Dermatology

Bacteria on children’s skin was similar to their mothers’ and affected by factors that included method of delivery and breastfeeding in a study of 154 children aged 10 years and younger.

Understanding the skin microbiome is important to determine whether certain bacteria may be helpful or harmful, but skin microbiome studies in children are limited, wrote Ting Zhu of Fudan University, Shanghai, China, and colleagues.

In a study published in the Journal of Investigative Dermatology, the researchers compared the skin microbiota of the 158 children aged 1-10 years and 50 mothers using 16S rRNA gene amplicon sequencing after collecting study samples from three skin areas: face, calf, and ventral forearm. The samples were pooled into 36 groups based on age, gender, and skin site.

“We observed significant differences in alpha diversity and the most prevalent taxa and identified factors that contributed to variation at each site,” the authors reported.

Overall, the “alpha diversity” – a measure of microbial diversity used in microbiome studies – of the skin microbiome increased with age, with the highest alpha diversity seen in the 10-year-olds (n = 28), notably on the face, but differences in alpha diversity between skin sites were seen only in the 1-year-olds (n = 26). Overall, the most commonly identified bacterial phyla at all skin sites in children were Proteobacteria (42%), Firmicutes (25%), Actinobacteria (13%), and Bacteroidetes (11%). In the three sites, the genera with high relative abundance (over 3%) included Streptococcus (13%), Enhydrobacter (6%), and Propionibacterium (5%). Of these, Streptococcus and Granulicatella showed negative linear correlations with age.

The researchers found significant differences between the bacterial communities of 10-year-olds delivered by Cesarean section and those delivered vaginally, particularly in the facial samples; however the difference wasn’t observed among face samples taken from 1-year-olds, according to the authors. They found significant variation in bacteria in calf samples based on whether the children were fed breast milk, formula, or a combination.

When the researchers examined the correlations between mother/child pairs, they found that the relative abundance of most bacteria in the children were more similar to their mothers than to unrelated adults, and they found the strongest correlations for the genera Deinococcus, Microbacterium, Chryseobacterium, Klebsiella, and Enhydrobacter. The relationships between the bacterial communities of mothers and children may be influenced by the shared living environment, topical products, and daily diet, they noted.

The study findings were limited by not controlling for certain variables, including daily diet, choice of topical products, bathing habits, and daily variation in environmental factors, the researchers wrote. However, the results show “that the skin microbiome is strongly affected by the surrounding microenvironment and that the alpha diversity of the skin microbiome increases during childhood,” they concluded.

The study was fully funded by Johnson & Johnson International, and several coauthors are employees of that company. Lead author Ms. Zhu had no financial conflicts to disclose.

SOURCE: Zhu T et al. J Invest Dermatol. 2019 August 13. doi: 10.1016/j.jid.2019.05.018.

Bacteria on children’s skin was similar to their mothers’ and affected by factors that included method of delivery and breastfeeding in a study of 154 children aged 10 years and younger.

Understanding the skin microbiome is important to determine whether certain bacteria may be helpful or harmful, but skin microbiome studies in children are limited, wrote Ting Zhu of Fudan University, Shanghai, China, and colleagues.

In a study published in the Journal of Investigative Dermatology, the researchers compared the skin microbiota of the 158 children aged 1-10 years and 50 mothers using 16S rRNA gene amplicon sequencing after collecting study samples from three skin areas: face, calf, and ventral forearm. The samples were pooled into 36 groups based on age, gender, and skin site.

“We observed significant differences in alpha diversity and the most prevalent taxa and identified factors that contributed to variation at each site,” the authors reported.

Overall, the “alpha diversity” – a measure of microbial diversity used in microbiome studies – of the skin microbiome increased with age, with the highest alpha diversity seen in the 10-year-olds (n = 28), notably on the face, but differences in alpha diversity between skin sites were seen only in the 1-year-olds (n = 26). Overall, the most commonly identified bacterial phyla at all skin sites in children were Proteobacteria (42%), Firmicutes (25%), Actinobacteria (13%), and Bacteroidetes (11%). In the three sites, the genera with high relative abundance (over 3%) included Streptococcus (13%), Enhydrobacter (6%), and Propionibacterium (5%). Of these, Streptococcus and Granulicatella showed negative linear correlations with age.

The researchers found significant differences between the bacterial communities of 10-year-olds delivered by Cesarean section and those delivered vaginally, particularly in the facial samples; however the difference wasn’t observed among face samples taken from 1-year-olds, according to the authors. They found significant variation in bacteria in calf samples based on whether the children were fed breast milk, formula, or a combination.

When the researchers examined the correlations between mother/child pairs, they found that the relative abundance of most bacteria in the children were more similar to their mothers than to unrelated adults, and they found the strongest correlations for the genera Deinococcus, Microbacterium, Chryseobacterium, Klebsiella, and Enhydrobacter. The relationships between the bacterial communities of mothers and children may be influenced by the shared living environment, topical products, and daily diet, they noted.

The study findings were limited by not controlling for certain variables, including daily diet, choice of topical products, bathing habits, and daily variation in environmental factors, the researchers wrote. However, the results show “that the skin microbiome is strongly affected by the surrounding microenvironment and that the alpha diversity of the skin microbiome increases during childhood,” they concluded.

The study was fully funded by Johnson & Johnson International, and several coauthors are employees of that company. Lead author Ms. Zhu had no financial conflicts to disclose.

SOURCE: Zhu T et al. J Invest Dermatol. 2019 August 13. doi: 10.1016/j.jid.2019.05.018.

Bacteria on children’s skin was similar to their mothers’ and affected by factors that included method of delivery and breastfeeding in a study of 154 children aged 10 years and younger.

Understanding the skin microbiome is important to determine whether certain bacteria may be helpful or harmful, but skin microbiome studies in children are limited, wrote Ting Zhu of Fudan University, Shanghai, China, and colleagues.

In a study published in the Journal of Investigative Dermatology, the researchers compared the skin microbiota of the 158 children aged 1-10 years and 50 mothers using 16S rRNA gene amplicon sequencing after collecting study samples from three skin areas: face, calf, and ventral forearm. The samples were pooled into 36 groups based on age, gender, and skin site.

