (if age appropriate) and the caregivers is a useful approach, particularly as related to the use of off-label medications to treat severe disease,” they said.

“This is the first time that pediatric psoriasis has been discussed as an independent topic within the guideline,” said one of the guideline authors, Dawn M.R. Davis, MD, of the Mayo Clinic, Rochester, Minn., in an interview. “Children have unique physiology and psychosocial aspects to their care relative to adults. In addition, psoriasis has some clinical manifestations that are oftentimes distinctly seen in children,” she commented. “Creation of a guideline specific to children allows us to summarize the similarities and differences of disease presentation and management. It also allows an opportunity to clarify what research data (especially therapeutics) have been studied in children and their uses, safety profiles, and dosing,” she noted.

Psoriasis can be a psychosocially debilitating disease, she emphasized. “In children, for example, isolated or prominent facial involvement is common, which can be embarrassing and impact relationships.”

The take-home message for clinicians, Dr. Davis said, is to keep in mind the multisystemic nature of psoriasis. “It is not limited to the skin,” she said. “Treating a patient with psoriasis necessitates practicing whole-person care” and considering the multiple comorbidities that impact quality of life and overall health in children, as well as adults with psoriasis, she commented. “Dermatologists can empower patients and their caregivers by educating them on the multifocal, complex nature of the disease.” She added, “We have much to learn regarding psoriasis in the pediatric population. More research into therapeutics, topical and systemic, is necessary to optimize patient care.”

The guideline was based on studies published in the PubMed and MEDLINE databases from January 2011 through December 31, 2017.

Dr. Menter and Craig A. Elmets, MD, professor of dermatology, at the University of Alabama, Birmingham, were cochairs of the work group. The pediatric guideline is the latest in a multipart series of AAD-NPF guidelines on psoriasis being published this year in the Journal of the American Academy of Dermatology.

Many of the guideline authors, including lead author Dr. Menter, disclosed relationships with multiple companies; however, a minimum 51% of workgroup members had no relevant conflicts of interest in accordance with AAD policy. There was no funding source. Dr. Davis disclosed serving as an investigator for Regeneron, with no compensation.

SOURCE: Menter et al. J Am Acad Dermatol. 2019. doi: 10.1016/j.jaad.2019.08.049.

Psoriasis management in children involves attention not only to treatment of the physical condition but also psychosocial wellness and quality of life, according to a new clinical guideline on the management of pediatric psoriasis from the American Academy of Dermatology and the National Psoriasis Foundation.

Psoriasis affects approximately 1% of children, either alone or associated with comorbid conditions such as psoriatic arthritis (PsA), wrote Alan Menter, MD, of Baylor University Medical Center, Dallas, and coauthors of the guideline.

In the guideline, published in the Journal of the American Academy of Dermatology, the multidisciplinary work group identified screening tools to measure disease severity, strategies for management of comorbidities, and the safety and effectiveness of topical, systemic, and phototherapy treatments.

To assess disease severity, the work group recommended not only the use of body surface area (BSA), similar to measurement of severity in adults, but also the use of the Children’s Dermatology Life Quality Index, a 10-question quality of life survey, as BSA alone does not account for the potential negative impact of the disease on quality of life in terms of physical, emotional, social, and psychological function.

“For example, a child with psoriasis limited to the face or the entire scalp does not have severe disease based on BSA definitions, but if this involvement causes shame, social withdrawal, or bullying, it satisfies criteria for severe disease based on impact beyond the skin,” they said.

The work group stated that a variety of conditions may trigger or exacerbate psoriasis in children, including infections, cutaneous trauma, or physiological, emotional, and environmental stressors.

The majority of children with PsA develop joint inflammation before skin disease, the work group wrote. In addition, children with psoriasis are at increased risk for rheumatoid arthritis, so clinicians may need to distinguish between a combination of psoriasis and musculoskeletal issues and cases of either psoriatic or rheumatoid arthritis in young patients.

The cardiovascular risk factors associated with metabolic syndrome are greater in children with psoriasis, compared with children without psoriasis, the work group noted. In addition, pediatric psoriasis patients have a higher prevalence of obesity than children without psoriasis, and they recommended that children with psoriasis be monitored for the development of obesity, and that obese children with psoriasis should be referred for weight management.

The work group noted that data are insufficient in children to support the link between psoriasis and cardiovascular disease that has been documented in adults with psoriasis. However, “patients with pediatric psoriasis should have American Academy of Pediatrics (AAP)–recommended age-related cardiovascular screening regardless of the presence of signs or symptoms,” they said.

The guideline also recommends screening for dyslipidemia and hypertension according to AAP guidelines and educating pediatric psoriasis patients about the risk of diabetes and regularly screening for diabetes and insulin resistance in those who are obese. Overweight children with psoriasis may be screened at the provider’s discretion, they wrote. Patients with signs of inflammatory bowel disease, which also is associated with psoriasis in adults, should be considered for referral to a gastroenterologist, they noted.

Children with psoriasis should be screened regularly for mental health conditions regardless of age, and they should be asked about substance abuse, according to the guideline, and those with concerns should be referred for additional assessment and management.

The guideline divides treatment of psoriasis in children into three categories: topical, phototherapy and photochemotherapy, and systemic treatments (nonbiologic or biologic).

For topicals, the guideline recommendations include corticosteroids as an off-label therapy, as well as ultra-high-potency topical corticosteroids as monotherapy. Overall, “selection of a therapeutic routine (potency, delivery vehicle, frequency of application) should take into account sites of involvement, type and thickness of psoriasis, age of the patient, total BSA of application, anticipated occlusion, and disease acuity, among other patient-, disease-, and drug-related factors,” the authors wrote. Other topical options included in the recommendations: calcineurin inhibitors, topical vitamin D analogues, tazarotene (off label), anthralin, and coal tar.

Phototherapy has a history of use in psoriasis treatment and remains part of the current recommendations, although data in children are limited, and data on the use of phototherapy for pustular psoriasis in children are insufficient to make specific treatment and dosing recommendations, the work group noted. The researchers also noted that in-office phototherapy may not be feasible for many patients, but that in-home ultraviolet light equipment or natural sunlight in moderation could be recommended as an alternative.

The use of systemic, nonbiologic treatments for pediatric psoriasis should be “based on baseline severity of disease, subtype of psoriasis, speed of disease progression, lack of response to more conservative therapies such as topical agents and phototherapy (when appropriate), impaired physical or psychological functioning or [quality of life] due to disease extent, and the presence of comorbidities such as PsA,” the workgroup said.

Options for systemic treatment include methotrexate, cyclosporine (notably for pustular as well as plaque and erythrodermic psoriasis), and systemic retinoids. In addition, fumaric acid esters may be an option for children with moderate to severe psoriasis, with recommended clinical and laboratory monitoring.

The increasing safety and efficacy data on biologics in pediatric psoriasis patients support their consideration among first-line systemic treatments, the work group suggested. “Etanercept and ustekinumab are now [Food and Drug Administration] approved for patients with psoriasis 4 years and older and 12 years and older, respectively,” they said, and infliximab and adalimumab have been used off label in children.

The work group concluded that research and knowledge gaps about pediatric psoriasis persist and include mechanism of disease onset, development of comorbidities, and identification of ideal dosing for various treatments.

Finally, the work group emphasized the importance of collaboration between dermatologists and primary care providers for managing psoriasis in children, as well as the importance of patient education.

“Dermatologists should be mindful of the unique aspects of the emotional development of children and the social dynamics of having a visible difference,” they wrote. “Shared decision making with the patient (if age appropriate) and the caregivers is a useful approach, particularly as related to the use of off-label medications to treat severe disease,” they said.

“This is the first time that pediatric psoriasis has been discussed as an independent topic within the guideline,” said one of the guideline authors, Dawn M.R. Davis, MD, of the Mayo Clinic, Rochester, Minn., in an interview. “Children have unique physiology and psychosocial aspects to their care relative to adults. In addition, psoriasis has some clinical manifestations that are oftentimes distinctly seen in children,” she commented. “Creation of a guideline specific to children allows us to summarize the similarities and differences of disease presentation and management. It also allows an opportunity to clarify what research data (especially therapeutics) have been studied in children and their uses, safety profiles, and dosing,” she noted.

Psoriasis can be a psychosocially debilitating disease, she emphasized. “In children, for example, isolated or prominent facial involvement is common, which can be embarrassing and impact relationships.”

The take-home message for clinicians, Dr. Davis said, is to keep in mind the multisystemic nature of psoriasis. “It is not limited to the skin,” she said. “Treating a patient with psoriasis necessitates practicing whole-person care” and considering the multiple comorbidities that impact quality of life and overall health in children, as well as adults with psoriasis, she commented. “Dermatologists can empower patients and their caregivers by educating them on the multifocal, complex nature of the disease.” She added, “We have much to learn regarding psoriasis in the pediatric population. More research into therapeutics, topical and systemic, is necessary to optimize patient care.”

The guideline was based on studies published in the PubMed and MEDLINE databases from January 2011 through December 31, 2017.

Dr. Menter and Craig A. Elmets, MD, professor of dermatology, at the University of Alabama, Birmingham, were cochairs of the work group. The pediatric guideline is the latest in a multipart series of AAD-NPF guidelines on psoriasis being published this year in the Journal of the American Academy of Dermatology.

Many of the guideline authors, including lead author Dr. Menter, disclosed relationships with multiple companies; however, a minimum 51% of workgroup members had no relevant conflicts of interest in accordance with AAD policy. There was no funding source. Dr. Davis disclosed serving as an investigator for Regeneron, with no compensation.

SOURCE: Menter et al. J Am Acad Dermatol. 2019. doi: 10.1016/j.jaad.2019.08.049.

Psoriasis management in children involves attention not only to treatment of the physical condition but also psychosocial wellness and quality of life, according to a new clinical guideline on the management of pediatric psoriasis from the American Academy of Dermatology and the National Psoriasis Foundation.

Psoriasis affects approximately 1% of children, either alone or associated with comorbid conditions such as psoriatic arthritis (PsA), wrote Alan Menter, MD, of Baylor University Medical Center, Dallas, and coauthors of the guideline.

In the guideline, published in the Journal of the American Academy of Dermatology, the multidisciplinary work group identified screening tools to measure disease severity, strategies for management of comorbidities, and the safety and effectiveness of topical, systemic, and phototherapy treatments.

To assess disease severity, the work group recommended not only the use of body surface area (BSA), similar to measurement of severity in adults, but also the use of the Children’s Dermatology Life Quality Index, a 10-question quality of life survey, as BSA alone does not account for the potential negative impact of the disease on quality of life in terms of physical, emotional, social, and psychological function.

“For example, a child with psoriasis limited to the face or the entire scalp does not have severe disease based on BSA definitions, but if this involvement causes shame, social withdrawal, or bullying, it satisfies criteria for severe disease based on impact beyond the skin,” they said.

The work group stated that a variety of conditions may trigger or exacerbate psoriasis in children, including infections, cutaneous trauma, or physiological, emotional, and environmental stressors.

The majority of children with PsA develop joint inflammation before skin disease, the work group wrote. In addition, children with psoriasis are at increased risk for rheumatoid arthritis, so clinicians may need to distinguish between a combination of psoriasis and musculoskeletal issues and cases of either psoriatic or rheumatoid arthritis in young patients.

The cardiovascular risk factors associated with metabolic syndrome are greater in children with psoriasis, compared with children without psoriasis, the work group noted. In addition, pediatric psoriasis patients have a higher prevalence of obesity than children without psoriasis, and they recommended that children with psoriasis be monitored for the development of obesity, and that obese children with psoriasis should be referred for weight management.

The work group noted that data are insufficient in children to support the link between psoriasis and cardiovascular disease that has been documented in adults with psoriasis. However, “patients with pediatric psoriasis should have American Academy of Pediatrics (AAP)–recommended age-related cardiovascular screening regardless of the presence of signs or symptoms,” they said.

The guideline also recommends screening for dyslipidemia and hypertension according to AAP guidelines and educating pediatric psoriasis patients about the risk of diabetes and regularly screening for diabetes and insulin resistance in those who are obese. Overweight children with psoriasis may be screened at the provider’s discretion, they wrote. Patients with signs of inflammatory bowel disease, which also is associated with psoriasis in adults, should be considered for referral to a gastroenterologist, they noted.

Children with psoriasis should be screened regularly for mental health conditions regardless of age, and they should be asked about substance abuse, according to the guideline, and those with concerns should be referred for additional assessment and management.

The guideline divides treatment of psoriasis in children into three categories: topical, phototherapy and photochemotherapy, and systemic treatments (nonbiologic or biologic).

For topicals, the guideline recommendations include corticosteroids as an off-label therapy, as well as ultra-high-potency topical corticosteroids as monotherapy. Overall, “selection of a therapeutic routine (potency, delivery vehicle, frequency of application) should take into account sites of involvement, type and thickness of psoriasis, age of the patient, total BSA of application, anticipated occlusion, and disease acuity, among other patient-, disease-, and drug-related factors,” the authors wrote. Other topical options included in the recommendations: calcineurin inhibitors, topical vitamin D analogues, tazarotene (off label), anthralin, and coal tar.

Phototherapy has a history of use in psoriasis treatment and remains part of the current recommendations, although data in children are limited, and data on the use of phototherapy for pustular psoriasis in children are insufficient to make specific treatment and dosing recommendations, the work group noted. The researchers also noted that in-office phototherapy may not be feasible for many patients, but that in-home ultraviolet light equipment or natural sunlight in moderation could be recommended as an alternative.

The use of systemic, nonbiologic treatments for pediatric psoriasis should be “based on baseline severity of disease, subtype of psoriasis, speed of disease progression, lack of response to more conservative therapies such as topical agents and phototherapy (when appropriate), impaired physical or psychological functioning or [quality of life] due to disease extent, and the presence of comorbidities such as PsA,” the workgroup said.

Options for systemic treatment include methotrexate, cyclosporine (notably for pustular as well as plaque and erythrodermic psoriasis), and systemic retinoids. In addition, fumaric acid esters may be an option for children with moderate to severe psoriasis, with recommended clinical and laboratory monitoring.

The increasing safety and efficacy data on biologics in pediatric psoriasis patients support their consideration among first-line systemic treatments, the work group suggested. “Etanercept and ustekinumab are now [Food and Drug Administration] approved for patients with psoriasis 4 years and older and 12 years and older, respectively,” they said, and infliximab and adalimumab have been used off label in children.

The work group concluded that research and knowledge gaps about pediatric psoriasis persist and include mechanism of disease onset, development of comorbidities, and identification of ideal dosing for various treatments.

Finally, the work group emphasized the importance of collaboration between dermatologists and primary care providers for managing psoriasis in children, as well as the importance of patient education.

“Dermatologists should be mindful of the unique aspects of the emotional development of children and the social dynamics of having a visible difference,” they wrote. “Shared decision making with the patient (if age appropriate) and the caregivers is a useful approach, particularly as related to the use of off-label medications to treat severe disease,” they said.

“This is the first time that pediatric psoriasis has been discussed as an independent topic within the guideline,” said one of the guideline authors, Dawn M.R. Davis, MD, of the Mayo Clinic, Rochester, Minn., in an interview. “Children have unique physiology and psychosocial aspects to their care relative to adults. In addition, psoriasis has some clinical manifestations that are oftentimes distinctly seen in children,” she commented. “Creation of a guideline specific to children allows us to summarize the similarities and differences of disease presentation and management. It also allows an opportunity to clarify what research data (especially therapeutics) have been studied in children and their uses, safety profiles, and dosing,” she noted.

Psoriasis can be a psychosocially debilitating disease, she emphasized. “In children, for example, isolated or prominent facial involvement is common, which can be embarrassing and impact relationships.”

The take-home message for clinicians, Dr. Davis said, is to keep in mind the multisystemic nature of psoriasis. “It is not limited to the skin,” she said. “Treating a patient with psoriasis necessitates practicing whole-person care” and considering the multiple comorbidities that impact quality of life and overall health in children, as well as adults with psoriasis, she commented. “Dermatologists can empower patients and their caregivers by educating them on the multifocal, complex nature of the disease.” She added, “We have much to learn regarding psoriasis in the pediatric population. More research into therapeutics, topical and systemic, is necessary to optimize patient care.”

The guideline was based on studies published in the PubMed and MEDLINE databases from January 2011 through December 31, 2017.

Dr. Menter and Craig A. Elmets, MD, professor of dermatology, at the University of Alabama, Birmingham, were cochairs of the work group. The pediatric guideline is the latest in a multipart series of AAD-NPF guidelines on psoriasis being published this year in the Journal of the American Academy of Dermatology.

Many of the guideline authors, including lead author Dr. Menter, disclosed relationships with multiple companies; however, a minimum 51% of workgroup members had no relevant conflicts of interest in accordance with AAD policy. There was no funding source. Dr. Davis disclosed serving as an investigator for Regeneron, with no compensation.

SOURCE: Menter et al. J Am Acad Dermatol. 2019. doi: 10.1016/j.jaad.2019.08.049.

LAS VEGAS – New acne treatment options include a tetracycline antibiotic and a recently approved topical formulation of minocycline, according to Linda Stein Gold, MD, who reviewed the data on these two therapies, as well as cannabidiol (CBD) and an androgen receptor antagonist, which are currently in clinical trials, at the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar.

When considering antibiotic therapy for patients with moderate to severe acne, sarecycline, approved for that indication in October 2018, has improved anti-inflammatory properties and a narrower spectrum of activity, compared with other tetracycline-class antibiotics used for the condition, according to Dr. Stein Gold, director of dermatology research at Henry Ford Health System in Detroit. In two identically designed, 12-week randomized trials, SC 1401 and SC1402, researchers evaluated the efficacy and safety of an approximate 1.5–mg/kg per day dose of sarecycline in comparison with placebo in patients with moderate to severe facial acne aged 9-45 years (J Drugs Dermatol. 2018 Sept 1;17[9]:987-96). “We started to see separation in the inflammatory lesions as early as week 3, and a nice separation versus placebo over the course of 12 weeks,” said Dr. Stein Gold, one of the study investigators. “In all, 22% of patients got clear or almost clear with monotherapy. That’s fairly good.”

She noted that there was consistency in the reductions of lesion count achieved in both studies. Improvements were seen through to 12 weeks, with statistically significant reduction seen as early as 3 weeks in both studies. Sarecycline was also statistically superior to placebo at every time point studied in both trials.

In order to be judged a successful outcome, the subject had to have a 12-week Investigator’s Global Assessment (IGA) score with a 2-point or greater decrease (improvement) from baseline score on the IGA in each location, for patients who have a baseline IGA of 2 or greater, and to be clear (0) or almost clear (1). The same IGA scale was used for the chest and back assessments as was used for facial acne; the researchers observed statistically significant improvements in IGA score for both chest and back acne across both studies at week 12.

Sarecycline also had a favorable safety profile, with no treatment-emergent vertigo or tinnitus adverse events, she noted. Treatment-emergent vestibular and phototoxic adverse events both occurred in fewer than 1% of sarecycline patients. Among females, rates of yeast infections were low. When she recommends a course of this drug for her patients, “I never overpromise,” she said. “I tell my acne patients, ‘We measure your success in weeks and months, not days.’ I always tell them, ‘Take a selfie today and take a selfie every few weeks. When you come back in, we’ll review your progress and see how things went.’ ”

Researchers have also been studying topical minocycline as a treatment option. Minocycline is a large molecule that Dr. Stein Gold characterized as being “very challenging” to deliver topically. “It’s also challenging to keep it stable in a topical formulation.” However, results from two identical phase 3 trials found 4% topical minocycline foam significantly reduced both inflammatory and noninflammatory lesions and improved IGA scores in patients with moderate to severe acne when treated daily for 12 weeks (J Am Acad Dermatol. 2019 Jan;80[1]:168-77).

“This drug has an interesting vehicle,” said Dr. Stein Gold, who was one of the study investigators. “If you take the vehicle itself and you put it next to sebum, it causes sebum to melt at lower temperatures. Why does this matter? If you’re dissolving sebum, maybe you’re creating an easier pathway for the drug to get delivered into the skin and into the hair follicles. We don’t know all the details.” In the two trials, 15%-31% of patients achieved clearance or near clearance of all lesions. “How did it do in terms of decreasing papules and pustules? It did pretty well,” she said. “We want drugs to meet their match in everything that we do.” In terms of tolerability, skin-related adverse events were reported in fewer than 1% of subjects treated with 4% topical minocycline foam. She noted that by delivering minocycline topically, “we get huge concentrations in the skin, but almost negligible amounts in the systemic circulation, which is important. We want to keep [the drug] in the skin; we don’t want it in our system.”