“We observed significant differences in alpha diversity and the most prevalent taxa and identified factors that contributed to variation at each site,” the authors reported.

Overall, the “alpha diversity” – a measure of microbial diversity used in microbiome studies – of the skin microbiome increased with age, with the highest alpha diversity seen in the 10-year-olds (n = 28), notably on the face, but differences in alpha diversity between skin sites were seen only in the 1-year-olds (n = 26). Overall, the most commonly identified bacterial phyla at all skin sites in children were Proteobacteria (42%), Firmicutes (25%), Actinobacteria (13%), and Bacteroidetes (11%). In the three sites, the genera with high relative abundance (over 3%) included Streptococcus (13%), Enhydrobacter (6%), and Propionibacterium (5%). Of these, Streptococcus and Granulicatella showed negative linear correlations with age.

The researchers found significant differences between the bacterial communities of 10-year-olds delivered by Cesarean section and those delivered vaginally, particularly in the facial samples; however the difference wasn’t observed among face samples taken from 1-year-olds, according to the authors. They found significant variation in bacteria in calf samples based on whether the children were fed breast milk, formula, or a combination.

When the researchers examined the correlations between mother/child pairs, they found that the relative abundance of most bacteria in the children were more similar to their mothers than to unrelated adults, and they found the strongest correlations for the genera Deinococcus, Microbacterium, Chryseobacterium, Klebsiella, and Enhydrobacter. The relationships between the bacterial communities of mothers and children may be influenced by the shared living environment, topical products, and daily diet, they noted.

The study findings were limited by not controlling for certain variables, including daily diet, choice of topical products, bathing habits, and daily variation in environmental factors, the researchers wrote. However, the results show “that the skin microbiome is strongly affected by the surrounding microenvironment and that the alpha diversity of the skin microbiome increases during childhood,” they concluded.

The study was fully funded by Johnson & Johnson International, and several coauthors are employees of that company. Lead author Ms. Zhu had no financial conflicts to disclose.

SOURCE: Zhu T et al. J Invest Dermatol. 2019 August 13. doi: 10.1016/j.jid.2019.05.018.

Psoriasis is a systemic immune-mediated disorder characterized by erythematous, scaly, well-demarcated plaques on the skin that affects approximately 3% of the world’s population.¹ The disease is moderate to severe for approximately 1 in 6 individuals with psoriasis.² These patients, particularly those with symptoms that are refractory to topical therapy and/or phototherapy, can benefit from the use of biologic agents, which are monoclonal antibodies and fusion proteins engineered to inhibit the action of cytokines that drive psoriatic inflammation.

In February 2019, the American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) released an updated set of guidelines for the use of biologics in treating adult patients with psoriasis.³ The prior guidelines were released in 2008 when just 3 biologics—etanercept, infliximab, and adalimumab—were approved by the US Food and Drug Administration (FDA) for the management of psoriasis. These older recommendations were mostly based on studies of the efficacy and safety of biologics for patients with psoriatic arthritis.⁴ Over the last 11 years, 8 novel biologics have gained FDA approval, and numerous large phase 2 and phase 3 trials evaluating the risks and benefits of biologics have been conducted. The new guidelines contain considerably more detail and are based on evidence more specific to psoriasis rather than to psoriatic arthritis. Given the large repertoire of biologics available today and the increased amount of published research regarding each one, these guidelines may aid dermatologists in choosing the optimal biologic and managing therapy.

The AAD-NPF recommendations discuss the mechanism of action, efficacy, safety, and adverse events of the 10 biologics that have been FDA approved for the treatment of psoriasis as of March 2019, plus risankizumab, which was pending FDA approval at the time of publication and was later approved in April 2019. They also address dosing regimens, potential to combine biologics with other therapies, and different forms of psoriasis for which each may be effective.³ The purpose of this discussion is to present these guidelines in a condensed form to prescribers of biologic therapies and review the most clinically significant considerations during each step of treatment. Of note, we highlight only treatment of adult patients and do not discuss information relevant to risankizumab, as it was not FDA approved when the AAD-NPF guidelines were released.

Choosing a Biologic

Biologic therapy may be considered for patients with psoriasis that affects more than 3% of the body’s surface and is recalcitrant to localized therapies. There is no particular first-line biologic recommended for all patients with psoriasis; rather, choice of therapy should be individualized to the patient, considering factors such as body parts affected, comorbidities, lifestyle, and drug cost.

All 10 FDA-approved biologics (Table) have been ranked by the AAD and NPF as having grade A evidence for efficacy as monotherapy in the treatment of moderate to severe plaque-type psoriasis. Involvement of difficult-to-treat areas may be considered when choosing a specific therapy. The tumor necrosis factor α (TNF-α) inhibitors etanercept and adalimumab, the IL-17 inhibitor secukinumab, and the IL-23 inhibitor guselkumab have the greatest evidence for efficacy in treatment of nail disease. For scalp involvement, etanercept and guselkumab have the highest-quality evidence, and for palmoplantar disease, adalimumab, secukinumab, and guselkumab are considered the most effective. The TNF-α inhibitors are considered the optimal treatment option for concurrent psoriatic arthritis, though the IL-12/IL-23 inhibitor ustekinumab and the IL-17 inhibitors secukinumab and ixekizumab also have shown grade A evidence of efficacy. Of note, because TNF-α inhibitors received the earliest FDA approval, there is most evidence available for this class. Therapies with lower evidence quality for certain forms of psoriasis may show real-world effectiveness in individual patients, though more trials will be necessary to generate a body of evidence to change these clinical recommendations.

Overweight and obese patients also require unique considerations when choosing a biologic. Infliximab is the only approved psoriasis biologic that utilizes proportional-to-weight dosing and hence may be particularly efficacious in patients with higher body mass. Ustekinumab dosing also takes patient weight into consideration; patients heavier than 100 kg should receive 90-mg doses at initiation and during maintenance compared to 45 mg for patients who weigh 100 kg or less. Other approved biologics also may be utilized in these patients but may require closer monitoring of treatment efficacy.

There are few serious contraindications for specific biologic therapies. Any history of allergic reaction to a particular therapy is an absolute contraindication to its use. In patients for whom IL-17 inhibitor treatment is being considered, inflammatory bowel disease (IBD) should be ruled out given the likelihood that IL-17 could reactivate or worsen IBD. Of note, TNF-α inhibitors and ustekinumab are approved therapies for patients with IBD and may be recommended in patients with comorbid psoriasis. Phase 2 and phase 3 trials have found no reactivation or worsening of IBD in patients with psoriasis who were treated with the IL-23 inhibitor tildrakizumab,⁶ and phase 2 trials of treatment of IBD with guselkumab are currently underway (ClinicalTrials.gov Identifier NCT03466411). In patients with New York Heart Association class III and class IV congestive heart failure or multiple sclerosis, initiation of TNF-α inhibitors should be avoided. Among 3 phase 3 trials encompassing nearly 3000 patients treated with the IL-17 inhibitor brodalumab, a total of 3 patients died by suicide^7,8; hence, the FDA has issued a black box warning cautioning against use of this drug in patients with history of suicidal ideation or recent suicidal behavior. Although a causal relationship between brodalumab and suicide has not been well established,⁹ a thorough psychiatric history should be obtained in those initiating treatment with brodalumab.

Initiation of Therapy

Prior to initiating biologic therapy, it is important to obtain a complete blood cell count, complete metabolic panel, tuberculosis testing, and hepatitis B virus (HBV) and hepatitis C virus serologies. Testing for human immunodeficiency virus may be pursued at the clinician’s discretion. It is important to address any positive or concerning results prior to starting biologics. In patients with active infections, therapy may be initiated alongside guidance from an infectious disease specialist. Those with a positive purified protein derivative test, T-SPOT test, or QuantiFERON-TB Gold test must be referred for chest radiographs to rule out active tuberculosis. Patients with active HBV infection should receive appropriate referral to initiate antiviral therapy as well as core antibody testing, and those with active hepatitis C virus infection may only receive biologics under the combined discretion of a dermatologist and an appropriate specialist. Patients with human immunodeficiency virus must concurrently receive highly active antiretroviral therapy, show normal CD4⁺ T-cell count and undetectable viral load, and have no recent history of opportunistic infection.

Therapy should be commenced using specific dosing regimens, which are unique for each biologic (Table). Patients also must be educated on routine follow-up to assess treatment response and tolerability.

Assessment and Optimization of Treatment Response

Patients taking biologics may experience primary treatment failure, defined as lack of response to therapy from initiation. One predisposing factor may be increased body mass; patients who are overweight and obese are less likely to respond to standard regimens of TNF-α inhibitors and 45-mg dosing of ustekinumab. In most cases, however, the cause of primary nonresponse is unpredictable. For patients in whom therapy has failed within the recommended initial time frame (Table), dose escalation or shortening of dosing intervals may be pursued. Recommended dosing adjustments are outlined in the Table. Alternatively, patients may be switched to a different biologic.

If desired effectiveness is not reached with biologic monotherapy, topical corticosteroids, topical vitamin D analogues, or narrowband UVB light therapy may be concurrently used for difficult-to-treat areas. Evidence for safety and effectiveness of systemic adjuncts to biologics is moderate to low, warranting caution with their use. Methotrexate, cyclosporine, and apremilast have synergistic effects with biologics, though they may increase the risk for immunosuppression-related complications. Acitretin, an oral retinoid, likely is the most reasonable systemic adjunct to biologics because of its lack of immunosuppressive properties.

In patients with a suboptimal response to biologics, particularly those taking therapies that require frequent dosing, poor compliance should be considered.¹⁰ These patients may be switched to a biologic with less-frequent maintenance dosing (Table). Ustekinumab and tildrakizumab may be the best options for optimizing compliance, as they require dosing only once every 12 weeks after administration of loading doses.

Secondary treatment failure is diminished efficacy of treatment following successful initial response despite no changes in regimen. The best-known factor contributing to secondary nonresponse to biologics is the development of antidrug antibodies (ADAs), a phenomenon known as immunogenicity. The development of efficacy-limiting ADAs has been observed in response to most biologics, though ADAs against etanercept and guselkumab do not limit therapeutic response. Patients taking adalimumab and infliximab have particularly well-documented efficacy-limiting immunogenicity, and those who develop ADAs to infliximab are considered more prone to developing infusion reactions. Methotrexate, which limits antibody formation, may concomitantly be prescribed in patients who experience secondary treatment failure. It should be considered in all patients taking infliximab to increase efficacy and tolerability of therapy.

Considerations During Active Therapy

In addition to monitoring adherence and response to regimens, dermatologists must be heavily involved in counseling patients regarding the risks and adverse effects associated with these therapies. During maintenance therapy with biologics, patients must follow up with the prescriber at minimum every 3 to 6 months to evaluate for continued efficacy of treatment, extent of side effects, and effects of treatment on overall health and quality of life. Given the immunosuppressive effects of biologics, annual testing for tuberculosis should be considered in high-risk individuals. In those who are considered at low risk, tuberculosis testing may be done at the discretion of the dermatologist. In those with a history of HBV infection, HBV serologies should be pursued routinely given the risk for reactivation.

Annual screening for nonmelanoma skin cancer should be performed in all patients taking biologics. Tumor necrosis factor α inhibitor therapy in particular confers an elevated risk for cutaneous squamous cell carcinoma, especially in patients who are immunosuppressed at baseline and those with history of UV phototherapy. Use of acitretin alongside TNF-α inhibitors or ustekinumab may prevent squamous cell carcinoma formation in high-risk patients.