(The Food and Drug Administration approved minocycline foam 4% in October 2019 for treating inflammatory lesions associated with non-nodular moderate to severe acne).

Another potential treatment on the horizon is cortexolone 17a-propionate, a novel androgen receptor antagonist that inhibits production of lipids and inflammatory cytokines from sebocytes in vitro. “When used around the sebaceous gland, we find that the amount of sebum produced goes down,” she said, noting that phase 3 trials of the agent have been completed.

“We also find that abnormal keratinization subsequently goes down. Just putting this on the skin significantly reduced acne as monotherapy in patients with moderate to severe acne. We were able to get them to clear or almost clear. It worked on comedones, papules, and pustules. Hopefully, it will get FDA approval. This fills the one unmet need we haven’t had topically in terms of decreasing sebum production.”

Clinical trials of CBD are also under way for acne and atopic dermatitis. “It could work for acne because there are some studies showing that might work on sebaceous glands to decrease sebum production,” she said. “CBD has been shown to have positive effects on abnormal keratinization, and it has been shown to have anti-inflammatory effects. Maybe we’ll have another mechanism of action for acne.”

Dr. Gold disclosed that she is on the speakers bureau for Almirall, Galderma, Leo Pharma, Ortho Dermatologics, Pfizer, and Sanofi/Regeneron. She is a consultant for Dermavant, Foamix, Galderma, Leo Pharma, Pfizer, Novartis, Ortho Dermatologics, and holds stock/stock options in AbbVie, Dermavant, Eli Lilly, Foamix, Galderma, Incyte, Leo Pharma, Novartis, Ortho Dermatologics, Pfizer, and Sol-Gel.

SDEF and this news organization are owned by the same parent company.

dbrunk@mdedge.com

LAS VEGAS – New acne treatment options include a tetracycline antibiotic and a recently approved topical formulation of minocycline, according to Linda Stein Gold, MD, who reviewed the data on these two therapies, as well as cannabidiol (CBD) and an androgen receptor antagonist, which are currently in clinical trials, at the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar.

When considering antibiotic therapy for patients with moderate to severe acne, sarecycline, approved for that indication in October 2018, has improved anti-inflammatory properties and a narrower spectrum of activity, compared with other tetracycline-class antibiotics used for the condition, according to Dr. Stein Gold, director of dermatology research at Henry Ford Health System in Detroit. In two identically designed, 12-week randomized trials, SC 1401 and SC1402, researchers evaluated the efficacy and safety of an approximate 1.5–mg/kg per day dose of sarecycline in comparison with placebo in patients with moderate to severe facial acne aged 9-45 years (J Drugs Dermatol. 2018 Sept 1;17[9]:987-96). “We started to see separation in the inflammatory lesions as early as week 3, and a nice separation versus placebo over the course of 12 weeks,” said Dr. Stein Gold, one of the study investigators. “In all, 22% of patients got clear or almost clear with monotherapy. That’s fairly good.”

She noted that there was consistency in the reductions of lesion count achieved in both studies. Improvements were seen through to 12 weeks, with statistically significant reduction seen as early as 3 weeks in both studies. Sarecycline was also statistically superior to placebo at every time point studied in both trials.

In order to be judged a successful outcome, the subject had to have a 12-week Investigator’s Global Assessment (IGA) score with a 2-point or greater decrease (improvement) from baseline score on the IGA in each location, for patients who have a baseline IGA of 2 or greater, and to be clear (0) or almost clear (1). The same IGA scale was used for the chest and back assessments as was used for facial acne; the researchers observed statistically significant improvements in IGA score for both chest and back acne across both studies at week 12.

Sarecycline also had a favorable safety profile, with no treatment-emergent vertigo or tinnitus adverse events, she noted. Treatment-emergent vestibular and phototoxic adverse events both occurred in fewer than 1% of sarecycline patients. Among females, rates of yeast infections were low. When she recommends a course of this drug for her patients, “I never overpromise,” she said. “I tell my acne patients, ‘We measure your success in weeks and months, not days.’ I always tell them, ‘Take a selfie today and take a selfie every few weeks. When you come back in, we’ll review your progress and see how things went.’ ”

Researchers have also been studying topical minocycline as a treatment option. Minocycline is a large molecule that Dr. Stein Gold characterized as being “very challenging” to deliver topically. “It’s also challenging to keep it stable in a topical formulation.” However, results from two identical phase 3 trials found 4% topical minocycline foam significantly reduced both inflammatory and noninflammatory lesions and improved IGA scores in patients with moderate to severe acne when treated daily for 12 weeks (J Am Acad Dermatol. 2019 Jan;80[1]:168-77).

“This drug has an interesting vehicle,” said Dr. Stein Gold, who was one of the study investigators. “If you take the vehicle itself and you put it next to sebum, it causes sebum to melt at lower temperatures. Why does this matter? If you’re dissolving sebum, maybe you’re creating an easier pathway for the drug to get delivered into the skin and into the hair follicles. We don’t know all the details.” In the two trials, 15%-31% of patients achieved clearance or near clearance of all lesions. “How did it do in terms of decreasing papules and pustules? It did pretty well,” she said. “We want drugs to meet their match in everything that we do.” In terms of tolerability, skin-related adverse events were reported in fewer than 1% of subjects treated with 4% topical minocycline foam. She noted that by delivering minocycline topically, “we get huge concentrations in the skin, but almost negligible amounts in the systemic circulation, which is important. We want to keep [the drug] in the skin; we don’t want it in our system.”

(The Food and Drug Administration approved minocycline foam 4% in October 2019 for treating inflammatory lesions associated with non-nodular moderate to severe acne).

Another potential treatment on the horizon is cortexolone 17a-propionate, a novel androgen receptor antagonist that inhibits production of lipids and inflammatory cytokines from sebocytes in vitro. “When used around the sebaceous gland, we find that the amount of sebum produced goes down,” she said, noting that phase 3 trials of the agent have been completed.

“We also find that abnormal keratinization subsequently goes down. Just putting this on the skin significantly reduced acne as monotherapy in patients with moderate to severe acne. We were able to get them to clear or almost clear. It worked on comedones, papules, and pustules. Hopefully, it will get FDA approval. This fills the one unmet need we haven’t had topically in terms of decreasing sebum production.”

Clinical trials of CBD are also under way for acne and atopic dermatitis. “It could work for acne because there are some studies showing that might work on sebaceous glands to decrease sebum production,” she said. “CBD has been shown to have positive effects on abnormal keratinization, and it has been shown to have anti-inflammatory effects. Maybe we’ll have another mechanism of action for acne.”

Dr. Gold disclosed that she is on the speakers bureau for Almirall, Galderma, Leo Pharma, Ortho Dermatologics, Pfizer, and Sanofi/Regeneron. She is a consultant for Dermavant, Foamix, Galderma, Leo Pharma, Pfizer, Novartis, Ortho Dermatologics, and holds stock/stock options in AbbVie, Dermavant, Eli Lilly, Foamix, Galderma, Incyte, Leo Pharma, Novartis, Ortho Dermatologics, Pfizer, and Sol-Gel.

SDEF and this news organization are owned by the same parent company.

dbrunk@mdedge.com

LAS VEGAS – New acne treatment options include a tetracycline antibiotic and a recently approved topical formulation of minocycline, according to Linda Stein Gold, MD, who reviewed the data on these two therapies, as well as cannabidiol (CBD) and an androgen receptor antagonist, which are currently in clinical trials, at the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar.

When considering antibiotic therapy for patients with moderate to severe acne, sarecycline, approved for that indication in October 2018, has improved anti-inflammatory properties and a narrower spectrum of activity, compared with other tetracycline-class antibiotics used for the condition, according to Dr. Stein Gold, director of dermatology research at Henry Ford Health System in Detroit. In two identically designed, 12-week randomized trials, SC 1401 and SC1402, researchers evaluated the efficacy and safety of an approximate 1.5–mg/kg per day dose of sarecycline in comparison with placebo in patients with moderate to severe facial acne aged 9-45 years (J Drugs Dermatol. 2018 Sept 1;17[9]:987-96). “We started to see separation in the inflammatory lesions as early as week 3, and a nice separation versus placebo over the course of 12 weeks,” said Dr. Stein Gold, one of the study investigators. “In all, 22% of patients got clear or almost clear with monotherapy. That’s fairly good.”

She noted that there was consistency in the reductions of lesion count achieved in both studies. Improvements were seen through to 12 weeks, with statistically significant reduction seen as early as 3 weeks in both studies. Sarecycline was also statistically superior to placebo at every time point studied in both trials.

In order to be judged a successful outcome, the subject had to have a 12-week Investigator’s Global Assessment (IGA) score with a 2-point or greater decrease (improvement) from baseline score on the IGA in each location, for patients who have a baseline IGA of 2 or greater, and to be clear (0) or almost clear (1). The same IGA scale was used for the chest and back assessments as was used for facial acne; the researchers observed statistically significant improvements in IGA score for both chest and back acne across both studies at week 12.

Sarecycline also had a favorable safety profile, with no treatment-emergent vertigo or tinnitus adverse events, she noted. Treatment-emergent vestibular and phototoxic adverse events both occurred in fewer than 1% of sarecycline patients. Among females, rates of yeast infections were low. When she recommends a course of this drug for her patients, “I never overpromise,” she said. “I tell my acne patients, ‘We measure your success in weeks and months, not days.’ I always tell them, ‘Take a selfie today and take a selfie every few weeks. When you come back in, we’ll review your progress and see how things went.’ ”

Researchers have also been studying topical minocycline as a treatment option. Minocycline is a large molecule that Dr. Stein Gold characterized as being “very challenging” to deliver topically. “It’s also challenging to keep it stable in a topical formulation.” However, results from two identical phase 3 trials found 4% topical minocycline foam significantly reduced both inflammatory and noninflammatory lesions and improved IGA scores in patients with moderate to severe acne when treated daily for 12 weeks (J Am Acad Dermatol. 2019 Jan;80[1]:168-77).

“This drug has an interesting vehicle,” said Dr. Stein Gold, who was one of the study investigators. “If you take the vehicle itself and you put it next to sebum, it causes sebum to melt at lower temperatures. Why does this matter? If you’re dissolving sebum, maybe you’re creating an easier pathway for the drug to get delivered into the skin and into the hair follicles. We don’t know all the details.” In the two trials, 15%-31% of patients achieved clearance or near clearance of all lesions. “How did it do in terms of decreasing papules and pustules? It did pretty well,” she said. “We want drugs to meet their match in everything that we do.” In terms of tolerability, skin-related adverse events were reported in fewer than 1% of subjects treated with 4% topical minocycline foam. She noted that by delivering minocycline topically, “we get huge concentrations in the skin, but almost negligible amounts in the systemic circulation, which is important. We want to keep [the drug] in the skin; we don’t want it in our system.”

(The Food and Drug Administration approved minocycline foam 4% in October 2019 for treating inflammatory lesions associated with non-nodular moderate to severe acne).

Another potential treatment on the horizon is cortexolone 17a-propionate, a novel androgen receptor antagonist that inhibits production of lipids and inflammatory cytokines from sebocytes in vitro. “When used around the sebaceous gland, we find that the amount of sebum produced goes down,” she said, noting that phase 3 trials of the agent have been completed.

“We also find that abnormal keratinization subsequently goes down. Just putting this on the skin significantly reduced acne as monotherapy in patients with moderate to severe acne. We were able to get them to clear or almost clear. It worked on comedones, papules, and pustules. Hopefully, it will get FDA approval. This fills the one unmet need we haven’t had topically in terms of decreasing sebum production.”

Clinical trials of CBD are also under way for acne and atopic dermatitis. “It could work for acne because there are some studies showing that might work on sebaceous glands to decrease sebum production,” she said. “CBD has been shown to have positive effects on abnormal keratinization, and it has been shown to have anti-inflammatory effects. Maybe we’ll have another mechanism of action for acne.”

Dr. Gold disclosed that she is on the speakers bureau for Almirall, Galderma, Leo Pharma, Ortho Dermatologics, Pfizer, and Sanofi/Regeneron. She is a consultant for Dermavant, Foamix, Galderma, Leo Pharma, Pfizer, Novartis, Ortho Dermatologics, and holds stock/stock options in AbbVie, Dermavant, Eli Lilly, Foamix, Galderma, Incyte, Leo Pharma, Novartis, Ortho Dermatologics, Pfizer, and Sol-Gel.

SDEF and this news organization are owned by the same parent company.

dbrunk@mdedge.com

LAS VEGAS – The way Neal Bhatia, MD, sees it, there is no such thing as a classical presentation of onychomycosis.

Doug Brunk/MDedge News

“This is where proving your diagnosis is half the battle, even though we are sometimes using empiric therapy in suspected cases,” he said at Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar. “Prove the diagnosis and get the extra tests necessary.”

According to Dr. Bhatia, director of clinical dermatology research at San Diego-based Therapeutics Clinical Research, tinea unguium, tinea corporis, tinea cruris, and tinea pedis account for more than half of all visits for dermatophytosis. With onychomycosis, the ultimate treatment goal from the standpoint of clinicians is no more fungus, he noted, while the desired endpoint from the standpoint of some patients is normal-looking nails.

“Endpoint failures in a research trial are not the same as what we tell patients in the clinic,” Dr. Bhatia said. “If you have a patient using something topical for 52 weeks and they see two-thirds of their nail improve, you’re not going to say, ‘Stop; you’re a failure now.’ You tell them, ‘Keep going and we’ll keep watching.’ But in the research world, it’s very different when you look at all of the different endpoints that have to be met at the finish line. It’s very important to measure success based on what that patient’s experiencing.”

According to Dr. Bhatia, diagnosing onychomycosis by visual assessment has a sensitivity of 77% and a specificity of 47%, while KOH has a sensitivity between 67% and 93% and specificity between 38% and 78%. PCR, meanwhile, “is quick, but it’s expensive and it has a high false-positive rate. So, in those difficult patients who aren’t responding [to treatment], maybe we can’t just trust our eyes alone [to make a diagnosis].”

Tests such as a KOH stain have low sensitivity, with high costs of more sensitive tests such as the periodic acid–Schiff (PAS) stain. In a recent study, researchers conducted a retrospective cohort analysis of 600 patients with toenail clippings sent for PAS stain during January 2000–December 2013 (J Am Acad Dermatol. 2015 May; 72(5):AB116). They reviewed records to determine which PAS stains were performed to confirm probable clinical diagnosis of onychomycosis.

The researchers found that 30% of toenail clippings were sent for confirmatory PAS staining by dermatologists, compared with 37% by podiatrists and 34% by other clinicians. Of these tests, 75% ordered by dermatologists were positive for fungus, compared with 81% ordered by podiatrists, and 66% ordered by other physicians. “The positive predictive value of clinical suspicion for true onychomycosis was high, and the findings question whether or not a confirmatory test is really necessary,” Dr. Bhatia said.

Preventative strategies to control recurrence of onychomycosis include using maintenance regimens of the recommended antifungal agent, discarding old shoes, alternating wearing different pairs of shoes, periodically disinfecting shoes, washing feet regularly, and alerting the physician to the first sign of infection.

In an effort to investigate strategies to minimize recurrence of onychomycosis, Dr. Bhatia and colleagues evaluated 73 patients over the course of 7 years who were taking either terbinafine or itraconazole (J Drugs Dermatol. 2016;15[3]:279-82). Thirty-six months later, the overall mean recurrence rate among patients was 14%. Prognostic factors influencing recurrence included patient’s family history; lifestyle; underlying physiology (presence of a very thick nail, extensive involvement of the entire nail unit, lateral nail disease and yellow spikes); physical trauma, especially in the elderly; concomitant disease, such as peripheral artery disease and/or diabetes; immunocompromised or immunosuppressed patients, and the presence of tinea pedis.

Based on their analysis, they recommended the following strategies to prevent or limit recurrence: prophylactic use of a topical antifungal twice-weekly for 2-3 years; periodic application of a topical antifungal to plantar surface and/or interdigital spaces; treatment of any coexisting tinea pedis; treating immediate family members; footwear and sock decontamination with antifungal powder; ultraviolet light or ozone; avoidance of activities known to risk spread of disease, such as communal swimming pools.

Dr. Bhatia concluded his presentation by noting that the ideal treatment for onychomycosis would not pose a systemic risk to the liver, heart, or other organs; would not require monitoring of labs; would not require debridement; and would not interact with other drugs. It would also penetrate the nail plate – especially the diseased nail – and would be quick drying.

SDEF and this news organization are owned by the same parent company.

Dr. Bhatia disclosed having affiliations with Actavis, Allergan, Anacor, Aqua, Bayer, Biofrontera, BiopharmX, Cipher, Dermira, Dusa, Exeltis, Ferndale, Foamix, Galderma, Intraderm, ISDIN, LaRoche-Posay, Leo, Novan, Novartis, PharmaDerm, Promius, Regeneron, Sanofi, Sun Pharma, and Valeant.

dbrunk@mdedge.com

LAS VEGAS – The way Neal Bhatia, MD, sees it, there is no such thing as a classical presentation of onychomycosis.

Doug Brunk/MDedge News

“This is where proving your diagnosis is half the battle, even though we are sometimes using empiric therapy in suspected cases,” he said at Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar. “Prove the diagnosis and get the extra tests necessary.”

According to Dr. Bhatia, director of clinical dermatology research at San Diego-based Therapeutics Clinical Research, tinea unguium, tinea corporis, tinea cruris, and tinea pedis account for more than half of all visits for dermatophytosis. With onychomycosis, the ultimate treatment goal from the standpoint of clinicians is no more fungus, he noted, while the desired endpoint from the standpoint of some patients is normal-looking nails.

“Endpoint failures in a research trial are not the same as what we tell patients in the clinic,” Dr. Bhatia said. “If you have a patient using something topical for 52 weeks and they see two-thirds of their nail improve, you’re not going to say, ‘Stop; you’re a failure now.’ You tell them, ‘Keep going and we’ll keep watching.’ But in the research world, it’s very different when you look at all of the different endpoints that have to be met at the finish line. It’s very important to measure success based on what that patient’s experiencing.”

According to Dr. Bhatia, diagnosing onychomycosis by visual assessment has a sensitivity of 77% and a specificity of 47%, while KOH has a sensitivity between 67% and 93% and specificity between 38% and 78%. PCR, meanwhile, “is quick, but it’s expensive and it has a high false-positive rate. So, in those difficult patients who aren’t responding [to treatment], maybe we can’t just trust our eyes alone [to make a diagnosis].”

Tests such as a KOH stain have low sensitivity, with high costs of more sensitive tests such as the periodic acid–Schiff (PAS) stain. In a recent study, researchers conducted a retrospective cohort analysis of 600 patients with toenail clippings sent for PAS stain during January 2000–December 2013 (J Am Acad Dermatol. 2015 May; 72(5):AB116). They reviewed records to determine which PAS stains were performed to confirm probable clinical diagnosis of onychomycosis.

The researchers found that 30% of toenail clippings were sent for confirmatory PAS staining by dermatologists, compared with 37% by podiatrists and 34% by other clinicians. Of these tests, 75% ordered by dermatologists were positive for fungus, compared with 81% ordered by podiatrists, and 66% ordered by other physicians. “The positive predictive value of clinical suspicion for true onychomycosis was high, and the findings question whether or not a confirmatory test is really necessary,” Dr. Bhatia said.

Preventative strategies to control recurrence of onychomycosis include using maintenance regimens of the recommended antifungal agent, discarding old shoes, alternating wearing different pairs of shoes, periodically disinfecting shoes, washing feet regularly, and alerting the physician to the first sign of infection.

In an effort to investigate strategies to minimize recurrence of onychomycosis, Dr. Bhatia and colleagues evaluated 73 patients over the course of 7 years who were taking either terbinafine or itraconazole (J Drugs Dermatol. 2016;15[3]:279-82). Thirty-six months later, the overall mean recurrence rate among patients was 14%. Prognostic factors influencing recurrence included patient’s family history; lifestyle; underlying physiology (presence of a very thick nail, extensive involvement of the entire nail unit, lateral nail disease and yellow spikes); physical trauma, especially in the elderly; concomitant disease, such as peripheral artery disease and/or diabetes; immunocompromised or immunosuppressed patients, and the presence of tinea pedis.

Based on their analysis, they recommended the following strategies to prevent or limit recurrence: prophylactic use of a topical antifungal twice-weekly for 2-3 years; periodic application of a topical antifungal to plantar surface and/or interdigital spaces; treatment of any coexisting tinea pedis; treating immediate family members; footwear and sock decontamination with antifungal powder; ultraviolet light or ozone; avoidance of activities known to risk spread of disease, such as communal swimming pools.

Dr. Bhatia concluded his presentation by noting that the ideal treatment for onychomycosis would not pose a systemic risk to the liver, heart, or other organs; would not require monitoring of labs; would not require debridement; and would not interact with other drugs. It would also penetrate the nail plate – especially the diseased nail – and would be quick drying.

SDEF and this news organization are owned by the same parent company.

Dr. Bhatia disclosed having affiliations with Actavis, Allergan, Anacor, Aqua, Bayer, Biofrontera, BiopharmX, Cipher, Dermira, Dusa, Exeltis, Ferndale, Foamix, Galderma, Intraderm, ISDIN, LaRoche-Posay, Leo, Novan, Novartis, PharmaDerm, Promius, Regeneron, Sanofi, Sun Pharma, and Valeant.

dbrunk@mdedge.com

LAS VEGAS – The way Neal Bhatia, MD, sees it, there is no such thing as a classical presentation of onychomycosis.

Doug Brunk/MDedge News

“This is where proving your diagnosis is half the battle, even though we are sometimes using empiric therapy in suspected cases,” he said at Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar. “Prove the diagnosis and get the extra tests necessary.”

According to Dr. Bhatia, director of clinical dermatology research at San Diego-based Therapeutics Clinical Research, tinea unguium, tinea corporis, tinea cruris, and tinea pedis account for more than half of all visits for dermatophytosis. With onychomycosis, the ultimate treatment goal from the standpoint of clinicians is no more fungus, he noted, while the desired endpoint from the standpoint of some patients is normal-looking nails.

“Endpoint failures in a research trial are not the same as what we tell patients in the clinic,” Dr. Bhatia said. “If you have a patient using something topical for 52 weeks and they see two-thirds of their nail improve, you’re not going to say, ‘Stop; you’re a failure now.’ You tell them, ‘Keep going and we’ll keep watching.’ But in the research world, it’s very different when you look at all of the different endpoints that have to be met at the finish line. It’s very important to measure success based on what that patient’s experiencing.”

According to Dr. Bhatia, diagnosing onychomycosis by visual assessment has a sensitivity of 77% and a specificity of 47%, while KOH has a sensitivity between 67% and 93% and specificity between 38% and 78%. PCR, meanwhile, “is quick, but it’s expensive and it has a high false-positive rate. So, in those difficult patients who aren’t responding [to treatment], maybe we can’t just trust our eyes alone [to make a diagnosis].”

Tests such as a KOH stain have low sensitivity, with high costs of more sensitive tests such as the periodic acid–Schiff (PAS) stain. In a recent study, researchers conducted a retrospective cohort analysis of 600 patients with toenail clippings sent for PAS stain during January 2000–December 2013 (J Am Acad Dermatol. 2015 May; 72(5):AB116). They reviewed records to determine which PAS stains were performed to confirm probable clinical diagnosis of onychomycosis.

The researchers found that 30% of toenail clippings were sent for confirmatory PAS staining by dermatologists, compared with 37% by podiatrists and 34% by other clinicians. Of these tests, 75% ordered by dermatologists were positive for fungus, compared with 81% ordered by podiatrists, and 66% ordered by other physicians. “The positive predictive value of clinical suspicion for true onychomycosis was high, and the findings question whether or not a confirmatory test is really necessary,” Dr. Bhatia said.

Preventative strategies to control recurrence of onychomycosis include using maintenance regimens of the recommended antifungal agent, discarding old shoes, alternating wearing different pairs of shoes, periodically disinfecting shoes, washing feet regularly, and alerting the physician to the first sign of infection.

In an effort to investigate strategies to minimize recurrence of onychomycosis, Dr. Bhatia and colleagues evaluated 73 patients over the course of 7 years who were taking either terbinafine or itraconazole (J Drugs Dermatol. 2016;15[3]:279-82). Thirty-six months later, the overall mean recurrence rate among patients was 14%. Prognostic factors influencing recurrence included patient’s family history; lifestyle; underlying physiology (presence of a very thick nail, extensive involvement of the entire nail unit, lateral nail disease and yellow spikes); physical trauma, especially in the elderly; concomitant disease, such as peripheral artery disease and/or diabetes; immunocompromised or immunosuppressed patients, and the presence of tinea pedis.

Based on their analysis, they recommended the following strategies to prevent or limit recurrence: prophylactic use of a topical antifungal twice-weekly for 2-3 years; periodic application of a topical antifungal to plantar surface and/or interdigital spaces; treatment of any coexisting tinea pedis; treating immediate family members; footwear and sock decontamination with antifungal powder; ultraviolet light or ozone; avoidance of activities known to risk spread of disease, such as communal swimming pools.

Dr. Bhatia concluded his presentation by noting that the ideal treatment for onychomycosis would not pose a systemic risk to the liver, heart, or other organs; would not require monitoring of labs; would not require debridement; and would not interact with other drugs. It would also penetrate the nail plate – especially the diseased nail – and would be quick drying.

SDEF and this news organization are owned by the same parent company.

Dr. Bhatia disclosed having affiliations with Actavis, Allergan, Anacor, Aqua, Bayer, Biofrontera, BiopharmX, Cipher, Dermira, Dusa, Exeltis, Ferndale, Foamix, Galderma, Intraderm, ISDIN, LaRoche-Posay, Leo, Novan, Novartis, PharmaDerm, Promius, Regeneron, Sanofi, Sun Pharma, and Valeant.

dbrunk@mdedge.com

LAS VEGAS – Dermatologists in Oregon have launched a project that targets melanoma by promoting education and early detection, with the goal of dramatically reducing melanoma deaths in the state of 4.2 million people.

Research shows that “early detection works in melanoma. And awareness seems to be important for the public in detecting melanoma early,” said Sancy Leachman, MD, PhD, professor and chair of the department of dermatology at Oregon Health & Science University, Portland, said at the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar.

Dr. Leachman, who is also the John D. Gray chair in melanoma research at OHSU, directs the “War on Melanoma” project, which was inspired by a project in the German state of Schleswig-Holstein that aimed to screen all residents aged over 21 years for melanoma. The project featured an education campaign and population-wide skin cancer screening, and mandated that certain patients – those at high risk and those who needed biopsies – would be referred to dermatologists (Br J Cancer. 2012 Feb 28;106[5]:970-4).

According to Dr. Leachman, the German project was initially a success, and was linked to a 50% decrease in melanoma mortality.

“In Oregon, we thought ‘that sounds very good, so we’re going to try that.’ ” But when it went national, the German project failed, she said, providing lessons for dermatologists in Oregon. “We’re going to try to improve upon the first [German] experiment by making ours controlled with a defined baseline. If it works, the plan is to extend it to select states nationwide.”

The War on Melanoma project was launched earlier this year. According to the university, the program is featuring or will feature the following elements:

• A media campaign called “Start Seeing Melanoma” that’s devoted to educating the public about the early detection of melanoma.
• The release of an iPhone app called MoleMapper that allows users to monitor moles over time.
• Education of medical professionals and partnerships with state-licensed skin care professionals such as massage therapists, cosmetologists, and tattoo artists.

In an interview at the meeting, Dr. Leachman said the project is expected to cost $1 million to $1.5 million over the first 18 months. At that time, she said, researchers will survey residents of Oregon and two control states – Washington and Utah– to see if their knowledge of melanoma has improved, compared with baseline survey results.

In 5 years, researchers plan to begin analyzing melanoma mortality in Oregon and the other states. “We hope to see a decline,” and to link it to increased awareness of melanoma, she said.

Dr. Leachman reported no relevant disclosures. She spoke during a forum on cutaneous malignancies at the meeting.

SDEF and this news organization are owned by the same parent company.

LAS VEGAS – Dermatologists in Oregon have launched a project that targets melanoma by promoting education and early detection, with the goal of dramatically reducing melanoma deaths in the state of 4.2 million people.

Research shows that “early detection works in melanoma. And awareness seems to be important for the public in detecting melanoma early,” said Sancy Leachman, MD, PhD, professor and chair of the department of dermatology at Oregon Health & Science University, Portland, said at the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar.

Dr. Leachman, who is also the John D. Gray chair in melanoma research at OHSU, directs the “War on Melanoma” project, which was inspired by a project in the German state of Schleswig-Holstein that aimed to screen all residents aged over 21 years for melanoma. The project featured an education campaign and population-wide skin cancer screening, and mandated that certain patients – those at high risk and those who needed biopsies – would be referred to dermatologists (Br J Cancer. 2012 Feb 28;106[5]:970-4).

According to Dr. Leachman, the German project was initially a success, and was linked to a 50% decrease in melanoma mortality.

“In Oregon, we thought ‘that sounds very good, so we’re going to try that.’ ” But when it went national, the German project failed, she said, providing lessons for dermatologists in Oregon. “We’re going to try to improve upon the first [German] experiment by making ours controlled with a defined baseline. If it works, the plan is to extend it to select states nationwide.”

The War on Melanoma project was launched earlier this year. According to the university, the program is featuring or will feature the following elements:

• A media campaign called “Start Seeing Melanoma” that’s devoted to educating the public about the early detection of melanoma.
• The release of an iPhone app called MoleMapper that allows users to monitor moles over time.
• Education of medical professionals and partnerships with state-licensed skin care professionals such as massage therapists, cosmetologists, and tattoo artists.

In an interview at the meeting, Dr. Leachman said the project is expected to cost $1 million to $1.5 million over the first 18 months. At that time, she said, researchers will survey residents of Oregon and two control states – Washington and Utah– to see if their knowledge of melanoma has improved, compared with baseline survey results.

In 5 years, researchers plan to begin analyzing melanoma mortality in Oregon and the other states. “We hope to see a decline,” and to link it to increased awareness of melanoma, she said.

Dr. Leachman reported no relevant disclosures. She spoke during a forum on cutaneous malignancies at the meeting.

SDEF and this news organization are owned by the same parent company.

LAS VEGAS – Dermatologists in Oregon have launched a project that targets melanoma by promoting education and early detection, with the goal of dramatically reducing melanoma deaths in the state of 4.2 million people.

Research shows that “early detection works in melanoma. And awareness seems to be important for the public in detecting melanoma early,” said Sancy Leachman, MD, PhD, professor and chair of the department of dermatology at Oregon Health & Science University, Portland, said at the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar.

Dr. Leachman, who is also the John D. Gray chair in melanoma research at OHSU, directs the “War on Melanoma” project, which was inspired by a project in the German state of Schleswig-Holstein that aimed to screen all residents aged over 21 years for melanoma. The project featured an education campaign and population-wide skin cancer screening, and mandated that certain patients – those at high risk and those who needed biopsies – would be referred to dermatologists (Br J Cancer. 2012 Feb 28;106[5]:970-4).

According to Dr. Leachman, the German project was initially a success, and was linked to a 50% decrease in melanoma mortality.

“In Oregon, we thought ‘that sounds very good, so we’re going to try that.’ ” But when it went national, the German project failed, she said, providing lessons for dermatologists in Oregon. “We’re going to try to improve upon the first [German] experiment by making ours controlled with a defined baseline. If it works, the plan is to extend it to select states nationwide.”

The War on Melanoma project was launched earlier this year. According to the university, the program is featuring or will feature the following elements:

• A media campaign called “Start Seeing Melanoma” that’s devoted to educating the public about the early detection of melanoma.
• The release of an iPhone app called MoleMapper that allows users to monitor moles over time.
• Education of medical professionals and partnerships with state-licensed skin care professionals such as massage therapists, cosmetologists, and tattoo artists.

In an interview at the meeting, Dr. Leachman said the project is expected to cost $1 million to $1.5 million over the first 18 months. At that time, she said, researchers will survey residents of Oregon and two control states – Washington and Utah– to see if their knowledge of melanoma has improved, compared with baseline survey results.

In 5 years, researchers plan to begin analyzing melanoma mortality in Oregon and the other states. “We hope to see a decline,” and to link it to increased awareness of melanoma, she said.

Dr. Leachman reported no relevant disclosures. She spoke during a forum on cutaneous malignancies at the meeting.

SDEF and this news organization are owned by the same parent company.

A 60-year-old man presented to our dermatology clinic with a chronic, recurrent pruritic rash on his hands and neck. He noted that the rash developed into blisters, which he would pick until they scabbed over. The rash only manifested on sun-exposed areas.

The patient did not take any medications. He admitted to drinking alcohol (4 beers/d on average) and had roughly a 50-pack year history of smoking. There was no family history of similar symptoms.

On physical exam, we noted erosions and ulcerations with hemorrhagic crust on the dorsal aspect of his hands, along with milia on the knuckle pads (FIGURE 1A). Further skin examination revealed hypopigmented scars on his shoulders and lower extremities bilaterally, with hypertrichosis of the cheeks (FIGURE 1B).

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

 

 

Diagnosis: Porphyria cutanea tarda

Based on the clinical presentation and the patient’s history of smoking and alcohol consumption, we suspected that this was a case of porphyria cutanea tarda (PCT). Laboratory studies, including a complete blood count, basic metabolic panel, iron studies, and liver function tests, were ordered. These revealed elevated levels of serum alanine transaminase (116 IU/L; reference range, 20-60 IU/L), aspartate aminotransferase (184 IU/L; reference range, 6-34 IU/L in men), and ferritin (1594 ng/mL; reference range, 12-300 ng/mL in men), consistent with PCT. Total porphyrins were then measured and found to be elevated (128.5 mcg/dL; reference range, 0 to 1 mcg/dL), which confirmed the diagnosis. Further testing revealed that the patient was positive for both hepatitis C virus (HCV) and hepatitis B virus infection.

Susceptibility factors for porphyria cutanea tarda include chronic alcohol use, HCV and/or HIV infection, estrogen therapy, and chronic/heavy smoking.

While PCT is the most common porphyria worldwide, it is nonetheless a rare disorder that results from deficient activity (< 20% of normal) of uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the heme synthetic pathway.^1,2 It is typically (~75% cases) an acquired disorder of mid- to late adulthood and more commonly affects males.¹ In the remainder of cases, patients have a genetic predisposition—a mutation of the UROD or HFE gene. Patients with a genetic predisposition may present earlier.^2,3 Susceptibility factors for both forms of PCT include chronic alcohol use, HCV and/or human immunodeficiency virus (HIV) infection, estrogen therapy, and a history of chronic/heavy smoking.^1,4

Cutaneous manifestations of PCT are caused by the accumulation of porphyrins, which are photo-oxidized in the skin.¹ Findings include photosensitivity, skin fragility, blistering, scarring, hypo- or hyperpigmentation, and milia in sun-exposed areas, such as the dorsum of the hands, forearms, face, ears, neck, and feet.^1,2 Hypertrichosis can occur, particularly on the cheeks and forearms.¹ Elevated transaminases often accompany cutaneous findings, due to porphyrin accumulation in hepatocytes and the hepatotoxic effects of alcohol, HCV infection, or iron overload.⁵ Iron overload, in part due to dysregulation of hepcidin, can lead to increased serum ferritin, iron, and transferrin saturation.¹

Differential includes autoimmune and autosomal conditions

Diseases that manifest with blistering, elevated porphyrins or porphyrin precursors, and iron overload should be included in the differential diagnosis.

Bullous pemphigoid is an autoimmune subepithelial blistering disorder that occurs when antibodies attack hemidesmosomes in the epidermis. It commonly manifests in the elderly and classically presents with tense bullae, typically on the trunk, abdomen, and proximal extremities. Serologic testing and biopsy can confirm the diagnosis.⁶

Continue to: Pseudoporphyria...

Pseudoporphyria has a similar presentation to PCT but with no abnormalities in porphyrin metabolism. Risk factors include UV radiation exposure; use of medications such as nonsteroidal anti-inflammatory drugs, diuretics, and retinoids; chronic renal failure; and hemodialysis.⁷

Acute intermittent porphyria is an autosomal dominant disorder due to deficiency of porphobilinogen deaminase, a heme biosynthetic enzyme. Clinical manifestations usually arise in adulthood and include neurovisceral attacks (eg, abdominal pain, vomiting, muscle weakness). Diagnosis during an acute attack can be made by measuring urinary 5-aminolaevulinc acid and porphobilinogen.¹

Hereditary hemochromatosis is an autosomal recessive disorder most commonly due to mutations in the HFE gene. Patients typically have iron overload and abnormal liver function test results. The main cutaneous finding is skin hyperpigmentation. Patients also may develop diabetes mellitus, arthropathy, cardiac disease, and hypopituitarism, although most are diagnosed with asymptomatic disease following routine laboratory studies.⁸

Confirm the diagnosis with total porphyrin measurement

The preferred initial test to confirm the diagnosis of PCT is measurement of plasma or urine total porphyrins, which will be elevated.¹ Further testing is then performed to discern PCT from the other, less common cutaneous porphyrias.¹ If needed, biopsy can be done to exclude other diagnoses. Testing for HIV and viral hepatitis infection may be performed when clinical suspicion is high.¹ Testing for UROD and HFE mutations may also be advised.¹

Treatment choice is guided by iron levels

For patients with normal iron levels, low-dose hydroxychloroquine 100 mg or chloroquine 125 mg twice per week can be used until restoration of normal plasma or urine porphyrin levels has been achieved for several months.¹ For those with iron excess (serum ferritin > 600 ng/dL), repeat phlebotomy is the preferred treatment; a unit of blood (350-500 mL) is typically removed, as tolerated, until iron stores return to normal.¹ In severe cases of PCT, these therapies can be used in combination.¹ Clinical remission with these methods can be expected within 6 to 9 months.⁹

Continue to: In addition...

In addition, it is important to provide patient education regarding proper sun protection and risk factor modification.¹ Underlying HIV and viral hepatitis infection should be managed appropriately by the relevant specialists.

With proper treatment, clinical remission can be expected within 6 to 9 months.

Our patient was counseled on proper sun protection and encouraged to cease alcohol consumption and smoking. We subsequently referred him to Hepatology for the treatment of his liver disease. Given that the patient’s ferritin level was so high (1594 ng/­mL), serial phlebotomy was initiated twice monthly until levels reached the lower limit of normal. He was also started on direct-acting antiviral therapy with Epclusa (sofosbuvir/velpatasvir) for 12 weeks for treatment of his HCV and is currently in remission.

CORRESPONDENCE
Christopher G. Bazewicz, MD, Department of Dermatology, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033; bazewicz@uchc.edu

A 60-year-old man presented to our dermatology clinic with a chronic, recurrent pruritic rash on his hands and neck. He noted that the rash developed into blisters, which he would pick until they scabbed over. The rash only manifested on sun-exposed areas.

The patient did not take any medications. He admitted to drinking alcohol (4 beers/d on average) and had roughly a 50-pack year history of smoking. There was no family history of similar symptoms.

On physical exam, we noted erosions and ulcerations with hemorrhagic crust on the dorsal aspect of his hands, along with milia on the knuckle pads (FIGURE 1A). Further skin examination revealed hypopigmented scars on his shoulders and lower extremities bilaterally, with hypertrichosis of the cheeks (FIGURE 1B).

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

 

 

Diagnosis: Porphyria cutanea tarda

Based on the clinical presentation and the patient’s history of smoking and alcohol consumption, we suspected that this was a case of porphyria cutanea tarda (PCT). Laboratory studies, including a complete blood count, basic metabolic panel, iron studies, and liver function tests, were ordered. These revealed elevated levels of serum alanine transaminase (116 IU/L; reference range, 20-60 IU/L), aspartate aminotransferase (184 IU/L; reference range, 6-34 IU/L in men), and ferritin (1594 ng/mL; reference range, 12-300 ng/mL in men), consistent with PCT. Total porphyrins were then measured and found to be elevated (128.5 mcg/dL; reference range, 0 to 1 mcg/dL), which confirmed the diagnosis. Further testing revealed that the patient was positive for both hepatitis C virus (HCV) and hepatitis B virus infection.