Because infliximab treatment poses an elevated risk of liver injury,¹¹ liver function tests should be repeated 3 months following initiation of treatment and then every 6 to 12 months subsequently if results are normal. Periodic assessment of suicidal ideation is recommended in patients on brodalumab therapy, which may necessitate more frequent follow-up visits and potentially psychiatry referrals in certain patients. Patients taking IL-17 inhibitors, particularly those who are concurrently taking methotrexate, are at increased risk for developing mucocutaneous Candida infections; these patients should be monitored for such infections and treated appropriately.¹²

It is additionally important for prescribing dermatologists to ensure that patients on biologics are following up with their general providers to receive timely age-appropriate preventative screenings and vaccines. Inactivated vaccinations may be administered during therapy with any biologic; however, live vaccinations may induce systemic infection in those who are immunocompromised, which theoretically includes individuals taking biologic agents, though incidence data in this patient population are scarce.¹³ Some experts believe that administration of live vaccines warrants temporary discontinuation of biologic therapy for 2 to 3 half-lives before and after vaccination (Table). Others recommend stopping treatment at least 4 weeks before and until 2 weeks after vaccination. For patients taking biologics with half-lives greater than 20 days, which would theoretically require stopping the drug 2 months prior to vaccination, the benefit of vaccination should be weighed against the risk of prolonged discontinuation of therapy. Until recently, this recommendation was particularly important, as a live herpes zoster vaccination was recommended by the Centers for Disease Control and Prevention for adults older than 60 years. In 2017, a new inactivated herpes zoster vaccine was introduced and is now the preferred vaccine for all patients older than 50 years.¹⁴ It is especially important that patients on biologics receive this vaccine to avoid temporary drug discontinuation.

Evidence that any particular class of biologics increases risk for solid tumors or lymphoreticular malignancy is limited. One case-control analysis reported that more than 12 months of treatment with TNF-α inhibitors may increase risk for malignancy; however, the confidence interval reported hardly allows for statistical significance.¹⁵ Another retrospective cohort study found no elevated incidence of cancer in patients on TNF-α inhibitors compared to nonbiologic comparators.¹⁶ Ustekinumab was shown to confer no increased risk for malignancy in 1 large study,¹⁵ but no large studies have been conducted for other classes of drugs. Given the limited and inconclusive evidence available, the guidelines recommend that age-appropriate cancer screenings recommended for the general population should be pursued in patients taking biologics.

Surgery while taking biologics may lead to stress-induced augmentation of immunosuppression, resulting in elevated risk of infection.¹⁷ Low-risk surgeries that do not warrant discontinuation of treatment include endoscopic, ophthalmologic, dermatologic, orthopedic, and breast procedures. In patients preparing for elective surgery in which respiratory, gastrointestinal, or genitourinary tracts will be entered, biologics may be discontinued at least 3 half-lives (Table) prior to surgery if the dermatologist and surgeon collaboratively deem that risk of infection outweighs benefit of continued therapy.¹⁸ Therapy may be resumed within 1 to 2 weeks postoperatively if there are no surgical complications.

Switching Biologics

Changing therapy to another biologic should be considered if there is no response to treatment or the patient experiences adverse effects while taking a particular biologic. Because evidence is limited regarding the ideal time frame between discontinuation of a prior medication and initiation of a new biologic, this interval should be determined at the discretion of the provider based on the patient’s disease severity and response to prior treatment. For individuals who experience primary or secondary treatment failure while maintaining appropriate dosing and treatment compliance, switching to a different biologic is recommended to maximize treatment response.¹⁹ Changing therapy to a biologic within the same class is generally effective,²⁰ and switching to a biologic with another mechanism of action should be considered if a class-specific adverse effect is the major reason for altering the regimen. Nonetheless, some patients may be unresponsive to biologic changes. Further research is necessary to determine which biologics may be most effective when previously used biologics have failed and particular factors that may predispose patients to biologic unresponsiveness.

Resuming Biologic Treatment Following Cessation

In cases where therapy is discontinued for any reason, it may be necessary to repeat initiation dosing when resuming treatment. In patients with severe or flaring disease or if more than 3 to 4 half-lives have passed since the most recent dose, it may be necessary to restart therapy with the loading dose (Table). Unfortunately, restarting therapy may preclude some patients from experiencing the maximal response that they attained prior to cessation. In such cases, switching biologic therapy to a different class may prove beneficial.

Final Thoughts

These recommendations contain valuable information that will assist dermatologists when initiating biologics and managing outcomes of their psoriasis patients. It is, however, crucial to bear in mind that these guidelines serve as merely a tool. Given the paucity of comprehensive research, particularly regarding some of the more recently approved therapies, there are many questions that are unanswered within the guidelines. Their utility for each individual patient situation is therefore limited, and clinical judgement may outweigh the information presented. The recommendations nevertheless provide a pivotal and unprecedented framework that promotes discourse among patients, dermatologists, and other providers to optimize the efficacy of biologic therapy for psoriasis.

Psoriasis is a systemic immune-mediated disorder characterized by erythematous, scaly, well-demarcated plaques on the skin that affects approximately 3% of the world’s population.¹ The disease is moderate to severe for approximately 1 in 6 individuals with psoriasis.² These patients, particularly those with symptoms that are refractory to topical therapy and/or phototherapy, can benefit from the use of biologic agents, which are monoclonal antibodies and fusion proteins engineered to inhibit the action of cytokines that drive psoriatic inflammation.

In February 2019, the American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) released an updated set of guidelines for the use of biologics in treating adult patients with psoriasis.³ The prior guidelines were released in 2008 when just 3 biologics—etanercept, infliximab, and adalimumab—were approved by the US Food and Drug Administration (FDA) for the management of psoriasis. These older recommendations were mostly based on studies of the efficacy and safety of biologics for patients with psoriatic arthritis.⁴ Over the last 11 years, 8 novel biologics have gained FDA approval, and numerous large phase 2 and phase 3 trials evaluating the risks and benefits of biologics have been conducted. The new guidelines contain considerably more detail and are based on evidence more specific to psoriasis rather than to psoriatic arthritis. Given the large repertoire of biologics available today and the increased amount of published research regarding each one, these guidelines may aid dermatologists in choosing the optimal biologic and managing therapy.

The AAD-NPF recommendations discuss the mechanism of action, efficacy, safety, and adverse events of the 10 biologics that have been FDA approved for the treatment of psoriasis as of March 2019, plus risankizumab, which was pending FDA approval at the time of publication and was later approved in April 2019. They also address dosing regimens, potential to combine biologics with other therapies, and different forms of psoriasis for which each may be effective.³ The purpose of this discussion is to present these guidelines in a condensed form to prescribers of biologic therapies and review the most clinically significant considerations during each step of treatment. Of note, we highlight only treatment of adult patients and do not discuss information relevant to risankizumab, as it was not FDA approved when the AAD-NPF guidelines were released.