Susceptibility factors for porphyria cutanea tarda include chronic alcohol use, HCV and/or HIV infection, estrogen therapy, and chronic/heavy smoking.

While PCT is the most common porphyria worldwide, it is nonetheless a rare disorder that results from deficient activity (< 20% of normal) of uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the heme synthetic pathway.^1,2 It is typically (~75% cases) an acquired disorder of mid- to late adulthood and more commonly affects males.¹ In the remainder of cases, patients have a genetic predisposition—a mutation of the UROD or HFE gene. Patients with a genetic predisposition may present earlier.^2,3 Susceptibility factors for both forms of PCT include chronic alcohol use, HCV and/or human immunodeficiency virus (HIV) infection, estrogen therapy, and a history of chronic/heavy smoking.^1,4

Cutaneous manifestations of PCT are caused by the accumulation of porphyrins, which are photo-oxidized in the skin.¹ Findings include photosensitivity, skin fragility, blistering, scarring, hypo- or hyperpigmentation, and milia in sun-exposed areas, such as the dorsum of the hands, forearms, face, ears, neck, and feet.^1,2 Hypertrichosis can occur, particularly on the cheeks and forearms.¹ Elevated transaminases often accompany cutaneous findings, due to porphyrin accumulation in hepatocytes and the hepatotoxic effects of alcohol, HCV infection, or iron overload.⁵ Iron overload, in part due to dysregulation of hepcidin, can lead to increased serum ferritin, iron, and transferrin saturation.¹

Differential includes autoimmune and autosomal conditions

Diseases that manifest with blistering, elevated porphyrins or porphyrin precursors, and iron overload should be included in the differential diagnosis.

Bullous pemphigoid is an autoimmune subepithelial blistering disorder that occurs when antibodies attack hemidesmosomes in the epidermis. It commonly manifests in the elderly and classically presents with tense bullae, typically on the trunk, abdomen, and proximal extremities. Serologic testing and biopsy can confirm the diagnosis.⁶

Continue to: Pseudoporphyria...

Pseudoporphyria has a similar presentation to PCT but with no abnormalities in porphyrin metabolism. Risk factors include UV radiation exposure; use of medications such as nonsteroidal anti-inflammatory drugs, diuretics, and retinoids; chronic renal failure; and hemodialysis.⁷

Acute intermittent porphyria is an autosomal dominant disorder due to deficiency of porphobilinogen deaminase, a heme biosynthetic enzyme. Clinical manifestations usually arise in adulthood and include neurovisceral attacks (eg, abdominal pain, vomiting, muscle weakness). Diagnosis during an acute attack can be made by measuring urinary 5-aminolaevulinc acid and porphobilinogen.¹

Hereditary hemochromatosis is an autosomal recessive disorder most commonly due to mutations in the HFE gene. Patients typically have iron overload and abnormal liver function test results. The main cutaneous finding is skin hyperpigmentation. Patients also may develop diabetes mellitus, arthropathy, cardiac disease, and hypopituitarism, although most are diagnosed with asymptomatic disease following routine laboratory studies.⁸

Confirm the diagnosis with total porphyrin measurement

The preferred initial test to confirm the diagnosis of PCT is measurement of plasma or urine total porphyrins, which will be elevated.¹ Further testing is then performed to discern PCT from the other, less common cutaneous porphyrias.¹ If needed, biopsy can be done to exclude other diagnoses. Testing for HIV and viral hepatitis infection may be performed when clinical suspicion is high.¹ Testing for UROD and HFE mutations may also be advised.¹

Treatment choice is guided by iron levels

For patients with normal iron levels, low-dose hydroxychloroquine 100 mg or chloroquine 125 mg twice per week can be used until restoration of normal plasma or urine porphyrin levels has been achieved for several months.¹ For those with iron excess (serum ferritin > 600 ng/dL), repeat phlebotomy is the preferred treatment; a unit of blood (350-500 mL) is typically removed, as tolerated, until iron stores return to normal.¹ In severe cases of PCT, these therapies can be used in combination.¹ Clinical remission with these methods can be expected within 6 to 9 months.⁹

Continue to: In addition...

In addition, it is important to provide patient education regarding proper sun protection and risk factor modification.¹ Underlying HIV and viral hepatitis infection should be managed appropriately by the relevant specialists.

With proper treatment, clinical remission can be expected within 6 to 9 months.

Our patient was counseled on proper sun protection and encouraged to cease alcohol consumption and smoking. We subsequently referred him to Hepatology for the treatment of his liver disease. Given that the patient’s ferritin level was so high (1594 ng/­mL), serial phlebotomy was initiated twice monthly until levels reached the lower limit of normal. He was also started on direct-acting antiviral therapy with Epclusa (sofosbuvir/velpatasvir) for 12 weeks for treatment of his HCV and is currently in remission.

CORRESPONDENCE
Christopher G. Bazewicz, MD, Department of Dermatology, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033; bazewicz@uchc.edu

A 60-year-old man presented to our dermatology clinic with a chronic, recurrent pruritic rash on his hands and neck. He noted that the rash developed into blisters, which he would pick until they scabbed over. The rash only manifested on sun-exposed areas.

The patient did not take any medications. He admitted to drinking alcohol (4 beers/d on average) and had roughly a 50-pack year history of smoking. There was no family history of similar symptoms.

On physical exam, we noted erosions and ulcerations with hemorrhagic crust on the dorsal aspect of his hands, along with milia on the knuckle pads (FIGURE 1A). Further skin examination revealed hypopigmented scars on his shoulders and lower extremities bilaterally, with hypertrichosis of the cheeks (FIGURE 1B).

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

 

 

Diagnosis: Porphyria cutanea tarda

Based on the clinical presentation and the patient’s history of smoking and alcohol consumption, we suspected that this was a case of porphyria cutanea tarda (PCT). Laboratory studies, including a complete blood count, basic metabolic panel, iron studies, and liver function tests, were ordered. These revealed elevated levels of serum alanine transaminase (116 IU/L; reference range, 20-60 IU/L), aspartate aminotransferase (184 IU/L; reference range, 6-34 IU/L in men), and ferritin (1594 ng/mL; reference range, 12-300 ng/mL in men), consistent with PCT. Total porphyrins were then measured and found to be elevated (128.5 mcg/dL; reference range, 0 to 1 mcg/dL), which confirmed the diagnosis. Further testing revealed that the patient was positive for both hepatitis C virus (HCV) and hepatitis B virus infection.

Susceptibility factors for porphyria cutanea tarda include chronic alcohol use, HCV and/or HIV infection, estrogen therapy, and chronic/heavy smoking.

While PCT is the most common porphyria worldwide, it is nonetheless a rare disorder that results from deficient activity (< 20% of normal) of uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the heme synthetic pathway.^1,2 It is typically (~75% cases) an acquired disorder of mid- to late adulthood and more commonly affects males.¹ In the remainder of cases, patients have a genetic predisposition—a mutation of the UROD or HFE gene. Patients with a genetic predisposition may present earlier.^2,3 Susceptibility factors for both forms of PCT include chronic alcohol use, HCV and/or human immunodeficiency virus (HIV) infection, estrogen therapy, and a history of chronic/heavy smoking.^1,4

Cutaneous manifestations of PCT are caused by the accumulation of porphyrins, which are photo-oxidized in the skin.¹ Findings include photosensitivity, skin fragility, blistering, scarring, hypo- or hyperpigmentation, and milia in sun-exposed areas, such as the dorsum of the hands, forearms, face, ears, neck, and feet.^1,2 Hypertrichosis can occur, particularly on the cheeks and forearms.¹ Elevated transaminases often accompany cutaneous findings, due to porphyrin accumulation in hepatocytes and the hepatotoxic effects of alcohol, HCV infection, or iron overload.⁵ Iron overload, in part due to dysregulation of hepcidin, can lead to increased serum ferritin, iron, and transferrin saturation.¹

Differential includes autoimmune and autosomal conditions

Diseases that manifest with blistering, elevated porphyrins or porphyrin precursors, and iron overload should be included in the differential diagnosis.

Bullous pemphigoid is an autoimmune subepithelial blistering disorder that occurs when antibodies attack hemidesmosomes in the epidermis. It commonly manifests in the elderly and classically presents with tense bullae, typically on the trunk, abdomen, and proximal extremities. Serologic testing and biopsy can confirm the diagnosis.⁶

Continue to: Pseudoporphyria...

Pseudoporphyria has a similar presentation to PCT but with no abnormalities in porphyrin metabolism. Risk factors include UV radiation exposure; use of medications such as nonsteroidal anti-inflammatory drugs, diuretics, and retinoids; chronic renal failure; and hemodialysis.⁷

Acute intermittent porphyria is an autosomal dominant disorder due to deficiency of porphobilinogen deaminase, a heme biosynthetic enzyme. Clinical manifestations usually arise in adulthood and include neurovisceral attacks (eg, abdominal pain, vomiting, muscle weakness). Diagnosis during an acute attack can be made by measuring urinary 5-aminolaevulinc acid and porphobilinogen.¹

Hereditary hemochromatosis is an autosomal recessive disorder most commonly due to mutations in the HFE gene. Patients typically have iron overload and abnormal liver function test results. The main cutaneous finding is skin hyperpigmentation. Patients also may develop diabetes mellitus, arthropathy, cardiac disease, and hypopituitarism, although most are diagnosed with asymptomatic disease following routine laboratory studies.⁸

Confirm the diagnosis with total porphyrin measurement

The preferred initial test to confirm the diagnosis of PCT is measurement of plasma or urine total porphyrins, which will be elevated.¹ Further testing is then performed to discern PCT from the other, less common cutaneous porphyrias.¹ If needed, biopsy can be done to exclude other diagnoses. Testing for HIV and viral hepatitis infection may be performed when clinical suspicion is high.¹ Testing for UROD and HFE mutations may also be advised.¹

Treatment choice is guided by iron levels

For patients with normal iron levels, low-dose hydroxychloroquine 100 mg or chloroquine 125 mg twice per week can be used until restoration of normal plasma or urine porphyrin levels has been achieved for several months.¹ For those with iron excess (serum ferritin > 600 ng/dL), repeat phlebotomy is the preferred treatment; a unit of blood (350-500 mL) is typically removed, as tolerated, until iron stores return to normal.¹ In severe cases of PCT, these therapies can be used in combination.¹ Clinical remission with these methods can be expected within 6 to 9 months.⁹

Continue to: In addition...

In addition, it is important to provide patient education regarding proper sun protection and risk factor modification.¹ Underlying HIV and viral hepatitis infection should be managed appropriately by the relevant specialists.

With proper treatment, clinical remission can be expected within 6 to 9 months.

Our patient was counseled on proper sun protection and encouraged to cease alcohol consumption and smoking. We subsequently referred him to Hepatology for the treatment of his liver disease. Given that the patient’s ferritin level was so high (1594 ng/­mL), serial phlebotomy was initiated twice monthly until levels reached the lower limit of normal. He was also started on direct-acting antiviral therapy with Epclusa (sofosbuvir/velpatasvir) for 12 weeks for treatment of his HCV and is currently in remission.

CORRESPONDENCE
Christopher G. Bazewicz, MD, Department of Dermatology, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033; bazewicz@uchc.edu

LAS VEGAS – The incidence of melanoma in the United States continues to increase, yet mortality from the disease has been stable and may even be starting to decline, according to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

At the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar, Laura Korb Ferris, MD, PhD, said that SEER data project 96,480 new cases of melanoma in 2019, as well as 7,230 deaths from the disease. In 2016, SEER projected 10,130 deaths from melanoma, “so we’re actually projecting a reduction in melanoma deaths,” said Dr. Ferris, director of clinical trials at the University of Pittsburgh Medical Center’s department of dermatology. She added that the death rate from melanoma in 2016 was 2.17 per 100,000 population, a reduction from 2.69 per 100,000 population in 2011, “so it looks like melanoma mortality may be stable,” or even reduced, despite an increase in melanoma incidence.

A study of SEER data between 1989 and 2009 found that melanoma incidence is increasing across all lesion thicknesses (J Natl Cancer Inst. 2015 Nov 12. doi: 10.1093/jnci/djv294). Specifically, the incidence increased most among thin lesions, but there was a smaller increased incidence of thick melanoma. “This suggests that the overall burden of disease is truly increasing, but it is primarily stemming from an increase in T1/T2 disease,” Dr. Ferris said. “This could be due in part to increased early detection.”

Improvements in melanoma-specific survival, she continued, are likely a combination of improved management of T4 disease, a shift toward detection of thinner T1/T2 melanoma, and increased detection of T1/T2 disease.

The SEER data also showed that the incidence of fatal cases of melanoma has decreased since 1989, but only in thick melanomas. This trend may indicate a modest improvement in the management of T4 tumors. “Optimistically, I think increased detection efforts are improving survival by early detection of thin but ultimately fatal melanomas,” Dr. Ferris said. “Hopefully we are finding disease earlier and we are preventing patients from progressing to these fatal T4 melanomas.”

Disparities in melanoma-specific survival also come into play. Men have poorer survival compared with women, whites have the highest survival, and non-Hispanic whites have a better survival than Hispanic whites, Dr. Ferris said, while lower rates of survival are seen in blacks and nonblack minorities, as well as among those in high poverty and those who are separated/nonmarried. Lesion type also matters. The highest survival is seen in those with superficial spreading melanoma, while lower survival is observed in those with nodular melanoma, and acral lentiginous melanoma.

Self-detection of melanoma is another strategy to consider. According to Dr. Ferris, results from multiple studies suggest that about 50% of all melanomas are detected by patients, but the ones they find tend to be thicker than the ones that clinicians detect during office visits. “It would be great if we can get that number higher than 50%,” Dr. Ferris said. “If patients really understood what melanoma is, what it looks like, and when they needed to seek medical attention, perhaps we could get that over 50% and see self-detection of thinner melanomas. That’s a very low-cost intervention.”

Targeted screening efforts that stratify by risk factors and by age “makes screening more efficient and more cost-effective,” she added. She cited one analysis, which found that clinicians need to screen 606 people and conduct 25 biopsies in order to find one melanoma. “That’s very resource intensive,” she said. “However, if you only screened people 50 or older or 65 or older, the number needed to screen goes down, and because your pretest probability is higher, your number need to biopsy goes down as well. If you factor in things like a history of atypical nevi or a personal history of melanoma, those patients are at a higher risk of developing melanoma.”

Dr. Ferris closed her presentation by noting that Australia leads other countries in melanoma prevention efforts. There, the combined incidence of skin cancer is higher than the incidence of any other type of cancer. Four decades ago, Australian health officials launched SunSmart, a series of initiatives intended to reduce skin cancer. These include implementation of policies for hat wearing and shade provision in schools and at work, availability of more effective sunscreens, inclusion of sun protection items as a tax-deductible expense for outdoor workers, increased availability since the 1980s of long-sleeved sun protective swimwear, a ban on the use of indoor tanning since 2014, provision of UV forecasts in weather, and a comprehensive program of grants for community shade structures (PLoSMed. 2019 Oct 8;16[10]:e1002932).

“One approach to melanoma prevention won’t fit all,” she concluded. “We need to focus on prevention, public education to improve knowledge and self-detection.”

Dr. Ferris disclosed that she is a consultant to and an investigator for DermTech and Scibase. She is also an investigator for Castle Biosciences.

SDEF and this news organization are owned by the same parent company. Dr. Ferris spoke during a forum on cutaneous malignancies at the meeting.

dbrunk@mdedge.com

LAS VEGAS – The incidence of melanoma in the United States continues to increase, yet mortality from the disease has been stable and may even be starting to decline, according to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

At the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar, Laura Korb Ferris, MD, PhD, said that SEER data project 96,480 new cases of melanoma in 2019, as well as 7,230 deaths from the disease. In 2016, SEER projected 10,130 deaths from melanoma, “so we’re actually projecting a reduction in melanoma deaths,” said Dr. Ferris, director of clinical trials at the University of Pittsburgh Medical Center’s department of dermatology. She added that the death rate from melanoma in 2016 was 2.17 per 100,000 population, a reduction from 2.69 per 100,000 population in 2011, “so it looks like melanoma mortality may be stable,” or even reduced, despite an increase in melanoma incidence.

A study of SEER data between 1989 and 2009 found that melanoma incidence is increasing across all lesion thicknesses (J Natl Cancer Inst. 2015 Nov 12. doi: 10.1093/jnci/djv294). Specifically, the incidence increased most among thin lesions, but there was a smaller increased incidence of thick melanoma. “This suggests that the overall burden of disease is truly increasing, but it is primarily stemming from an increase in T1/T2 disease,” Dr. Ferris said. “This could be due in part to increased early detection.”

Improvements in melanoma-specific survival, she continued, are likely a combination of improved management of T4 disease, a shift toward detection of thinner T1/T2 melanoma, and increased detection of T1/T2 disease.

The SEER data also showed that the incidence of fatal cases of melanoma has decreased since 1989, but only in thick melanomas. This trend may indicate a modest improvement in the management of T4 tumors. “Optimistically, I think increased detection efforts are improving survival by early detection of thin but ultimately fatal melanomas,” Dr. Ferris said. “Hopefully we are finding disease earlier and we are preventing patients from progressing to these fatal T4 melanomas.”

Disparities in melanoma-specific survival also come into play. Men have poorer survival compared with women, whites have the highest survival, and non-Hispanic whites have a better survival than Hispanic whites, Dr. Ferris said, while lower rates of survival are seen in blacks and nonblack minorities, as well as among those in high poverty and those who are separated/nonmarried. Lesion type also matters. The highest survival is seen in those with superficial spreading melanoma, while lower survival is observed in those with nodular melanoma, and acral lentiginous melanoma.

Self-detection of melanoma is another strategy to consider. According to Dr. Ferris, results from multiple studies suggest that about 50% of all melanomas are detected by patients, but the ones they find tend to be thicker than the ones that clinicians detect during office visits. “It would be great if we can get that number higher than 50%,” Dr. Ferris said. “If patients really understood what melanoma is, what it looks like, and when they needed to seek medical attention, perhaps we could get that over 50% and see self-detection of thinner melanomas. That’s a very low-cost intervention.”

Targeted screening efforts that stratify by risk factors and by age “makes screening more efficient and more cost-effective,” she added. She cited one analysis, which found that clinicians need to screen 606 people and conduct 25 biopsies in order to find one melanoma. “That’s very resource intensive,” she said. “However, if you only screened people 50 or older or 65 or older, the number needed to screen goes down, and because your pretest probability is higher, your number need to biopsy goes down as well. If you factor in things like a history of atypical nevi or a personal history of melanoma, those patients are at a higher risk of developing melanoma.”

Dr. Ferris closed her presentation by noting that Australia leads other countries in melanoma prevention efforts. There, the combined incidence of skin cancer is higher than the incidence of any other type of cancer. Four decades ago, Australian health officials launched SunSmart, a series of initiatives intended to reduce skin cancer. These include implementation of policies for hat wearing and shade provision in schools and at work, availability of more effective sunscreens, inclusion of sun protection items as a tax-deductible expense for outdoor workers, increased availability since the 1980s of long-sleeved sun protective swimwear, a ban on the use of indoor tanning since 2014, provision of UV forecasts in weather, and a comprehensive program of grants for community shade structures (PLoSMed. 2019 Oct 8;16[10]:e1002932).

“One approach to melanoma prevention won’t fit all,” she concluded. “We need to focus on prevention, public education to improve knowledge and self-detection.”

Dr. Ferris disclosed that she is a consultant to and an investigator for DermTech and Scibase. She is also an investigator for Castle Biosciences.

SDEF and this news organization are owned by the same parent company. Dr. Ferris spoke during a forum on cutaneous malignancies at the meeting.

dbrunk@mdedge.com

LAS VEGAS – The incidence of melanoma in the United States continues to increase, yet mortality from the disease has been stable and may even be starting to decline, according to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

At the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar, Laura Korb Ferris, MD, PhD, said that SEER data project 96,480 new cases of melanoma in 2019, as well as 7,230 deaths from the disease. In 2016, SEER projected 10,130 deaths from melanoma, “so we’re actually projecting a reduction in melanoma deaths,” said Dr. Ferris, director of clinical trials at the University of Pittsburgh Medical Center’s department of dermatology. She added that the death rate from melanoma in 2016 was 2.17 per 100,000 population, a reduction from 2.69 per 100,000 population in 2011, “so it looks like melanoma mortality may be stable,” or even reduced, despite an increase in melanoma incidence.