Choosing a Biologic

Biologic therapy may be considered for patients with psoriasis that affects more than 3% of the body’s surface and is recalcitrant to localized therapies. There is no particular first-line biologic recommended for all patients with psoriasis; rather, choice of therapy should be individualized to the patient, considering factors such as body parts affected, comorbidities, lifestyle, and drug cost.

All 10 FDA-approved biologics (Table) have been ranked by the AAD and NPF as having grade A evidence for efficacy as monotherapy in the treatment of moderate to severe plaque-type psoriasis. Involvement of difficult-to-treat areas may be considered when choosing a specific therapy. The tumor necrosis factor α (TNF-α) inhibitors etanercept and adalimumab, the IL-17 inhibitor secukinumab, and the IL-23 inhibitor guselkumab have the greatest evidence for efficacy in treatment of nail disease. For scalp involvement, etanercept and guselkumab have the highest-quality evidence, and for palmoplantar disease, adalimumab, secukinumab, and guselkumab are considered the most effective. The TNF-α inhibitors are considered the optimal treatment option for concurrent psoriatic arthritis, though the IL-12/IL-23 inhibitor ustekinumab and the IL-17 inhibitors secukinumab and ixekizumab also have shown grade A evidence of efficacy. Of note, because TNF-α inhibitors received the earliest FDA approval, there is most evidence available for this class. Therapies with lower evidence quality for certain forms of psoriasis may show real-world effectiveness in individual patients, though more trials will be necessary to generate a body of evidence to change these clinical recommendations.

Overweight and obese patients also require unique considerations when choosing a biologic. Infliximab is the only approved psoriasis biologic that utilizes proportional-to-weight dosing and hence may be particularly efficacious in patients with higher body mass. Ustekinumab dosing also takes patient weight into consideration; patients heavier than 100 kg should receive 90-mg doses at initiation and during maintenance compared to 45 mg for patients who weigh 100 kg or less. Other approved biologics also may be utilized in these patients but may require closer monitoring of treatment efficacy.

There are few serious contraindications for specific biologic therapies. Any history of allergic reaction to a particular therapy is an absolute contraindication to its use. In patients for whom IL-17 inhibitor treatment is being considered, inflammatory bowel disease (IBD) should be ruled out given the likelihood that IL-17 could reactivate or worsen IBD. Of note, TNF-α inhibitors and ustekinumab are approved therapies for patients with IBD and may be recommended in patients with comorbid psoriasis. Phase 2 and phase 3 trials have found no reactivation or worsening of IBD in patients with psoriasis who were treated with the IL-23 inhibitor tildrakizumab,⁶ and phase 2 trials of treatment of IBD with guselkumab are currently underway (ClinicalTrials.gov Identifier NCT03466411). In patients with New York Heart Association class III and class IV congestive heart failure or multiple sclerosis, initiation of TNF-α inhibitors should be avoided. Among 3 phase 3 trials encompassing nearly 3000 patients treated with the IL-17 inhibitor brodalumab, a total of 3 patients died by suicide^7,8; hence, the FDA has issued a black box warning cautioning against use of this drug in patients with history of suicidal ideation or recent suicidal behavior. Although a causal relationship between brodalumab and suicide has not been well established,⁹ a thorough psychiatric history should be obtained in those initiating treatment with brodalumab.

Initiation of Therapy

Prior to initiating biologic therapy, it is important to obtain a complete blood cell count, complete metabolic panel, tuberculosis testing, and hepatitis B virus (HBV) and hepatitis C virus serologies. Testing for human immunodeficiency virus may be pursued at the clinician’s discretion. It is important to address any positive or concerning results prior to starting biologics. In patients with active infections, therapy may be initiated alongside guidance from an infectious disease specialist. Those with a positive purified protein derivative test, T-SPOT test, or QuantiFERON-TB Gold test must be referred for chest radiographs to rule out active tuberculosis. Patients with active HBV infection should receive appropriate referral to initiate antiviral therapy as well as core antibody testing, and those with active hepatitis C virus infection may only receive biologics under the combined discretion of a dermatologist and an appropriate specialist. Patients with human immunodeficiency virus must concurrently receive highly active antiretroviral therapy, show normal CD4⁺ T-cell count and undetectable viral load, and have no recent history of opportunistic infection.

Therapy should be commenced using specific dosing regimens, which are unique for each biologic (Table). Patients also must be educated on routine follow-up to assess treatment response and tolerability.

Assessment and Optimization of Treatment Response

Patients taking biologics may experience primary treatment failure, defined as lack of response to therapy from initiation. One predisposing factor may be increased body mass; patients who are overweight and obese are less likely to respond to standard regimens of TNF-α inhibitors and 45-mg dosing of ustekinumab. In most cases, however, the cause of primary nonresponse is unpredictable. For patients in whom therapy has failed within the recommended initial time frame (Table), dose escalation or shortening of dosing intervals may be pursued. Recommended dosing adjustments are outlined in the Table. Alternatively, patients may be switched to a different biologic.

If desired effectiveness is not reached with biologic monotherapy, topical corticosteroids, topical vitamin D analogues, or narrowband UVB light therapy may be concurrently used for difficult-to-treat areas. Evidence for safety and effectiveness of systemic adjuncts to biologics is moderate to low, warranting caution with their use. Methotrexate, cyclosporine, and apremilast have synergistic effects with biologics, though they may increase the risk for immunosuppression-related complications. Acitretin, an oral retinoid, likely is the most reasonable systemic adjunct to biologics because of its lack of immunosuppressive properties.

In patients with a suboptimal response to biologics, particularly those taking therapies that require frequent dosing, poor compliance should be considered.¹⁰ These patients may be switched to a biologic with less-frequent maintenance dosing (Table). Ustekinumab and tildrakizumab may be the best options for optimizing compliance, as they require dosing only once every 12 weeks after administration of loading doses.

Secondary treatment failure is diminished efficacy of treatment following successful initial response despite no changes in regimen. The best-known factor contributing to secondary nonresponse to biologics is the development of antidrug antibodies (ADAs), a phenomenon known as immunogenicity. The development of efficacy-limiting ADAs has been observed in response to most biologics, though ADAs against etanercept and guselkumab do not limit therapeutic response. Patients taking adalimumab and infliximab have particularly well-documented efficacy-limiting immunogenicity, and those who develop ADAs to infliximab are considered more prone to developing infusion reactions. Methotrexate, which limits antibody formation, may concomitantly be prescribed in patients who experience secondary treatment failure. It should be considered in all patients taking infliximab to increase efficacy and tolerability of therapy.

Considerations During Active Therapy

In addition to monitoring adherence and response to regimens, dermatologists must be heavily involved in counseling patients regarding the risks and adverse effects associated with these therapies. During maintenance therapy with biologics, patients must follow up with the prescriber at minimum every 3 to 6 months to evaluate for continued efficacy of treatment, extent of side effects, and effects of treatment on overall health and quality of life. Given the immunosuppressive effects of biologics, annual testing for tuberculosis should be considered in high-risk individuals. In those who are considered at low risk, tuberculosis testing may be done at the discretion of the dermatologist. In those with a history of HBV infection, HBV serologies should be pursued routinely given the risk for reactivation.

Annual screening for nonmelanoma skin cancer should be performed in all patients taking biologics. Tumor necrosis factor α inhibitor therapy in particular confers an elevated risk for cutaneous squamous cell carcinoma, especially in patients who are immunosuppressed at baseline and those with history of UV phototherapy. Use of acitretin alongside TNF-α inhibitors or ustekinumab may prevent squamous cell carcinoma formation in high-risk patients.

Because infliximab treatment poses an elevated risk of liver injury,¹¹ liver function tests should be repeated 3 months following initiation of treatment and then every 6 to 12 months subsequently if results are normal. Periodic assessment of suicidal ideation is recommended in patients on brodalumab therapy, which may necessitate more frequent follow-up visits and potentially psychiatry referrals in certain patients. Patients taking IL-17 inhibitors, particularly those who are concurrently taking methotrexate, are at increased risk for developing mucocutaneous Candida infections; these patients should be monitored for such infections and treated appropriately.¹²

It is additionally important for prescribing dermatologists to ensure that patients on biologics are following up with their general providers to receive timely age-appropriate preventative screenings and vaccines. Inactivated vaccinations may be administered during therapy with any biologic; however, live vaccinations may induce systemic infection in those who are immunocompromised, which theoretically includes individuals taking biologic agents, though incidence data in this patient population are scarce.¹³ Some experts believe that administration of live vaccines warrants temporary discontinuation of biologic therapy for 2 to 3 half-lives before and after vaccination (Table). Others recommend stopping treatment at least 4 weeks before and until 2 weeks after vaccination. For patients taking biologics with half-lives greater than 20 days, which would theoretically require stopping the drug 2 months prior to vaccination, the benefit of vaccination should be weighed against the risk of prolonged discontinuation of therapy. Until recently, this recommendation was particularly important, as a live herpes zoster vaccination was recommended by the Centers for Disease Control and Prevention for adults older than 60 years. In 2017, a new inactivated herpes zoster vaccine was introduced and is now the preferred vaccine for all patients older than 50 years.¹⁴ It is especially important that patients on biologics receive this vaccine to avoid temporary drug discontinuation.

Evidence that any particular class of biologics increases risk for solid tumors or lymphoreticular malignancy is limited. One case-control analysis reported that more than 12 months of treatment with TNF-α inhibitors may increase risk for malignancy; however, the confidence interval reported hardly allows for statistical significance.¹⁵ Another retrospective cohort study found no elevated incidence of cancer in patients on TNF-α inhibitors compared to nonbiologic comparators.¹⁶ Ustekinumab was shown to confer no increased risk for malignancy in 1 large study,¹⁵ but no large studies have been conducted for other classes of drugs. Given the limited and inconclusive evidence available, the guidelines recommend that age-appropriate cancer screenings recommended for the general population should be pursued in patients taking biologics.

Surgery while taking biologics may lead to stress-induced augmentation of immunosuppression, resulting in elevated risk of infection.¹⁷ Low-risk surgeries that do not warrant discontinuation of treatment include endoscopic, ophthalmologic, dermatologic, orthopedic, and breast procedures. In patients preparing for elective surgery in which respiratory, gastrointestinal, or genitourinary tracts will be entered, biologics may be discontinued at least 3 half-lives (Table) prior to surgery if the dermatologist and surgeon collaboratively deem that risk of infection outweighs benefit of continued therapy.¹⁸ Therapy may be resumed within 1 to 2 weeks postoperatively if there are no surgical complications.

Switching Biologics

Changing therapy to another biologic should be considered if there is no response to treatment or the patient experiences adverse effects while taking a particular biologic. Because evidence is limited regarding the ideal time frame between discontinuation of a prior medication and initiation of a new biologic, this interval should be determined at the discretion of the provider based on the patient’s disease severity and response to prior treatment. For individuals who experience primary or secondary treatment failure while maintaining appropriate dosing and treatment compliance, switching to a different biologic is recommended to maximize treatment response.¹⁹ Changing therapy to a biologic within the same class is generally effective,²⁰ and switching to a biologic with another mechanism of action should be considered if a class-specific adverse effect is the major reason for altering the regimen. Nonetheless, some patients may be unresponsive to biologic changes. Further research is necessary to determine which biologics may be most effective when previously used biologics have failed and particular factors that may predispose patients to biologic unresponsiveness.

Resuming Biologic Treatment Following Cessation

In cases where therapy is discontinued for any reason, it may be necessary to repeat initiation dosing when resuming treatment. In patients with severe or flaring disease or if more than 3 to 4 half-lives have passed since the most recent dose, it may be necessary to restart therapy with the loading dose (Table). Unfortunately, restarting therapy may preclude some patients from experiencing the maximal response that they attained prior to cessation. In such cases, switching biologic therapy to a different class may prove beneficial.

Final Thoughts

These recommendations contain valuable information that will assist dermatologists when initiating biologics and managing outcomes of their psoriasis patients. It is, however, crucial to bear in mind that these guidelines serve as merely a tool. Given the paucity of comprehensive research, particularly regarding some of the more recently approved therapies, there are many questions that are unanswered within the guidelines. Their utility for each individual patient situation is therefore limited, and clinical judgement may outweigh the information presented. The recommendations nevertheless provide a pivotal and unprecedented framework that promotes discourse among patients, dermatologists, and other providers to optimize the efficacy of biologic therapy for psoriasis.