A study of SEER data between 1989 and 2009 found that melanoma incidence is increasing across all lesion thicknesses (J Natl Cancer Inst. 2015 Nov 12. doi: 10.1093/jnci/djv294). Specifically, the incidence increased most among thin lesions, but there was a smaller increased incidence of thick melanoma. “This suggests that the overall burden of disease is truly increasing, but it is primarily stemming from an increase in T1/T2 disease,” Dr. Ferris said. “This could be due in part to increased early detection.”

Improvements in melanoma-specific survival, she continued, are likely a combination of improved management of T4 disease, a shift toward detection of thinner T1/T2 melanoma, and increased detection of T1/T2 disease.

The SEER data also showed that the incidence of fatal cases of melanoma has decreased since 1989, but only in thick melanomas. This trend may indicate a modest improvement in the management of T4 tumors. “Optimistically, I think increased detection efforts are improving survival by early detection of thin but ultimately fatal melanomas,” Dr. Ferris said. “Hopefully we are finding disease earlier and we are preventing patients from progressing to these fatal T4 melanomas.”

Disparities in melanoma-specific survival also come into play. Men have poorer survival compared with women, whites have the highest survival, and non-Hispanic whites have a better survival than Hispanic whites, Dr. Ferris said, while lower rates of survival are seen in blacks and nonblack minorities, as well as among those in high poverty and those who are separated/nonmarried. Lesion type also matters. The highest survival is seen in those with superficial spreading melanoma, while lower survival is observed in those with nodular melanoma, and acral lentiginous melanoma.

Self-detection of melanoma is another strategy to consider. According to Dr. Ferris, results from multiple studies suggest that about 50% of all melanomas are detected by patients, but the ones they find tend to be thicker than the ones that clinicians detect during office visits. “It would be great if we can get that number higher than 50%,” Dr. Ferris said. “If patients really understood what melanoma is, what it looks like, and when they needed to seek medical attention, perhaps we could get that over 50% and see self-detection of thinner melanomas. That’s a very low-cost intervention.”

Targeted screening efforts that stratify by risk factors and by age “makes screening more efficient and more cost-effective,” she added. She cited one analysis, which found that clinicians need to screen 606 people and conduct 25 biopsies in order to find one melanoma. “That’s very resource intensive,” she said. “However, if you only screened people 50 or older or 65 or older, the number needed to screen goes down, and because your pretest probability is higher, your number need to biopsy goes down as well. If you factor in things like a history of atypical nevi or a personal history of melanoma, those patients are at a higher risk of developing melanoma.”

Dr. Ferris closed her presentation by noting that Australia leads other countries in melanoma prevention efforts. There, the combined incidence of skin cancer is higher than the incidence of any other type of cancer. Four decades ago, Australian health officials launched SunSmart, a series of initiatives intended to reduce skin cancer. These include implementation of policies for hat wearing and shade provision in schools and at work, availability of more effective sunscreens, inclusion of sun protection items as a tax-deductible expense for outdoor workers, increased availability since the 1980s of long-sleeved sun protective swimwear, a ban on the use of indoor tanning since 2014, provision of UV forecasts in weather, and a comprehensive program of grants for community shade structures (PLoSMed. 2019 Oct 8;16[10]:e1002932).

“One approach to melanoma prevention won’t fit all,” she concluded. “We need to focus on prevention, public education to improve knowledge and self-detection.”

Dr. Ferris disclosed that she is a consultant to and an investigator for DermTech and Scibase. She is also an investigator for Castle Biosciences.

SDEF and this news organization are owned by the same parent company. Dr. Ferris spoke during a forum on cutaneous malignancies at the meeting.

dbrunk@mdedge.com

A 50-year-old man presents with a 1-year history of an itchy, bumpy rash on his chest. He denies any history of similar rash and says there have been no “extraordinary changes” in his life that could have triggered this manifestation. Despite consulting various primary care providers, he has been unable to acquire either a definitive diagnosis or effective treatment.

The patient works exclusively in a climate-controlled office. Although there were no changes to laundry detergent, body soap, deodorant, or other products that might have precipitated the rash’s manifestation, he tried alternate products to see what effect they might have. Nothing beneficial came from these experiments. Similarly, the family dogs were temporarily “banished” with no improvement to his condition.

From the outset, the rash and the associated itching have been confined to the patient’s chest. No one else in his family is similarly affected.

The patient is otherwise quite well. He takes no prescription medications and denies any recent foreign travel.

EXAMINATION
The papulovesicular rash is strikingly uniform. The patient’s entire chest is covered with tiny vesicles, many with clear fluid inside. The lesions average 1.2 to 2 mm in width, and nearly all are quite palpable. Each lesion is slightly erythematous but neither warm nor tender on palpation.

Examination of the rest of the patient’s exposed skin reveals no similar lesions. His back, hands, and genitals are notably free of any such lesions.

A shave biopsy is performed, utilizing a saucerization technique, and the specimen is submitted to pathology for routine processing. The report confirms the papulovesicular nature of the lesions—but more significantly, it shows consistent acantholysis (loss of intracellular connections between keratinocytes), along with focal lymphohistiocytic infiltrates.

What’s the diagnosis?

DISCUSSION
This is a classic presentation of Grover disease, also known as transient acantholytic dermatosis (AD). While not rare, it is seen only occasionally in dermatology practices. When it does walk through the door, it is twice as likely to be seen in a male than in a female patient and less commonly seen in those with darker skin.

AD is easy enough to diagnose clinically, without biopsy, particularly in classic cases such as this one. The distribution and morphology of the rash, as well as the gender and age of the patient, are all typical of this idiopathic condition. The biopsy results, besides being consistent with AD, did serve to rule out other items in the differential (eg, bacterial folliculitis, pemphigus, and acne).

Since AD was first described in 1974 by R.W. Grover, MD, much research has been conducted to flesh out the nature of the disease, its potential causes, and possible treatment. One certainty about so-called transient AD is that most cases are far from transient—in fact, they can last for a year or more. Attempts have been made to connect AD with internal disease (eg, occult malignancy) or even mercury exposure, but these theories have not been corroborated.

Consistent treatment success has also been elusive. Most patients achieve decent relief with the use of topical steroid creams, with or without the addition of anti-inflammatory medications (eg, doxycycline). Other options include isotretinoin and psoralen plus ultraviolet A (PUVA) photochemotherapy. Fortunately, most cases eventually clear up.

TAKE-HOME LEARNING POINTS

• Grover disease, also known as transient acantholytic dermatosis (AD), usually manifests with an acute eruption of papulovesicular lesions.
• AD lesions tend to be confined to the chest and are typically pruritic.
• Clinical diagnosis is usually adequate, although biopsy, which will reveal typical findings of acantholysis, may be necessary to rule out other items in the differential.
• Treatment with topical steroids, oral doxycycline, and “tincture of time” usually suffices, but resolution may take a year or more.

A 50-year-old man presents with a 1-year history of an itchy, bumpy rash on his chest. He denies any history of similar rash and says there have been no “extraordinary changes” in his life that could have triggered this manifestation. Despite consulting various primary care providers, he has been unable to acquire either a definitive diagnosis or effective treatment.

The patient works exclusively in a climate-controlled office. Although there were no changes to laundry detergent, body soap, deodorant, or other products that might have precipitated the rash’s manifestation, he tried alternate products to see what effect they might have. Nothing beneficial came from these experiments. Similarly, the family dogs were temporarily “banished” with no improvement to his condition.

From the outset, the rash and the associated itching have been confined to the patient’s chest. No one else in his family is similarly affected.

The patient is otherwise quite well. He takes no prescription medications and denies any recent foreign travel.

EXAMINATION
The papulovesicular rash is strikingly uniform. The patient’s entire chest is covered with tiny vesicles, many with clear fluid inside. The lesions average 1.2 to 2 mm in width, and nearly all are quite palpable. Each lesion is slightly erythematous but neither warm nor tender on palpation.

Examination of the rest of the patient’s exposed skin reveals no similar lesions. His back, hands, and genitals are notably free of any such lesions.

A shave biopsy is performed, utilizing a saucerization technique, and the specimen is submitted to pathology for routine processing. The report confirms the papulovesicular nature of the lesions—but more significantly, it shows consistent acantholysis (loss of intracellular connections between keratinocytes), along with focal lymphohistiocytic infiltrates.

What’s the diagnosis?

DISCUSSION
This is a classic presentation of Grover disease, also known as transient acantholytic dermatosis (AD). While not rare, it is seen only occasionally in dermatology practices. When it does walk through the door, it is twice as likely to be seen in a male than in a female patient and less commonly seen in those with darker skin.

AD is easy enough to diagnose clinically, without biopsy, particularly in classic cases such as this one. The distribution and morphology of the rash, as well as the gender and age of the patient, are all typical of this idiopathic condition. The biopsy results, besides being consistent with AD, did serve to rule out other items in the differential (eg, bacterial folliculitis, pemphigus, and acne).

Since AD was first described in 1974 by R.W. Grover, MD, much research has been conducted to flesh out the nature of the disease, its potential causes, and possible treatment. One certainty about so-called transient AD is that most cases are far from transient—in fact, they can last for a year or more. Attempts have been made to connect AD with internal disease (eg, occult malignancy) or even mercury exposure, but these theories have not been corroborated.

Consistent treatment success has also been elusive. Most patients achieve decent relief with the use of topical steroid creams, with or without the addition of anti-inflammatory medications (eg, doxycycline). Other options include isotretinoin and psoralen plus ultraviolet A (PUVA) photochemotherapy. Fortunately, most cases eventually clear up.

TAKE-HOME LEARNING POINTS

• Grover disease, also known as transient acantholytic dermatosis (AD), usually manifests with an acute eruption of papulovesicular lesions.
• AD lesions tend to be confined to the chest and are typically pruritic.
• Clinical diagnosis is usually adequate, although biopsy, which will reveal typical findings of acantholysis, may be necessary to rule out other items in the differential.
• Treatment with topical steroids, oral doxycycline, and “tincture of time” usually suffices, but resolution may take a year or more.

A 50-year-old man presents with a 1-year history of an itchy, bumpy rash on his chest. He denies any history of similar rash and says there have been no “extraordinary changes” in his life that could have triggered this manifestation. Despite consulting various primary care providers, he has been unable to acquire either a definitive diagnosis or effective treatment.

The patient works exclusively in a climate-controlled office. Although there were no changes to laundry detergent, body soap, deodorant, or other products that might have precipitated the rash’s manifestation, he tried alternate products to see what effect they might have. Nothing beneficial came from these experiments. Similarly, the family dogs were temporarily “banished” with no improvement to his condition.

From the outset, the rash and the associated itching have been confined to the patient’s chest. No one else in his family is similarly affected.

The patient is otherwise quite well. He takes no prescription medications and denies any recent foreign travel.

EXAMINATION
The papulovesicular rash is strikingly uniform. The patient’s entire chest is covered with tiny vesicles, many with clear fluid inside. The lesions average 1.2 to 2 mm in width, and nearly all are quite palpable. Each lesion is slightly erythematous but neither warm nor tender on palpation.

Examination of the rest of the patient’s exposed skin reveals no similar lesions. His back, hands, and genitals are notably free of any such lesions.

A shave biopsy is performed, utilizing a saucerization technique, and the specimen is submitted to pathology for routine processing. The report confirms the papulovesicular nature of the lesions—but more significantly, it shows consistent acantholysis (loss of intracellular connections between keratinocytes), along with focal lymphohistiocytic infiltrates.

What’s the diagnosis?

DISCUSSION
This is a classic presentation of Grover disease, also known as transient acantholytic dermatosis (AD). While not rare, it is seen only occasionally in dermatology practices. When it does walk through the door, it is twice as likely to be seen in a male than in a female patient and less commonly seen in those with darker skin.

AD is easy enough to diagnose clinically, without biopsy, particularly in classic cases such as this one. The distribution and morphology of the rash, as well as the gender and age of the patient, are all typical of this idiopathic condition. The biopsy results, besides being consistent with AD, did serve to rule out other items in the differential (eg, bacterial folliculitis, pemphigus, and acne).

Since AD was first described in 1974 by R.W. Grover, MD, much research has been conducted to flesh out the nature of the disease, its potential causes, and possible treatment. One certainty about so-called transient AD is that most cases are far from transient—in fact, they can last for a year or more. Attempts have been made to connect AD with internal disease (eg, occult malignancy) or even mercury exposure, but these theories have not been corroborated.

Consistent treatment success has also been elusive. Most patients achieve decent relief with the use of topical steroid creams, with or without the addition of anti-inflammatory medications (eg, doxycycline). Other options include isotretinoin and psoralen plus ultraviolet A (PUVA) photochemotherapy. Fortunately, most cases eventually clear up.

TAKE-HOME LEARNING POINTS

• Grover disease, also known as transient acantholytic dermatosis (AD), usually manifests with an acute eruption of papulovesicular lesions.
• AD lesions tend to be confined to the chest and are typically pruritic.
• Clinical diagnosis is usually adequate, although biopsy, which will reveal typical findings of acantholysis, may be necessary to rule out other items in the differential.
• Treatment with topical steroids, oral doxycycline, and “tincture of time” usually suffices, but resolution may take a year or more.

The FP conducted a physical exam and noticed bilateral dorsal foot dermatitis with occasional small vesicles and lichenified papules, which was suggestive of chronic contact or irritant dermatitis. The patient’s favorite pair of boots offered another clue as to the most likely contact allergens. (The boots were leather, and leather is treated with tanning agents and dyes.) A biopsy was not performed but would be expected to show spongiosis with some degree of lichenification (thickening of the dermis)—a sign of the acute on chronic nature of this process. The diagnosis of irritant or allergic contact dermatitis was made empirically.

The differential diagnosis for rashes on the feet can be broad and includes common tinea pedis, pitted keratolysis, stasis dermatitis, psoriasis, eczemas of various types, keratoderma, and contact dermatitis.

Many patients misconstrue that materials they use every day are exempt from becoming allergens. In counseling patients about this, point out that contact allergens often arise from repeated exposure. For example, dentists often develop dental amalgam allergies, hair professionals develop hair dye allergies, and machinists commonly develop cutting oil allergies. These reactions can and do occur years into their use.

The patient was started on topical clobetasol 0.05% ointment bid for 3 weeks, which provided quick relief and cleared his feet of the patches and plaques. He continued to wear his boots until contact allergy patch testing was performed in the office over a series of 3 days. This revealed an allergy to chromium, a common leather tanning agent. The patient was advised to avoid leather products including jackets, car upholstery, and gloves. After he carefully chose different footwear without a leather insole or tongue, the patient required no further therapy and remained clear.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained).

The FP conducted a physical exam and noticed bilateral dorsal foot dermatitis with occasional small vesicles and lichenified papules, which was suggestive of chronic contact or irritant dermatitis. The patient’s favorite pair of boots offered another clue as to the most likely contact allergens. (The boots were leather, and leather is treated with tanning agents and dyes.) A biopsy was not performed but would be expected to show spongiosis with some degree of lichenification (thickening of the dermis)—a sign of the acute on chronic nature of this process. The diagnosis of irritant or allergic contact dermatitis was made empirically.

The differential diagnosis for rashes on the feet can be broad and includes common tinea pedis, pitted keratolysis, stasis dermatitis, psoriasis, eczemas of various types, keratoderma, and contact dermatitis.

Many patients misconstrue that materials they use every day are exempt from becoming allergens. In counseling patients about this, point out that contact allergens often arise from repeated exposure. For example, dentists often develop dental amalgam allergies, hair professionals develop hair dye allergies, and machinists commonly develop cutting oil allergies. These reactions can and do occur years into their use.

The patient was started on topical clobetasol 0.05% ointment bid for 3 weeks, which provided quick relief and cleared his feet of the patches and plaques. He continued to wear his boots until contact allergy patch testing was performed in the office over a series of 3 days. This revealed an allergy to chromium, a common leather tanning agent. The patient was advised to avoid leather products including jackets, car upholstery, and gloves. After he carefully chose different footwear without a leather insole or tongue, the patient required no further therapy and remained clear.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained).

The FP conducted a physical exam and noticed bilateral dorsal foot dermatitis with occasional small vesicles and lichenified papules, which was suggestive of chronic contact or irritant dermatitis. The patient’s favorite pair of boots offered another clue as to the most likely contact allergens. (The boots were leather, and leather is treated with tanning agents and dyes.) A biopsy was not performed but would be expected to show spongiosis with some degree of lichenification (thickening of the dermis)—a sign of the acute on chronic nature of this process. The diagnosis of irritant or allergic contact dermatitis was made empirically.

The differential diagnosis for rashes on the feet can be broad and includes common tinea pedis, pitted keratolysis, stasis dermatitis, psoriasis, eczemas of various types, keratoderma, and contact dermatitis.

Many patients misconstrue that materials they use every day are exempt from becoming allergens. In counseling patients about this, point out that contact allergens often arise from repeated exposure. For example, dentists often develop dental amalgam allergies, hair professionals develop hair dye allergies, and machinists commonly develop cutting oil allergies. These reactions can and do occur years into their use.

The patient was started on topical clobetasol 0.05% ointment bid for 3 weeks, which provided quick relief and cleared his feet of the patches and plaques. He continued to wear his boots until contact allergy patch testing was performed in the office over a series of 3 days. This revealed an allergy to chromium, a common leather tanning agent. The patient was advised to avoid leather products including jackets, car upholstery, and gloves. After he carefully chose different footwear without a leather insole or tongue, the patient required no further therapy and remained clear.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained).

People with psoriasis appear to have both an increased risk of cancer and an increased risk of cancer-related mortality, according to a meta-analysis of cohort and case-control studies.

Compared with a psoriasis-free population, having a diagnosis of severe psoriasis was associated with a 22% increase in cancer risk, Alex Trafford of the University of Manchester (England) and colleagues reported in JAMA Dermatology. The risk of cancer mortality was also increased by 22% among those with severe psoriasis.

The site-specific risks ranged from a low of 18% for colon cancer to more than a twofold increased risk for oral and esophageal cancer, according to the investigators.

Since these were associations only, any underlying mechanism is still unclear, they wrote. The chronic inflammation that drives psoriasis can also drive the development of cancer, but immunomodulatory therapies may also play a part, they suggested.

“Of particular relevance in this regard are biological therapies, which are being increasingly used for the management of psoriasis,” they added. “Although preliminary studies have suggested little to no increased risk of cancer incidence in patients with psoriasis receiving these therapies, further study allowing greater follow-up and increased power is required to properly examine the potential cancer risk, particularly for site-specific cancers.”

The analysis included 58 studies, published between 1983 and 2017. Nine of these reported risks for cancer incidence among patients with severe psoriasis, and seven reported the risk of cancer mortality among patients with all severities of psoriasis.

Overall, severe psoriasis was associated with an increased cancer risk of 22%; for all severities of psoriasis combined, the risk increase was 18%. Relative risks for specific cancer types were as follows: colon, 1.18; colorectal, 1.34; kidney, 1.58; laryngeal, 1.79; liver, 1.83; lymphoma, 1.40; non-Hodgkin lymphoma, 1.28; keratinocyte cancers, 1.71; esophageal 2.05; oral cavity, 2.80; and pancreatic, 1.41.

Overall cancer mortality risk was 22% higher in patients with severe psoriasis than the general population. Site-specific relative mortality risks included liver, 1.43; esophageal 2.53; and pancreatic, 1.31.

In light of these findings, clinicians should stress lifestyle modifications known to decrease cancer risk, the investigators said. “Although it has been noted that lifestyle behavior change is challenging for healthcare professionals to implement, the importance of a more holistic approach to psoriasis care involving lifestyle behavior change is reinforced through the results of this meta-analysis.”