Psoriasis is a systemic immune-mediated disorder characterized by erythematous, scaly, well-demarcated plaques on the skin that affects approximately 3% of the world’s population.¹ The disease is moderate to severe for approximately 1 in 6 individuals with psoriasis.² These patients, particularly those with symptoms that are refractory to topical therapy and/or phototherapy, can benefit from the use of biologic agents, which are monoclonal antibodies and fusion proteins engineered to inhibit the action of cytokines that drive psoriatic inflammation.

In February 2019, the American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) released an updated set of guidelines for the use of biologics in treating adult patients with psoriasis.³ The prior guidelines were released in 2008 when just 3 biologics—etanercept, infliximab, and adalimumab—were approved by the US Food and Drug Administration (FDA) for the management of psoriasis. These older recommendations were mostly based on studies of the efficacy and safety of biologics for patients with psoriatic arthritis.⁴ Over the last 11 years, 8 novel biologics have gained FDA approval, and numerous large phase 2 and phase 3 trials evaluating the risks and benefits of biologics have been conducted. The new guidelines contain considerably more detail and are based on evidence more specific to psoriasis rather than to psoriatic arthritis. Given the large repertoire of biologics available today and the increased amount of published research regarding each one, these guidelines may aid dermatologists in choosing the optimal biologic and managing therapy.

The AAD-NPF recommendations discuss the mechanism of action, efficacy, safety, and adverse events of the 10 biologics that have been FDA approved for the treatment of psoriasis as of March 2019, plus risankizumab, which was pending FDA approval at the time of publication and was later approved in April 2019. They also address dosing regimens, potential to combine biologics with other therapies, and different forms of psoriasis for which each may be effective.³ The purpose of this discussion is to present these guidelines in a condensed form to prescribers of biologic therapies and review the most clinically significant considerations during each step of treatment. Of note, we highlight only treatment of adult patients and do not discuss information relevant to risankizumab, as it was not FDA approved when the AAD-NPF guidelines were released.

Choosing a Biologic

Biologic therapy may be considered for patients with psoriasis that affects more than 3% of the body’s surface and is recalcitrant to localized therapies. There is no particular first-line biologic recommended for all patients with psoriasis; rather, choice of therapy should be individualized to the patient, considering factors such as body parts affected, comorbidities, lifestyle, and drug cost.

All 10 FDA-approved biologics (Table) have been ranked by the AAD and NPF as having grade A evidence for efficacy as monotherapy in the treatment of moderate to severe plaque-type psoriasis. Involvement of difficult-to-treat areas may be considered when choosing a specific therapy. The tumor necrosis factor α (TNF-α) inhibitors etanercept and adalimumab, the IL-17 inhibitor secukinumab, and the IL-23 inhibitor guselkumab have the greatest evidence for efficacy in treatment of nail disease. For scalp involvement, etanercept and guselkumab have the highest-quality evidence, and for palmoplantar disease, adalimumab, secukinumab, and guselkumab are considered the most effective. The TNF-α inhibitors are considered the optimal treatment option for concurrent psoriatic arthritis, though the IL-12/IL-23 inhibitor ustekinumab and the IL-17 inhibitors secukinumab and ixekizumab also have shown grade A evidence of efficacy. Of note, because TNF-α inhibitors received the earliest FDA approval, there is most evidence available for this class. Therapies with lower evidence quality for certain forms of psoriasis may show real-world effectiveness in individual patients, though more trials will be necessary to generate a body of evidence to change these clinical recommendations.

Overweight and obese patients also require unique considerations when choosing a biologic. Infliximab is the only approved psoriasis biologic that utilizes proportional-to-weight dosing and hence may be particularly efficacious in patients with higher body mass. Ustekinumab dosing also takes patient weight into consideration; patients heavier than 100 kg should receive 90-mg doses at initiation and during maintenance compared to 45 mg for patients who weigh 100 kg or less. Other approved biologics also may be utilized in these patients but may require closer monitoring of treatment efficacy.

There are few serious contraindications for specific biologic therapies. Any history of allergic reaction to a particular therapy is an absolute contraindication to its use. In patients for whom IL-17 inhibitor treatment is being considered, inflammatory bowel disease (IBD) should be ruled out given the likelihood that IL-17 could reactivate or worsen IBD. Of note, TNF-α inhibitors and ustekinumab are approved therapies for patients with IBD and may be recommended in patients with comorbid psoriasis. Phase 2 and phase 3 trials have found no reactivation or worsening of IBD in patients with psoriasis who were treated with the IL-23 inhibitor tildrakizumab,⁶ and phase 2 trials of treatment of IBD with guselkumab are currently underway (ClinicalTrials.gov Identifier NCT03466411). In patients with New York Heart Association class III and class IV congestive heart failure or multiple sclerosis, initiation of TNF-α inhibitors should be avoided. Among 3 phase 3 trials encompassing nearly 3000 patients treated with the IL-17 inhibitor brodalumab, a total of 3 patients died by suicide^7,8; hence, the FDA has issued a black box warning cautioning against use of this drug in patients with history of suicidal ideation or recent suicidal behavior. Although a causal relationship between brodalumab and suicide has not been well established,⁹ a thorough psychiatric history should be obtained in those initiating treatment with brodalumab.

Initiation of Therapy

Prior to initiating biologic therapy, it is important to obtain a complete blood cell count, complete metabolic panel, tuberculosis testing, and hepatitis B virus (HBV) and hepatitis C virus serologies. Testing for human immunodeficiency virus may be pursued at the clinician’s discretion. It is important to address any positive or concerning results prior to starting biologics. In patients with active infections, therapy may be initiated alongside guidance from an infectious disease specialist. Those with a positive purified protein derivative test, T-SPOT test, or QuantiFERON-TB Gold test must be referred for chest radiographs to rule out active tuberculosis. Patients with active HBV infection should receive appropriate referral to initiate antiviral therapy as well as core antibody testing, and those with active hepatitis C virus infection may only receive biologics under the combined discretion of a dermatologist and an appropriate specialist. Patients with human immunodeficiency virus must concurrently receive highly active antiretroviral therapy, show normal CD4⁺ T-cell count and undetectable viral load, and have no recent history of opportunistic infection.