Among the coauthors were Darren M. Ashcroft, PhD, the senior author, and Christopher Griffiths, MD, both of the University of Manchester. Dr. Ashcroft reported receiving research grants from AbbVie, Almirall, Celgene, Eli Lilly, Novartis, UCB, and the Leo Foundation. Dr. Griffiths reported receiving honoraria and/or research grants from AbbVie, Almirall, Bristol-Myers Squibb, Celgene, Eli Lilly, Galderma, Janssen, Leo Pharma, Novartis, Sandoz, and UCB. The lead author and the other authors had no disclosures. The Global Psoriasis Atlas (GPA) Collaborating Organizations (the International Federation of Psoriasis Associations, the International League of Dermatological Societies, and the International Psoriasis Council) were involved with funding of the study.
 

msullivan@mdedge.com

SOURCE: Trafford A et al. JAMA Dermatol. 2019 Oct 16. doi:10.1001/jamadermatol.2019.3056.

People with psoriasis appear to have both an increased risk of cancer and an increased risk of cancer-related mortality, according to a meta-analysis of cohort and case-control studies.

Compared with a psoriasis-free population, having a diagnosis of severe psoriasis was associated with a 22% increase in cancer risk, Alex Trafford of the University of Manchester (England) and colleagues reported in JAMA Dermatology. The risk of cancer mortality was also increased by 22% among those with severe psoriasis.

The site-specific risks ranged from a low of 18% for colon cancer to more than a twofold increased risk for oral and esophageal cancer, according to the investigators.

Since these were associations only, any underlying mechanism is still unclear, they wrote. The chronic inflammation that drives psoriasis can also drive the development of cancer, but immunomodulatory therapies may also play a part, they suggested.

“Of particular relevance in this regard are biological therapies, which are being increasingly used for the management of psoriasis,” they added. “Although preliminary studies have suggested little to no increased risk of cancer incidence in patients with psoriasis receiving these therapies, further study allowing greater follow-up and increased power is required to properly examine the potential cancer risk, particularly for site-specific cancers.”

The analysis included 58 studies, published between 1983 and 2017. Nine of these reported risks for cancer incidence among patients with severe psoriasis, and seven reported the risk of cancer mortality among patients with all severities of psoriasis.

Overall, severe psoriasis was associated with an increased cancer risk of 22%; for all severities of psoriasis combined, the risk increase was 18%. Relative risks for specific cancer types were as follows: colon, 1.18; colorectal, 1.34; kidney, 1.58; laryngeal, 1.79; liver, 1.83; lymphoma, 1.40; non-Hodgkin lymphoma, 1.28; keratinocyte cancers, 1.71; esophageal 2.05; oral cavity, 2.80; and pancreatic, 1.41.

Overall cancer mortality risk was 22% higher in patients with severe psoriasis than the general population. Site-specific relative mortality risks included liver, 1.43; esophageal 2.53; and pancreatic, 1.31.

In light of these findings, clinicians should stress lifestyle modifications known to decrease cancer risk, the investigators said. “Although it has been noted that lifestyle behavior change is challenging for healthcare professionals to implement, the importance of a more holistic approach to psoriasis care involving lifestyle behavior change is reinforced through the results of this meta-analysis.”

Among the coauthors were Darren M. Ashcroft, PhD, the senior author, and Christopher Griffiths, MD, both of the University of Manchester. Dr. Ashcroft reported receiving research grants from AbbVie, Almirall, Celgene, Eli Lilly, Novartis, UCB, and the Leo Foundation. Dr. Griffiths reported receiving honoraria and/or research grants from AbbVie, Almirall, Bristol-Myers Squibb, Celgene, Eli Lilly, Galderma, Janssen, Leo Pharma, Novartis, Sandoz, and UCB. The lead author and the other authors had no disclosures. The Global Psoriasis Atlas (GPA) Collaborating Organizations (the International Federation of Psoriasis Associations, the International League of Dermatological Societies, and the International Psoriasis Council) were involved with funding of the study.
 

msullivan@mdedge.com

SOURCE: Trafford A et al. JAMA Dermatol. 2019 Oct 16. doi:10.1001/jamadermatol.2019.3056.

People with psoriasis appear to have both an increased risk of cancer and an increased risk of cancer-related mortality, according to a meta-analysis of cohort and case-control studies.

Compared with a psoriasis-free population, having a diagnosis of severe psoriasis was associated with a 22% increase in cancer risk, Alex Trafford of the University of Manchester (England) and colleagues reported in JAMA Dermatology. The risk of cancer mortality was also increased by 22% among those with severe psoriasis.

The site-specific risks ranged from a low of 18% for colon cancer to more than a twofold increased risk for oral and esophageal cancer, according to the investigators.

Since these were associations only, any underlying mechanism is still unclear, they wrote. The chronic inflammation that drives psoriasis can also drive the development of cancer, but immunomodulatory therapies may also play a part, they suggested.

“Of particular relevance in this regard are biological therapies, which are being increasingly used for the management of psoriasis,” they added. “Although preliminary studies have suggested little to no increased risk of cancer incidence in patients with psoriasis receiving these therapies, further study allowing greater follow-up and increased power is required to properly examine the potential cancer risk, particularly for site-specific cancers.”

The analysis included 58 studies, published between 1983 and 2017. Nine of these reported risks for cancer incidence among patients with severe psoriasis, and seven reported the risk of cancer mortality among patients with all severities of psoriasis.

Overall, severe psoriasis was associated with an increased cancer risk of 22%; for all severities of psoriasis combined, the risk increase was 18%. Relative risks for specific cancer types were as follows: colon, 1.18; colorectal, 1.34; kidney, 1.58; laryngeal, 1.79; liver, 1.83; lymphoma, 1.40; non-Hodgkin lymphoma, 1.28; keratinocyte cancers, 1.71; esophageal 2.05; oral cavity, 2.80; and pancreatic, 1.41.

Overall cancer mortality risk was 22% higher in patients with severe psoriasis than the general population. Site-specific relative mortality risks included liver, 1.43; esophageal 2.53; and pancreatic, 1.31.

In light of these findings, clinicians should stress lifestyle modifications known to decrease cancer risk, the investigators said. “Although it has been noted that lifestyle behavior change is challenging for healthcare professionals to implement, the importance of a more holistic approach to psoriasis care involving lifestyle behavior change is reinforced through the results of this meta-analysis.”

Among the coauthors were Darren M. Ashcroft, PhD, the senior author, and Christopher Griffiths, MD, both of the University of Manchester. Dr. Ashcroft reported receiving research grants from AbbVie, Almirall, Celgene, Eli Lilly, Novartis, UCB, and the Leo Foundation. Dr. Griffiths reported receiving honoraria and/or research grants from AbbVie, Almirall, Bristol-Myers Squibb, Celgene, Eli Lilly, Galderma, Janssen, Leo Pharma, Novartis, Sandoz, and UCB. The lead author and the other authors had no disclosures. The Global Psoriasis Atlas (GPA) Collaborating Organizations (the International Federation of Psoriasis Associations, the International League of Dermatological Societies, and the International Psoriasis Council) were involved with funding of the study.
 

msullivan@mdedge.com

SOURCE: Trafford A et al. JAMA Dermatol. 2019 Oct 16. doi:10.1001/jamadermatol.2019.3056.

Lyme disease is a complex multisystem bacterial infection affecting the skin, joints, heart, and nervous system. The full spectrum of disease was first recognized and the disease was named in the 1970s during an outbreak of arthritis in children in the town of Lyme, Connecticut.¹

This review describes the epidemiology and pathogenesis of Lyme disease, the advantages and disadvantages of current diagnostic methods, and diagnostic algorithms.

THE MOST COMMON TICK-BORNE INFECTION IN NORTH AMERICA

Lyme disease is the most common tick-borne infection in North America.^2,3 In the United States, more than 30,000 cases are reported annually. In fact, in 2017, the number of cases was about 42,000, a 16% increase from the previous year, according to the US Centers for Disease Control and Prevention (CDC).

From Sigal LH. Myths and facts about Lyme disease. Cleve Clin J Med 1997; 64(4):203–209.

The infection is caused by Borrelia burgdorferi, a particularly arthritogenic spirochete transmitted by Ixodes scapularis (the black-legged deer tick, (Figure 1) and Ixodes pacificus (the Western black-legged tick). Although the infection can occur at any time of the year, its peak incidence is in May to late September, coinciding with increased outdoor recreational activity in areas where ticks live.^3,4 The typical tick habitat consists of deciduous woodland with sufficient humidity provided by a good layer of decaying vegetation. However, people can contract Lyme disease in their own backyard.³

Most cases of Lyme disease are seen in the northeastern United States, mainly in suburban and rural areas.^2,3 Other areas affected include the midwestern states of Minnesota, Wisconsin, and Michigan, as well as northern California.⁴ Fourteen states and the District of Columbia report a high average incidence (> 10 cases per 100,000 persons) (Table 1).²

FIRST COMES IgM, THEN IgG

The pathogenesis and the different stages of infection should inform laboratory testing in Lyme disease.

It is estimated that only 5% of infected ticks that bite people actually transmit their spirochetes to the human host.⁵ However, once infected, the patient’s innate immune system mounts a response that results in the classic erythema migrans rash at the bite site. A rash develops in only about 85% of patients who are infected and can appear at any time between 3 and 30 days, but most commonly after 7 days. Hence, a rash occurring within the first few hours of tick contact is not erythema migrans and does not indicate infection, but rather an early reaction to tick salivary antigens.⁵

Antibody levels remain below the detection limits of currently available serologic tests in the first 7 days after exposure. Immunoglobulin M (IgM) antibody titers peak between 8 and 14 days after tick contact, but IgM antibodies may never develop if the patient is started on early appropriate antimicrobial therapy.⁵

If the infection is not treated, the spirochete may disseminate through the blood from the bite site to different tissues.³ Both cell-mediated and antibody-mediated immunity swing into action to kill the spirochetes at this stage. The IgM antibody response occurs in 1 to 2 weeks, followed by a robust IgG response in 2 to 4 weeks.⁶

Because IgM can also cross-react with antigens other than those associated with B burgdorferi, the IgM test is less specific than the IgG test for Lyme disease.

Once a patient is exposed and mounts an antibody-mediated response to the spirochete, the antibody profile may persist for months to years, even after successful antibiotic treatment and cure of the disease.⁵

Despite the immune system’s robust series of defenses, untreated B burgdorferi infection can persist, as the organism has a bag of tricks to evade destruction. It can decrease its expression of specific immunogenic surface-exposed proteins, change its antigenic properties through recombination, and bind to the patient’s extracellular matrix proteins to facilitate further dissemination.³

Certain host-genetic factors also play a role in the pathogenesis of Lyme disease, such as the HLA-DR4 allele, which has been associated with antibiotic-refractory Lyme-related arthritis.³

LYME DISEASE EVOLVES THROUGH STAGES

Lyme disease evolves through stages broadly classified as early and late infection, with significant variability in its presentation.⁷

Early infection

Early disease is further subdivided into “localized” infection (stage 1), characterized by a single erythema migrans lesion and local lymphadenopathy, and “disseminated” infection (stage 2), associated with multiple erythema migrans lesions distant from the bite site, facial nerve palsy, radiculoneuritis, meningitis, carditis, or migratory arthritis or arthralgia.⁸

Highly specific physical findings include erythema migrans, cranial nerve palsy, high-grade or progressive conduction block, and recurrent migratory polyarthritis. Less specific symptoms and signs of Lyme disease include arthralgia, myalgia, neck stiffness, palpitations, and myocarditis.⁵

Erythema migrans lesions are evident in at least 85% of patients with early disease.⁹ If they are not apparent on physical examination, they may be located at hidden sites and may be atypical in appearance or transient.⁵

If treatment is not started in the initial stage of the disease, 60% of infected patients may develop disseminated infection.⁵ Progressive, untreated infection can manifest with Lyme arthritis and neuroborreliosis.⁷

Noncutaneous manifestations are less common now than in the past due to increased awareness of the disease and early initiation of treatment.¹⁰

Late infection

Manifestations of late (stage 3) infection include oligoarthritis (affecting any joint but often the knee) and neuroborreliosis. Clinical signs and symptoms of Lyme disease may take months to resolve even after appropriate antimicrobial therapy is completed. This should not be interpreted as ongoing, persistent infection, but as related to host immune-mediated activity.⁵

 

 

INTERPRET LABORATORY RESULTS BASED ON PRETEST PROBABILITY

The usefulness of a laboratory test depends on the individual patient’s pretest probability of infection, which in turn depends on the patient’s epidemiologic risk of exposure and clinical features of Lyme disease. Patients with a high pretest probability—eg, a history of a tick bite followed by the classic erythema migrans rash—do not need testing and can start antimicrobial therapy right away.¹¹

Serologic tests are the gold standard

Prompt diagnosis is important, as early Lyme disease is easily treatable without any future sequelae.¹¹

Tests for Lyme disease can be divided into direct methods, which detect the spirochete itself by culture or by polymerase chain reaction (PCR), and indirect methods, which detect antibodies (Table 2). Direct tests lack sensitivity for Lyme disease; hence, serologic tests remain the gold standard. Currently recommended is a standard 2-tier testing strategy using an enzyme-linked immunosorbent assay (ELISA) followed by Western blot for confirmation.

DIRECT METHODS

Culture lacks sensitivity

A number of factors limit the sensitivity of direct culture for diagnosing Lyme disease. B burgdorferi does not grow easily in culture, requiring special media, low temperatures, and long periods of incubation. Only a relatively few spirochetes are present in human tissues and body fluids to begin with, and bacterial counts are further reduced with duration and dissemination of infection.⁵ All of these limit the possibility of detecting this organism.

Polymerase chain reaction may help in some situations

Molecular assays are not part of the standard evaluation and should be used only in conjunction with serologic testing.⁷ These tests have high specificity but lack consistent sensitivity.

That said, PCR testing may be useful:

• In early infection, before antibody responses develop
• In reinfection, when serologic tests are not reliable because the antibodies persist for many years after an infection in many patients
• In endemic areas where serologic testing has high false-positive rates due to high baseline population seropositivity for anti-Borrelia antibodies caused by subclinical infection.³

PCR assays that target plasmid-borne genes encoding outer surface proteins A and C (OspA and OspC) and VisE (variable major protein-like sequence, expressed) are more sensitive than those that detect chromosomal 16s ribosomal ribonucleic acid (rRNA) genes, as plasmid-rich “blebs” are shed in larger concentrations than chromosomal DNA during active infection.⁷ However, these plasmid-contained genes persist in body tissues and fluids even after the infection is cleared, and their detection may not necessarily correlate with ongoing disease.⁸ Detection of chromosomal 16s rRNA genes is a better predictor of true organism viability.

The sensitivity of PCR for borrelial DNA depends on the type of sample. If a skin biopsy sample is taken of the leading edge of an erythema migrans lesion, the sensitivity is 69% and the specificity is 100%. In patients with Lyme arthritis, PCR of the synovial fluid has a sensitivity of up to 80%. However, the sensitivity of PCR of the cerebrospinal fluid of patients with neurologic manifestations of Lyme disease is only 19%.⁷ PCR of other clinical samples, including blood and urine, is not recommended, as spirochetes are primarily confined to tissues, and very few are present in these body fluids.^3,12

The disadvantage of PCR is that a positive result does not always mean active infection, as the DNA of the dead microbe persists for several months even after successful treatment.⁸

INDIRECT METHODS

Enzyme-linked immunosorbent assay

ELISAs detect anti-Borrelia antibodies. Early-generation ELISAs, still used in many laboratories, use whole-cell extracts of B burgdorferi. Examples are the Vidas Lyme screen (Biomérieux, biomerieux-usa.com) and the Wampole B burgdorferi IgG/M EIA II assay (Alere, www.alere.com). Newer ELISAs use recombinant proteins.¹³

Three major targets for ELISA antibodies are flagellin (Fla), outer surface protein C (OspC), and VisE, especially the invariable region 6 (IR6). Among these, VisE-IR6 is the most conserved region in B burgdorferi.

Early-generation assays have a sensitivity of 89% and specificity of 72%.¹¹ However, the patient’s serum may have antibodies that cross-react with unrelated bacterial antigens, leading to false-positive results (Table 3). Whole-cell sonicate assays are not recommended as an independent test and must be confirmed with Western blot testing when assay results are indeterminate or positive.¹¹

Newer-generation ELISAs detect antibodies targeting recombinant proteins of VisE, especially a synthetic peptide C6, within IR6.¹³ VisE-IR6 is the most conserved region of the B burgdorferi complex, and its detection is a highly specific finding, supporting the diagnosis of Lyme disease. Antibodies against VisE-IR6 antigen are the earliest to develop.⁵ An example of a newer-generation serologic test is the VisE C6 Lyme EIA kit, approved as a first-tier test by the US Food and Drug Administration in 2001. This test has a specificity of 99%,^14,15 and its specificity is further increased when used in conjunction with Western blot (99.5%).¹⁵ The advantage of the C6 antibody test is that it is more sensitive than 2-tier testing during early infection (sensitivity 29%–74% vs 17%–40% in early localized infection, and 56%–90% vs 27%–78% in early disseminated infection).⁶

During early infection, older and newer ELISAs are less sensitive because of the limited number of antigens expressed at this stage.¹³ All patients suspected of having early Lyme disease who are seronegative at initial testing should have follow-up testing to look for seroconversion.¹³

Western blot

Western blot (immunoblot) testing identifies IgM and IgG antibodies against specific B burgdorferi antigens. It is considered positive if it detects at least 2 of a possible 3 specific IgM bands in the first 4 weeks of disease or at least 5 of 10 specific IgG bands after 4 weeks of disease (Table 4 and Figure 2).¹⁶

The nature of the bands indicates the duration of infection: Western blot bands against 23-kD OspC and 41-kD FlaB are seen in early localized infection, whereas bands against all 3 B burgdorferi proteins will be seen after several weeks of disease.¹⁷ The IgM result should be interpreted carefully, as only 2 bands are required for the test to be positive, and IgM binds to antigen less specifically than IgG.¹²

 

 

Interpreting the IgM Western blot test: The ‘1-month rule’

If clinical symptoms and signs of Lyme disease have been present for more than 1 month, IgM reactivity alone should not be used to support the diagnosis, in view of the likelihood of a false-positive test result in this situation.¹⁸ This is called the “1-month rule” in the diagnosis of Lyme disease.¹³

In early localized infection, Western blot is only half as sensitive as ELISA testing. Since the overall sensitivity of a 2-step algorithm is equal to that of its least sensitive component, 2-tiered testing is not useful in early disease.¹³

Although currently considered the most specific test for confirmation of Lyme disease, Western blot has limitations. It is technically and interpretively complex and is thus not universally available.¹³ The blots are scored by visual examination, compromising the reproducibility of the test, although densitometric blot analysis techniques and automated scanning and scoring attempt to address some of these limitations.¹³ Like the ELISA, Western blot can have false-positive results in healthy individuals without tick exposure, as nonspecific IgM immunoblots develop faint bands. This is because of cross-reaction between B burgdorferi antigens and antigens from other microorganisms. Around 50% of healthy adults show low-level serum IgG reactivity against the FlaB antigen, leading to false-positive results as well. In cases in which the Western blot result is indeterminate, other etiologies must be considered.

False-positive IgM Western blots are a significant problem. In a 5-year retrospective study done at 63 US Air Force healthcare facilities, 113 (53.3%) of 212 IgM Western blots were falsely positive.¹⁹ A false-positive test was defined as one that failed to meet seropositivity (a first-tier test omitted or negative, > 30 days of symptoms with negative IgG blot), lack of exposure including residing in areas without documented tick habitats, patients having atypical or no symptoms, and negative serology within 30 days of a positive test.

In a similar study done in a highly endemic area, 50 (27.5%) of 182 patients had a false-positive test.²⁰ Physicians need to be careful when interpreting IgM Western blots. It is always important to consider locale, epidemiology, and symptoms when interpreting the test.

Limitations of serologic tests for Lyme disease

Currently available serologic tests have inherent limitations:

• Antibodies against B burgdorferi take at least 1 week to develop
• The background rate of seropositivity in endemic areas can be up to 4%, affecting the utility of a positive test result
• Serologic tests cannot be used as tests of cure because antibodies can persist for months to years even after appropriate antimicrobial therapy and cure of disease; thus, a positive serologic result could represent active infection or remote exposure²¹
• Antibodies can cross-react with related bacteria, including other borrelial or treponemal spirochetes
• False-positive serologic test results can also occur in association with other medical conditions such as polyclonal gammopathies and systemic lupus erythematosus.¹²

RECOMMENDATIONS FOR TESTING

Standard 2-tier testing

The CDC released recommendations for diagnosing Lyme disease after a second national conference of serologic diagnosis of Lyme disease in October 1994.¹⁸ The 2-tiered testing method, involving a sensitive ELISA followed by the Western blot to confirm positive and indeterminate ELISA results, was suggested as the gold standard for diagnosis (Figure 3). Of note, negative ELISA results do not require further testing.¹¹

The sensitivity of 2-tiered testing depends on the stage of the disease. Unfortunately, this method has a wide range of sensitivity (17% to 78%) in stage 1 disease. In the same stage, the sensitivity increases from 14.1% in patients with a single erythema migrans lesion and early localized infection to 65.4% in those with multiple lesions. The algorithm has excellent sensitivity in late stage 3 infection (96% to 100%).⁵

A 2-step ELISA algorithm

A 2-step ELISA algorithm (without the Western blot) that includes the whole-cell sonicate assay followed by the VisE C6 peptide assay actually showed higher sensitivity and comparable specificity compared with 2-tiered testing in early localized disease (sensitivity 61%–74% vs 29%–48%, respectively; specificity 99.5% for both methods).²² This higher sensitivity was even more pronounced in early disseminated infection (sensitivity 100% vs 40%, respectively). By late infection, the sensitivities of both testing strategies reached 100%. Compared with the Western blot, the 2-step ELISA algorithm was simpler to execute in a reproducible fashion.⁵

The Infectious Diseases Society of America is revising its current guidelines, with an update expected late this year, which may shift the recommendation from 2-tiered testing to the 2-step ELISA algorithm.

Multiplex testing

To overcome the intrinsic problems of protein-based assays, a multiplexed, array-based assay for the diagnosis of tick-borne infections called Tick-Borne Disease Serochip (TBD-Serochip) was established using recombinant antigens that identify key immunodominant epitopes.⁸ More studies are needed to establish the validity and usefulness of these tests in clinical practice.

Who should not be tested?

The American College of Physicians⁶ recommends against testing in patients:

• Presenting with nonspecific symptoms (eg, headache, myalgia, fatigue, arthralgia) without objective signs of Lyme disease
• With low pretest probability of infection based on epidemiologic exposures and clinical features
• Living in Lyme-endemic areas with no history of tick exposure⁶
• Presenting less than 1 week after tick exposure⁵
• Seeking a test of cure for treated Lyme disease.

DIAGNOSIS IN SPECIAL SITUATIONS

Early Lyme disease

The classic erythema migrans lesion on physical examination of a patient with suspected Lyme disease is diagnostic and does not require laboratory confirmation.¹⁰

In ambiguous cases, 2-tiered testing of a serum sample during the acute presentation and again 4 to 6 weeks later can be useful. In patients who remain seronegative on paired serum samples despite symptoms lasting longer than 6 weeks and no antibiotic treatment in the interim, the diagnosis of Lyme disease is unlikely, and another diagnosis should be sought.³

Antimicrobial therapy may block the serologic response; hence, negative serologic testing in patients started on empiric antibiotics should not rule out Lyme disease.⁶

PCR or bacterial culture testing is not recommended in the evaluation of suspected early Lyme disease.

Central nervous system Lyme disease

Central nervous system Lyme disease is diagnosed by 2-tiered testing using peripheral blood samples because all patients with this infectious manifestation should have mounted an adequate IgG response in the blood.¹¹

B cells migrate to and proliferate inside the central nervous system, leading to intrathecal production of anti-Borrelia antibodies. An index of cerebrospinal fluid to serum antibody greater than 1 is thus also indicative of neuroborreliosis.¹² Thus, performing lumbar puncture to detect intrathecal production of antibodies may support the diagnosis of central nervous system Lyme disease; however, it is not necessary.¹¹

Antibodies persist in the central nervous system for many years after appropriate antimicrobial treatment.

Lyme arthritis

Articular involvement in Lyme disease is characterized by a robust humoral response such that a negative IgG serologic test virtually rules out Lyme arthritis.²³ PCR testing of synovial fluid for borrelial DNA has a sensitivity of 80% but may become falsely negative after 1 to 2 months of antibiotic treatment.^24,25 In an algorithm suggested by Puius et al,²³ PCR testing of synovial fluid should be done in patients who have minimal to no response after 2 months of appropriate oral antimicrobial therapy to determine whether intravenous antibiotics are merited.

Table 5 summarizes the tests of choice in different clinical stages of infection.

Acknowledgment: The authors would like to acknowledge Anita Modi, MD, and Ceena N. Jacob, MD, for reviewing the manuscript and providing valuable suggestions, and Belinda Yen-Lieberman, PhD, for contributing pictures of the Western blot test results.

Lyme disease is a complex multisystem bacterial infection affecting the skin, joints, heart, and nervous system. The full spectrum of disease was first recognized and the disease was named in the 1970s during an outbreak of arthritis in children in the town of Lyme, Connecticut.¹

This review describes the epidemiology and pathogenesis of Lyme disease, the advantages and disadvantages of current diagnostic methods, and diagnostic algorithms.

THE MOST COMMON TICK-BORNE INFECTION IN NORTH AMERICA

Lyme disease is the most common tick-borne infection in North America.^2,3 In the United States, more than 30,000 cases are reported annually. In fact, in 2017, the number of cases was about 42,000, a 16% increase from the previous year, according to the US Centers for Disease Control and Prevention (CDC).

From Sigal LH. Myths and facts about Lyme disease. Cleve Clin J Med 1997; 64(4):203–209.

The infection is caused by Borrelia burgdorferi, a particularly arthritogenic spirochete transmitted by Ixodes scapularis (the black-legged deer tick, (Figure 1) and Ixodes pacificus (the Western black-legged tick). Although the infection can occur at any time of the year, its peak incidence is in May to late September, coinciding with increased outdoor recreational activity in areas where ticks live.^3,4 The typical tick habitat consists of deciduous woodland with sufficient humidity provided by a good layer of decaying vegetation. However, people can contract Lyme disease in their own backyard.³

Most cases of Lyme disease are seen in the northeastern United States, mainly in suburban and rural areas.^2,3 Other areas affected include the midwestern states of Minnesota, Wisconsin, and Michigan, as well as northern California.⁴ Fourteen states and the District of Columbia report a high average incidence (> 10 cases per 100,000 persons) (Table 1).²

FIRST COMES IgM, THEN IgG

The pathogenesis and the different stages of infection should inform laboratory testing in Lyme disease.

It is estimated that only 5% of infected ticks that bite people actually transmit their spirochetes to the human host.⁵ However, once infected, the patient’s innate immune system mounts a response that results in the classic erythema migrans rash at the bite site. A rash develops in only about 85% of patients who are infected and can appear at any time between 3 and 30 days, but most commonly after 7 days. Hence, a rash occurring within the first few hours of tick contact is not erythema migrans and does not indicate infection, but rather an early reaction to tick salivary antigens.⁵

Antibody levels remain below the detection limits of currently available serologic tests in the first 7 days after exposure. Immunoglobulin M (IgM) antibody titers peak between 8 and 14 days after tick contact, but IgM antibodies may never develop if the patient is started on early appropriate antimicrobial therapy.⁵

If the infection is not treated, the spirochete may disseminate through the blood from the bite site to different tissues.³ Both cell-mediated and antibody-mediated immunity swing into action to kill the spirochetes at this stage. The IgM antibody response occurs in 1 to 2 weeks, followed by a robust IgG response in 2 to 4 weeks.⁶

Because IgM can also cross-react with antigens other than those associated with B burgdorferi, the IgM test is less specific than the IgG test for Lyme disease.

Once a patient is exposed and mounts an antibody-mediated response to the spirochete, the antibody profile may persist for months to years, even after successful antibiotic treatment and cure of the disease.⁵

Despite the immune system’s robust series of defenses, untreated B burgdorferi infection can persist, as the organism has a bag of tricks to evade destruction. It can decrease its expression of specific immunogenic surface-exposed proteins, change its antigenic properties through recombination, and bind to the patient’s extracellular matrix proteins to facilitate further dissemination.³

Certain host-genetic factors also play a role in the pathogenesis of Lyme disease, such as the HLA-DR4 allele, which has been associated with antibiotic-refractory Lyme-related arthritis.³

LYME DISEASE EVOLVES THROUGH STAGES

Lyme disease evolves through stages broadly classified as early and late infection, with significant variability in its presentation.⁷

Early infection

Early disease is further subdivided into “localized” infection (stage 1), characterized by a single erythema migrans lesion and local lymphadenopathy, and “disseminated” infection (stage 2), associated with multiple erythema migrans lesions distant from the bite site, facial nerve palsy, radiculoneuritis, meningitis, carditis, or migratory arthritis or arthralgia.⁸

Highly specific physical findings include erythema migrans, cranial nerve palsy, high-grade or progressive conduction block, and recurrent migratory polyarthritis. Less specific symptoms and signs of Lyme disease include arthralgia, myalgia, neck stiffness, palpitations, and myocarditis.⁵

Erythema migrans lesions are evident in at least 85% of patients with early disease.⁹ If they are not apparent on physical examination, they may be located at hidden sites and may be atypical in appearance or transient.⁵

If treatment is not started in the initial stage of the disease, 60% of infected patients may develop disseminated infection.⁵ Progressive, untreated infection can manifest with Lyme arthritis and neuroborreliosis.⁷

Noncutaneous manifestations are less common now than in the past due to increased awareness of the disease and early initiation of treatment.¹⁰

Late infection

Manifestations of late (stage 3) infection include oligoarthritis (affecting any joint but often the knee) and neuroborreliosis. Clinical signs and symptoms of Lyme disease may take months to resolve even after appropriate antimicrobial therapy is completed. This should not be interpreted as ongoing, persistent infection, but as related to host immune-mediated activity.⁵

 

 

INTERPRET LABORATORY RESULTS BASED ON PRETEST PROBABILITY

The usefulness of a laboratory test depends on the individual patient’s pretest probability of infection, which in turn depends on the patient’s epidemiologic risk of exposure and clinical features of Lyme disease. Patients with a high pretest probability—eg, a history of a tick bite followed by the classic erythema migrans rash—do not need testing and can start antimicrobial therapy right away.¹¹

Serologic tests are the gold standard

Prompt diagnosis is important, as early Lyme disease is easily treatable without any future sequelae.¹¹

Tests for Lyme disease can be divided into direct methods, which detect the spirochete itself by culture or by polymerase chain reaction (PCR), and indirect methods, which detect antibodies (Table 2). Direct tests lack sensitivity for Lyme disease; hence, serologic tests remain the gold standard. Currently recommended is a standard 2-tier testing strategy using an enzyme-linked immunosorbent assay (ELISA) followed by Western blot for confirmation.

DIRECT METHODS

Culture lacks sensitivity

A number of factors limit the sensitivity of direct culture for diagnosing Lyme disease. B burgdorferi does not grow easily in culture, requiring special media, low temperatures, and long periods of incubation. Only a relatively few spirochetes are present in human tissues and body fluids to begin with, and bacterial counts are further reduced with duration and dissemination of infection.⁵ All of these limit the possibility of detecting this organism.

Polymerase chain reaction may help in some situations

Molecular assays are not part of the standard evaluation and should be used only in conjunction with serologic testing.⁷ These tests have high specificity but lack consistent sensitivity.

That said, PCR testing may be useful:

• In early infection, before antibody responses develop
• In reinfection, when serologic tests are not reliable because the antibodies persist for many years after an infection in many patients
• In endemic areas where serologic testing has high false-positive rates due to high baseline population seropositivity for anti-Borrelia antibodies caused by subclinical infection.³

PCR assays that target plasmid-borne genes encoding outer surface proteins A and C (OspA and OspC) and VisE (variable major protein-like sequence, expressed) are more sensitive than those that detect chromosomal 16s ribosomal ribonucleic acid (rRNA) genes, as plasmid-rich “blebs” are shed in larger concentrations than chromosomal DNA during active infection.⁷ However, these plasmid-contained genes persist in body tissues and fluids even after the infection is cleared, and their detection may not necessarily correlate with ongoing disease.⁸ Detection of chromosomal 16s rRNA genes is a better predictor of true organism viability.

The sensitivity of PCR for borrelial DNA depends on the type of sample. If a skin biopsy sample is taken of the leading edge of an erythema migrans lesion, the sensitivity is 69% and the specificity is 100%. In patients with Lyme arthritis, PCR of the synovial fluid has a sensitivity of up to 80%. However, the sensitivity of PCR of the cerebrospinal fluid of patients with neurologic manifestations of Lyme disease is only 19%.⁷ PCR of other clinical samples, including blood and urine, is not recommended, as spirochetes are primarily confined to tissues, and very few are present in these body fluids.^3,12

The disadvantage of PCR is that a positive result does not always mean active infection, as the DNA of the dead microbe persists for several months even after successful treatment.⁸

INDIRECT METHODS

Enzyme-linked immunosorbent assay

ELISAs detect anti-Borrelia antibodies. Early-generation ELISAs, still used in many laboratories, use whole-cell extracts of B burgdorferi. Examples are the Vidas Lyme screen (Biomérieux, biomerieux-usa.com) and the Wampole B burgdorferi IgG/M EIA II assay (Alere, www.alere.com). Newer ELISAs use recombinant proteins.¹³

Three major targets for ELISA antibodies are flagellin (Fla), outer surface protein C (OspC), and VisE, especially the invariable region 6 (IR6). Among these, VisE-IR6 is the most conserved region in B burgdorferi.

Early-generation assays have a sensitivity of 89% and specificity of 72%.¹¹ However, the patient’s serum may have antibodies that cross-react with unrelated bacterial antigens, leading to false-positive results (Table 3). Whole-cell sonicate assays are not recommended as an independent test and must be confirmed with Western blot testing when assay results are indeterminate or positive.¹¹

Newer-generation ELISAs detect antibodies targeting recombinant proteins of VisE, especially a synthetic peptide C6, within IR6.¹³ VisE-IR6 is the most conserved region of the B burgdorferi complex, and its detection is a highly specific finding, supporting the diagnosis of Lyme disease. Antibodies against VisE-IR6 antigen are the earliest to develop.⁵ An example of a newer-generation serologic test is the VisE C6 Lyme EIA kit, approved as a first-tier test by the US Food and Drug Administration in 2001. This test has a specificity of 99%,^14,15 and its specificity is further increased when used in conjunction with Western blot (99.5%).¹⁵ The advantage of the C6 antibody test is that it is more sensitive than 2-tier testing during early infection (sensitivity 29%–74% vs 17%–40% in early localized infection, and 56%–90% vs 27%–78% in early disseminated infection).⁶

During early infection, older and newer ELISAs are less sensitive because of the limited number of antigens expressed at this stage.¹³ All patients suspected of having early Lyme disease who are seronegative at initial testing should have follow-up testing to look for seroconversion.¹³

Western blot

Western blot (immunoblot) testing identifies IgM and IgG antibodies against specific B burgdorferi antigens. It is considered positive if it detects at least 2 of a possible 3 specific IgM bands in the first 4 weeks of disease or at least 5 of 10 specific IgG bands after 4 weeks of disease (Table 4 and Figure 2).¹⁶

The nature of the bands indicates the duration of infection: Western blot bands against 23-kD OspC and 41-kD FlaB are seen in early localized infection, whereas bands against all 3 B burgdorferi proteins will be seen after several weeks of disease.¹⁷ The IgM result should be interpreted carefully, as only 2 bands are required for the test to be positive, and IgM binds to antigen less specifically than IgG.¹²

 

 

Interpreting the IgM Western blot test: The ‘1-month rule’

If clinical symptoms and signs of Lyme disease have been present for more than 1 month, IgM reactivity alone should not be used to support the diagnosis, in view of the likelihood of a false-positive test result in this situation.¹⁸ This is called the “1-month rule” in the diagnosis of Lyme disease.¹³

In early localized infection, Western blot is only half as sensitive as ELISA testing. Since the overall sensitivity of a 2-step algorithm is equal to that of its least sensitive component, 2-tiered testing is not useful in early disease.¹³

Although currently considered the most specific test for confirmation of Lyme disease, Western blot has limitations. It is technically and interpretively complex and is thus not universally available.¹³ The blots are scored by visual examination, compromising the reproducibility of the test, although densitometric blot analysis techniques and automated scanning and scoring attempt to address some of these limitations.¹³ Like the ELISA, Western blot can have false-positive results in healthy individuals without tick exposure, as nonspecific IgM immunoblots develop faint bands. This is because of cross-reaction between B burgdorferi antigens and antigens from other microorganisms. Around 50% of healthy adults show low-level serum IgG reactivity against the FlaB antigen, leading to false-positive results as well. In cases in which the Western blot result is indeterminate, other etiologies must be considered.

False-positive IgM Western blots are a significant problem. In a 5-year retrospective study done at 63 US Air Force healthcare facilities, 113 (53.3%) of 212 IgM Western blots were falsely positive.¹⁹ A false-positive test was defined as one that failed to meet seropositivity (a first-tier test omitted or negative, > 30 days of symptoms with negative IgG blot), lack of exposure including residing in areas without documented tick habitats, patients having atypical or no symptoms, and negative serology within 30 days of a positive test.

In a similar study done in a highly endemic area, 50 (27.5%) of 182 patients had a false-positive test.²⁰ Physicians need to be careful when interpreting IgM Western blots. It is always important to consider locale, epidemiology, and symptoms when interpreting the test.

Limitations of serologic tests for Lyme disease

Currently available serologic tests have inherent limitations:

• Antibodies against B burgdorferi take at least 1 week to develop
• The background rate of seropositivity in endemic areas can be up to 4%, affecting the utility of a positive test result
• Serologic tests cannot be used as tests of cure because antibodies can persist for months to years even after appropriate antimicrobial therapy and cure of disease; thus, a positive serologic result could represent active infection or remote exposure²¹
• Antibodies can cross-react with related bacteria, including other borrelial or treponemal spirochetes
• False-positive serologic test results can also occur in association with other medical conditions such as polyclonal gammopathies and systemic lupus erythematosus.¹²

RECOMMENDATIONS FOR TESTING

Standard 2-tier testing

The CDC released recommendations for diagnosing Lyme disease after a second national conference of serologic diagnosis of Lyme disease in October 1994.¹⁸ The 2-tiered testing method, involving a sensitive ELISA followed by the Western blot to confirm positive and indeterminate ELISA results, was suggested as the gold standard for diagnosis (Figure 3). Of note, negative ELISA results do not require further testing.¹¹

The sensitivity of 2-tiered testing depends on the stage of the disease. Unfortunately, this method has a wide range of sensitivity (17% to 78%) in stage 1 disease. In the same stage, the sensitivity increases from 14.1% in patients with a single erythema migrans lesion and early localized infection to 65.4% in those with multiple lesions. The algorithm has excellent sensitivity in late stage 3 infection (96% to 100%).⁵

A 2-step ELISA algorithm

A 2-step ELISA algorithm (without the Western blot) that includes the whole-cell sonicate assay followed by the VisE C6 peptide assay actually showed higher sensitivity and comparable specificity compared with 2-tiered testing in early localized disease (sensitivity 61%–74% vs 29%–48%, respectively; specificity 99.5% for both methods).²² This higher sensitivity was even more pronounced in early disseminated infection (sensitivity 100% vs 40%, respectively). By late infection, the sensitivities of both testing strategies reached 100%. Compared with the Western blot, the 2-step ELISA algorithm was simpler to execute in a reproducible fashion.⁵

The Infectious Diseases Society of America is revising its current guidelines, with an update expected late this year, which may shift the recommendation from 2-tiered testing to the 2-step ELISA algorithm.

Multiplex testing

To overcome the intrinsic problems of protein-based assays, a multiplexed, array-based assay for the diagnosis of tick-borne infections called Tick-Borne Disease Serochip (TBD-Serochip) was established using recombinant antigens that identify key immunodominant epitopes.⁸ More studies are needed to establish the validity and usefulness of these tests in clinical practice.

Who should not be tested?

The American College of Physicians⁶ recommends against testing in patients:

• Presenting with nonspecific symptoms (eg, headache, myalgia, fatigue, arthralgia) without objective signs of Lyme disease
• With low pretest probability of infection based on epidemiologic exposures and clinical features
• Living in Lyme-endemic areas with no history of tick exposure⁶
• Presenting less than 1 week after tick exposure⁵
• Seeking a test of cure for treated Lyme disease.

DIAGNOSIS IN SPECIAL SITUATIONS

Early Lyme disease

The classic erythema migrans lesion on physical examination of a patient with suspected Lyme disease is diagnostic and does not require laboratory confirmation.¹⁰

In ambiguous cases, 2-tiered testing of a serum sample during the acute presentation and again 4 to 6 weeks later can be useful. In patients who remain seronegative on paired serum samples despite symptoms lasting longer than 6 weeks and no antibiotic treatment in the interim, the diagnosis of Lyme disease is unlikely, and another diagnosis should be sought.³

Antimicrobial therapy may block the serologic response; hence, negative serologic testing in patients started on empiric antibiotics should not rule out Lyme disease.⁶

PCR or bacterial culture testing is not recommended in the evaluation of suspected early Lyme disease.

Central nervous system Lyme disease

Central nervous system Lyme disease is diagnosed by 2-tiered testing using peripheral blood samples because all patients with this infectious manifestation should have mounted an adequate IgG response in the blood.¹¹

B cells migrate to and proliferate inside the central nervous system, leading to intrathecal production of anti-Borrelia antibodies. An index of cerebrospinal fluid to serum antibody greater than 1 is thus also indicative of neuroborreliosis.¹² Thus, performing lumbar puncture to detect intrathecal production of antibodies may support the diagnosis of central nervous system Lyme disease; however, it is not necessary.¹¹

Antibodies persist in the central nervous system for many years after appropriate antimicrobial treatment.

Lyme arthritis

Articular involvement in Lyme disease is characterized by a robust humoral response such that a negative IgG serologic test virtually rules out Lyme arthritis.²³ PCR testing of synovial fluid for borrelial DNA has a sensitivity of 80% but may become falsely negative after 1 to 2 months of antibiotic treatment.^24,25 In an algorithm suggested by Puius et al,²³ PCR testing of synovial fluid should be done in patients who have minimal to no response after 2 months of appropriate oral antimicrobial therapy to determine whether intravenous antibiotics are merited.

Table 5 summarizes the tests of choice in different clinical stages of infection.

Acknowledgment: The authors would like to acknowledge Anita Modi, MD, and Ceena N. Jacob, MD, for reviewing the manuscript and providing valuable suggestions, and Belinda Yen-Lieberman, PhD, for contributing pictures of the Western blot test results.

Lyme disease is a complex multisystem bacterial infection affecting the skin, joints, heart, and nervous system. The full spectrum of disease was first recognized and the disease was named in the 1970s during an outbreak of arthritis in children in the town of Lyme, Connecticut.¹

This review describes the epidemiology and pathogenesis of Lyme disease, the advantages and disadvantages of current diagnostic methods, and diagnostic algorithms.

THE MOST COMMON TICK-BORNE INFECTION IN NORTH AMERICA

Lyme disease is the most common tick-borne infection in North America.^2,3 In the United States, more than 30,000 cases are reported annually. In fact, in 2017, the number of cases was about 42,000, a 16% increase from the previous year, according to the US Centers for Disease Control and Prevention (CDC).

From Sigal LH. Myths and facts about Lyme disease. Cleve Clin J Med 1997; 64(4):203–209.

The infection is caused by Borrelia burgdorferi, a particularly arthritogenic spirochete transmitted by Ixodes scapularis (the black-legged deer tick, (Figure 1) and Ixodes pacificus (the Western black-legged tick). Although the infection can occur at any time of the year, its peak incidence is in May to late September, coinciding with increased outdoor recreational activity in areas where ticks live.^3,4 The typical tick habitat consists of deciduous woodland with sufficient humidity provided by a good layer of decaying vegetation. However, people can contract Lyme disease in their own backyard.³

Most cases of Lyme disease are seen in the northeastern United States, mainly in suburban and rural areas.^2,3 Other areas affected include the midwestern states of Minnesota, Wisconsin, and Michigan, as well as northern California.⁴ Fourteen states and the District of Columbia report a high average incidence (> 10 cases per 100,000 persons) (Table 1).²

FIRST COMES IgM, THEN IgG

The pathogenesis and the different stages of infection should inform laboratory testing in Lyme disease.

It is estimated that only 5% of infected ticks that bite people actually transmit their spirochetes to the human host.⁵ However, once infected, the patient’s innate immune system mounts a response that results in the classic erythema migrans rash at the bite site. A rash develops in only about 85% of patients who are infected and can appear at any time between 3 and 30 days, but most commonly after 7 days. Hence, a rash occurring within the first few hours of tick contact is not erythema migrans and does not indicate infection, but rather an early reaction to tick salivary antigens.⁵

Antibody levels remain below the detection limits of currently available serologic tests in the first 7 days after exposure. Immunoglobulin M (IgM) antibody titers peak between 8 and 14 days after tick contact, but IgM antibodies may never develop if the patient is started on early appropriate antimicrobial therapy.⁵

If the infection is not treated, the spirochete may disseminate through the blood from the bite site to different tissues.³ Both cell-mediated and antibody-mediated immunity swing into action to kill the spirochetes at this stage. The IgM antibody response occurs in 1 to 2 weeks, followed by a robust IgG response in 2 to 4 weeks.⁶

Because IgM can also cross-react with antigens other than those associated with B burgdorferi, the IgM test is less specific than the IgG test for Lyme disease.

Once a patient is exposed and mounts an antibody-mediated response to the spirochete, the antibody profile may persist for months to years, even after successful antibiotic treatment and cure of the disease.⁵

Despite the immune system’s robust series of defenses, untreated B burgdorferi infection can persist, as the organism has a bag of tricks to evade destruction. It can decrease its expression of specific immunogenic surface-exposed proteins, change its antigenic properties through recombination, and bind to the patient’s extracellular matrix proteins to facilitate further dissemination.³

Certain host-genetic factors also play a role in the pathogenesis of Lyme disease, such as the HLA-DR4 allele, which has been associated with antibiotic-refractory Lyme-related arthritis.³

LYME DISEASE EVOLVES THROUGH STAGES

Lyme disease evolves through stages broadly classified as early and late infection, with significant variability in its presentation.⁷

Early infection

Early disease is further subdivided into “localized” infection (stage 1), characterized by a single erythema migrans lesion and local lymphadenopathy, and “disseminated” infection (stage 2), associated with multiple erythema migrans lesions distant from the bite site, facial nerve palsy, radiculoneuritis, meningitis, carditis, or migratory arthritis or arthralgia.⁸

Highly specific physical findings include erythema migrans, cranial nerve palsy, high-grade or progressive conduction block, and recurrent migratory polyarthritis. Less specific symptoms and signs of Lyme disease include arthralgia, myalgia, neck stiffness, palpitations, and myocarditis.⁵

Erythema migrans lesions are evident in at least 85% of patients with early disease.⁹ If they are not apparent on physical examination, they may be located at hidden sites and may be atypical in appearance or transient.⁵

If treatment is not started in the initial stage of the disease, 60% of infected patients may develop disseminated infection.⁵ Progressive, untreated infection can manifest with Lyme arthritis and neuroborreliosis.⁷

Noncutaneous manifestations are less common now than in the past due to increased awareness of the disease and early initiation of treatment.¹⁰

Late infection

Manifestations of late (stage 3) infection include oligoarthritis (affecting any joint but often the knee) and neuroborreliosis. Clinical signs and symptoms of Lyme disease may take months to resolve even after appropriate antimicrobial therapy is completed. This should not be interpreted as ongoing, persistent infection, but as related to host immune-mediated activity.⁵

 

 

INTERPRET LABORATORY RESULTS BASED ON PRETEST PROBABILITY

The usefulness of a laboratory test depends on the individual patient’s pretest probability of infection, which in turn depends on the patient’s epidemiologic risk of exposure and clinical features of Lyme disease. Patients with a high pretest probability—eg, a history of a tick bite followed by the classic erythema migrans rash—do not need testing and can start antimicrobial therapy right away.¹¹

Serologic tests are the gold standard

Prompt diagnosis is important, as early Lyme disease is easily treatable without any future sequelae.¹¹

Tests for Lyme disease can be divided into direct methods, which detect the spirochete itself by culture or by polymerase chain reaction (PCR), and indirect methods, which detect antibodies (Table 2). Direct tests lack sensitivity for Lyme disease; hence, serologic tests remain the gold standard. Currently recommended is a standard 2-tier testing strategy using an enzyme-linked immunosorbent assay (ELISA) followed by Western blot for confirmation.

DIRECT METHODS

Culture lacks sensitivity

A number of factors limit the sensitivity of direct culture for diagnosing Lyme disease. B burgdorferi does not grow easily in culture, requiring special media, low temperatures, and long periods of incubation. Only a relatively few spirochetes are present in human tissues and body fluids to begin with, and bacterial counts are further reduced with duration and dissemination of infection.⁵ All of these limit the possibility of detecting this organism.

Polymerase chain reaction may help in some situations

Molecular assays are not part of the standard evaluation and should be used only in conjunction with serologic testing.⁷ These tests have high specificity but lack consistent sensitivity.

That said, PCR testing may be useful:

• In early infection, before antibody responses develop
• In reinfection, when serologic tests are not reliable because the antibodies persist for many years after an infection in many patients
• In endemic areas where serologic testing has high false-positive rates due to high baseline population seropositivity for anti-Borrelia antibodies caused by subclinical infection.³

PCR assays that target plasmid-borne genes encoding outer surface proteins A and C (OspA and OspC) and VisE (variable major protein-like sequence, expressed) are more sensitive than those that detect chromosomal 16s ribosomal ribonucleic acid (rRNA) genes, as plasmid-rich “blebs” are shed in larger concentrations than chromosomal DNA during active infection.⁷ However, these plasmid-contained genes persist in body tissues and fluids even after the infection is cleared, and their detection may not necessarily correlate with ongoing disease.⁸ Detection of chromosomal 16s rRNA genes is a better predictor of true organism viability.

The sensitivity of PCR for borrelial DNA depends on the type of sample. If a skin biopsy sample is taken of the leading edge of an erythema migrans lesion, the sensitivity is 69% and the specificity is 100%. In patients with Lyme arthritis, PCR of the synovial fluid has a sensitivity of up to 80%. However, the sensitivity of PCR of the cerebrospinal fluid of patients with neurologic manifestations of Lyme disease is only 19%.⁷ PCR of other clinical samples, including blood and urine, is not recommended, as spirochetes are primarily confined to tissues, and very few are present in these body fluids.^3,12

The disadvantage of PCR is that a positive result does not always mean active infection, as the DNA of the dead microbe persists for several months even after successful treatment.⁸

INDIRECT METHODS

Enzyme-linked immunosorbent assay

ELISAs detect anti-Borrelia antibodies. Early-generation ELISAs, still used in many laboratories, use whole-cell extracts of B burgdorferi. Examples are the Vidas Lyme screen (Biomérieux, biomerieux-usa.com) and the Wampole B burgdorferi IgG/M EIA II assay (Alere, www.alere.com). Newer ELISAs use recombinant proteins.¹³

Three major targets for ELISA antibodies are flagellin (Fla), outer surface protein C (OspC), and VisE, especially the invariable region 6 (IR6). Among these, VisE-IR6 is the most conserved region in B burgdorferi.

Early-generation assays have a sensitivity of 89% and specificity of 72%.¹¹ However, the patient’s serum may have antibodies that cross-react with unrelated bacterial antigens, leading to false-positive results (Table 3). Whole-cell sonicate assays are not recommended as an independent test and must be confirmed with Western blot testing when assay results are indeterminate or positive.¹¹

Newer-generation ELISAs detect antibodies targeting recombinant proteins of VisE, especially a synthetic peptide C6, within IR6.¹³ VisE-IR6 is the most conserved region of the B burgdorferi complex, and its detection is a highly specific finding, supporting the diagnosis of Lyme disease. Antibodies against VisE-IR6 antigen are the earliest to develop.⁵ An example of a newer-generation serologic test is the VisE C6 Lyme EIA kit, approved as a first-tier test by the US Food and Drug Administration in 2001. This test has a specificity of 99%,^14,15 and its specificity is further increased when used in conjunction with Western blot (99.5%).¹⁵ The advantage of the C6 antibody test is that it is more sensitive than 2-tier testing during early infection (sensitivity 29%–74% vs 17%–40% in early localized infection, and 56%–90% vs 27%–78% in early disseminated infection).⁶

During early infection, older and newer ELISAs are less sensitive because of the limited number of antigens expressed at this stage.¹³ All patients suspected of having early Lyme disease who are seronegative at initial testing should have follow-up testing to look for seroconversion.¹³

Western blot

Western blot (immunoblot) testing identifies IgM and IgG antibodies against specific B burgdorferi antigens. It is considered positive if it detects at least 2 of a possible 3 specific IgM bands in the first 4 weeks of disease or at least 5 of 10 specific IgG bands after 4 weeks of disease (Table 4 and Figure 2).¹⁶

The nature of the bands indicates the duration of infection: Western blot bands against 23-kD OspC and 41-kD FlaB are seen in early localized infection, whereas bands against all 3 B burgdorferi proteins will be seen after several weeks of disease.¹⁷ The IgM result should be interpreted carefully, as only 2 bands are required for the test to be positive, and IgM binds to antigen less specifically than IgG.¹²

 

 

Interpreting the IgM Western blot test: The ‘1-month rule’

If clinical symptoms and signs of Lyme disease have been present for more than 1 month, IgM reactivity alone should not be used to support the diagnosis, in view of the likelihood of a false-positive test result in this situation.¹⁸ This is called the “1-month rule” in the diagnosis of Lyme disease.¹³

In early localized infection, Western blot is only half as sensitive as ELISA testing. Since the overall sensitivity of a 2-step algorithm is equal to that of its least sensitive component, 2-tiered testing is not useful in early disease.¹³

Although currently considered the most specific test for confirmation of Lyme disease, Western blot has limitations. It is technically and interpretively complex and is thus not universally available.¹³ The blots are scored by visual examination, compromising the reproducibility of the test, although densitometric blot analysis techniques and automated scanning and scoring attempt to address some of these limitations.¹³ Like the ELISA, Western blot can have false-positive results in healthy individuals without tick exposure, as nonspecific IgM immunoblots develop faint bands. This is because of cross-reaction between B burgdorferi antigens and antigens from other microorganisms. Around 50% of healthy adults show low-level serum IgG reactivity against the FlaB antigen, leading to false-positive results as well. In cases in which the Western blot result is indeterminate, other etiologies must be considered.

False-positive IgM Western blots are a significant problem. In a 5-year retrospective study done at 63 US Air Force healthcare facilities, 113 (53.3%) of 212 IgM Western blots were falsely positive.¹⁹ A false-positive test was defined as one that failed to meet seropositivity (a first-tier test omitted or negative, > 30 days of symptoms with negative IgG blot), lack of exposure including residing in areas without documented tick habitats, patients having atypical or no symptoms, and negative serology within 30 days of a positive test.

In a similar study done in a highly endemic area, 50 (27.5%) of 182 patients had a false-positive test.²⁰ Physicians need to be careful when interpreting IgM Western blots. It is always important to consider locale, epidemiology, and symptoms when interpreting the test.

Limitations of serologic tests for Lyme disease

Currently available serologic tests have inherent limitations:

• Antibodies against B burgdorferi take at least 1 week to develop
• The background rate of seropositivity in endemic areas can be up to 4%, affecting the utility of a positive test result
• Serologic tests cannot be used as tests of cure because antibodies can persist for months to years even after appropriate antimicrobial therapy and cure of disease; thus, a positive serologic result could represent active infection or remote exposure²¹
• Antibodies can cross-react with related bacteria, including other borrelial or treponemal spirochetes
• False-positive serologic test results can also occur in association with other medical conditions such as polyclonal gammopathies and systemic lupus erythematosus.¹²

RECOMMENDATIONS FOR TESTING

Standard 2-tier testing

The CDC released recommendations for diagnosing Lyme disease after a second national conference of serologic diagnosis of Lyme disease in October 1994.¹⁸ The 2-tiered testing method, involving a sensitive ELISA followed by the Western blot to confirm positive and indeterminate ELISA results, was suggested as the gold standard for diagnosis (Figure 3). Of note, negative ELISA results do not require further testing.¹¹

The sensitivity of 2-tiered testing depends on the stage of the disease. Unfortunately, this method has a wide range of sensitivity (17% to 78%) in stage 1 disease. In the same stage, the sensitivity increases from 14.1% in patients with a single erythema migrans lesion and early localized infection to 65.4% in those with multiple lesions. The algorithm has excellent sensitivity in late stage 3 infection (96% to 100%).⁵

A 2-step ELISA algorithm

A 2-step ELISA algorithm (without the Western blot) that includes the whole-cell sonicate assay followed by the VisE C6 peptide assay actually showed higher sensitivity and comparable specificity compared with 2-tiered testing in early localized disease (sensitivity 61%–74% vs 29%–48%, respectively; specificity 99.5% for both methods).²² This higher sensitivity was even more pronounced in early disseminated infection (sensitivity 100% vs 40%, respectively). By late infection, the sensitivities of both testing strategies reached 100%. Compared with the Western blot, the 2-step ELISA algorithm was simpler to execute in a reproducible fashion.⁵

The Infectious Diseases Society of America is revising its current guidelines, with an update expected late this year, which may shift the recommendation from 2-tiered testing to the 2-step ELISA algorithm.

Multiplex testing

To overcome the intrinsic problems of protein-based assays, a multiplexed, array-based assay for the diagnosis of tick-borne infections called Tick-Borne Disease Serochip (TBD-Serochip) was established using recombinant antigens that identify key immunodominant epitopes.⁸ More studies are needed to establish the validity and usefulness of these tests in clinical practice.

Who should not be tested?

The American College of Physicians⁶ recommends against testing in patients:

• Presenting with nonspecific symptoms (eg, headache, myalgia, fatigue, arthralgia) without objective signs of Lyme disease
• With low pretest probability of infection based on epidemiologic exposures and clinical features
• Living in Lyme-endemic areas with no history of tick exposure⁶
• Presenting less than 1 week after tick exposure⁵
• Seeking a test of cure for treated Lyme disease.

DIAGNOSIS IN SPECIAL SITUATIONS

Early Lyme disease

The classic erythema migrans lesion on physical examination of a patient with suspected Lyme disease is diagnostic and does not require laboratory confirmation.¹⁰

In ambiguous cases, 2-tiered testing of a serum sample during the acute presentation and again 4 to 6 weeks later can be useful. In patients who remain seronegative on paired serum samples despite symptoms lasting longer than 6 weeks and no antibiotic treatment in the interim, the diagnosis of Lyme disease is unlikely, and another diagnosis should be sought.³

Antimicrobial therapy may block the serologic response; hence, negative serologic testing in patients started on empiric antibiotics should not rule out Lyme disease.⁶

PCR or bacterial culture testing is not recommended in the evaluation of suspected early Lyme disease.

Central nervous system Lyme disease

Central nervous system Lyme disease is diagnosed by 2-tiered testing using peripheral blood samples because all patients with this infectious manifestation should have mounted an adequate IgG response in the blood.¹¹

B cells migrate to and proliferate inside the central nervous system, leading to intrathecal production of anti-Borrelia antibodies. An index of cerebrospinal fluid to serum antibody greater than 1 is thus also indicative of neuroborreliosis.¹² Thus, performing lumbar puncture to detect intrathecal production of antibodies may support the diagnosis of central nervous system Lyme disease; however, it is not necessary.¹¹

Antibodies persist in the central nervous system for many years after appropriate antimicrobial treatment.

Lyme arthritis

Articular involvement in Lyme disease is characterized by a robust humoral response such that a negative IgG serologic test virtually rules out Lyme arthritis.²³ PCR testing of synovial fluid for borrelial DNA has a sensitivity of 80% but may become falsely negative after 1 to 2 months of antibiotic treatment.^24,25 In an algorithm suggested by Puius et al,²³ PCR testing of synovial fluid should be done in patients who have minimal to no response after 2 months of appropriate oral antimicrobial therapy to determine whether intravenous antibiotics are merited.

Table 5 summarizes the tests of choice in different clinical stages of infection.

Acknowledgment: The authors would like to acknowledge Anita Modi, MD, and Ceena N. Jacob, MD, for reviewing the manuscript and providing valuable suggestions, and Belinda Yen-Lieberman, PhD, for contributing pictures of the Western blot test results.