Therapy should be commenced using specific dosing regimens, which are unique for each biologic (Table). Patients also must be educated on routine follow-up to assess treatment response and tolerability.

Assessment and Optimization of Treatment Response

Patients taking biologics may experience primary treatment failure, defined as lack of response to therapy from initiation. One predisposing factor may be increased body mass; patients who are overweight and obese are less likely to respond to standard regimens of TNF-α inhibitors and 45-mg dosing of ustekinumab. In most cases, however, the cause of primary nonresponse is unpredictable. For patients in whom therapy has failed within the recommended initial time frame (Table), dose escalation or shortening of dosing intervals may be pursued. Recommended dosing adjustments are outlined in the Table. Alternatively, patients may be switched to a different biologic.

If desired effectiveness is not reached with biologic monotherapy, topical corticosteroids, topical vitamin D analogues, or narrowband UVB light therapy may be concurrently used for difficult-to-treat areas. Evidence for safety and effectiveness of systemic adjuncts to biologics is moderate to low, warranting caution with their use. Methotrexate, cyclosporine, and apremilast have synergistic effects with biologics, though they may increase the risk for immunosuppression-related complications. Acitretin, an oral retinoid, likely is the most reasonable systemic adjunct to biologics because of its lack of immunosuppressive properties.

In patients with a suboptimal response to biologics, particularly those taking therapies that require frequent dosing, poor compliance should be considered.¹⁰ These patients may be switched to a biologic with less-frequent maintenance dosing (Table). Ustekinumab and tildrakizumab may be the best options for optimizing compliance, as they require dosing only once every 12 weeks after administration of loading doses.

Secondary treatment failure is diminished efficacy of treatment following successful initial response despite no changes in regimen. The best-known factor contributing to secondary nonresponse to biologics is the development of antidrug antibodies (ADAs), a phenomenon known as immunogenicity. The development of efficacy-limiting ADAs has been observed in response to most biologics, though ADAs against etanercept and guselkumab do not limit therapeutic response. Patients taking adalimumab and infliximab have particularly well-documented efficacy-limiting immunogenicity, and those who develop ADAs to infliximab are considered more prone to developing infusion reactions. Methotrexate, which limits antibody formation, may concomitantly be prescribed in patients who experience secondary treatment failure. It should be considered in all patients taking infliximab to increase efficacy and tolerability of therapy.

Considerations During Active Therapy

In addition to monitoring adherence and response to regimens, dermatologists must be heavily involved in counseling patients regarding the risks and adverse effects associated with these therapies. During maintenance therapy with biologics, patients must follow up with the prescriber at minimum every 3 to 6 months to evaluate for continued efficacy of treatment, extent of side effects, and effects of treatment on overall health and quality of life. Given the immunosuppressive effects of biologics, annual testing for tuberculosis should be considered in high-risk individuals. In those who are considered at low risk, tuberculosis testing may be done at the discretion of the dermatologist. In those with a history of HBV infection, HBV serologies should be pursued routinely given the risk for reactivation.

Annual screening for nonmelanoma skin cancer should be performed in all patients taking biologics. Tumor necrosis factor α inhibitor therapy in particular confers an elevated risk for cutaneous squamous cell carcinoma, especially in patients who are immunosuppressed at baseline and those with history of UV phototherapy. Use of acitretin alongside TNF-α inhibitors or ustekinumab may prevent squamous cell carcinoma formation in high-risk patients.

Because infliximab treatment poses an elevated risk of liver injury,¹¹ liver function tests should be repeated 3 months following initiation of treatment and then every 6 to 12 months subsequently if results are normal. Periodic assessment of suicidal ideation is recommended in patients on brodalumab therapy, which may necessitate more frequent follow-up visits and potentially psychiatry referrals in certain patients. Patients taking IL-17 inhibitors, particularly those who are concurrently taking methotrexate, are at increased risk for developing mucocutaneous Candida infections; these patients should be monitored for such infections and treated appropriately.¹²

It is additionally important for prescribing dermatologists to ensure that patients on biologics are following up with their general providers to receive timely age-appropriate preventative screenings and vaccines. Inactivated vaccinations may be administered during therapy with any biologic; however, live vaccinations may induce systemic infection in those who are immunocompromised, which theoretically includes individuals taking biologic agents, though incidence data in this patient population are scarce.¹³ Some experts believe that administration of live vaccines warrants temporary discontinuation of biologic therapy for 2 to 3 half-lives before and after vaccination (Table). Others recommend stopping treatment at least 4 weeks before and until 2 weeks after vaccination. For patients taking biologics with half-lives greater than 20 days, which would theoretically require stopping the drug 2 months prior to vaccination, the benefit of vaccination should be weighed against the risk of prolonged discontinuation of therapy. Until recently, this recommendation was particularly important, as a live herpes zoster vaccination was recommended by the Centers for Disease Control and Prevention for adults older than 60 years. In 2017, a new inactivated herpes zoster vaccine was introduced and is now the preferred vaccine for all patients older than 50 years.¹⁴ It is especially important that patients on biologics receive this vaccine to avoid temporary drug discontinuation.

Evidence that any particular class of biologics increases risk for solid tumors or lymphoreticular malignancy is limited. One case-control analysis reported that more than 12 months of treatment with TNF-α inhibitors may increase risk for malignancy; however, the confidence interval reported hardly allows for statistical significance.¹⁵ Another retrospective cohort study found no elevated incidence of cancer in patients on TNF-α inhibitors compared to nonbiologic comparators.¹⁶ Ustekinumab was shown to confer no increased risk for malignancy in 1 large study,¹⁵ but no large studies have been conducted for other classes of drugs. Given the limited and inconclusive evidence available, the guidelines recommend that age-appropriate cancer screenings recommended for the general population should be pursued in patients taking biologics.

Surgery while taking biologics may lead to stress-induced augmentation of immunosuppression, resulting in elevated risk of infection.¹⁷ Low-risk surgeries that do not warrant discontinuation of treatment include endoscopic, ophthalmologic, dermatologic, orthopedic, and breast procedures. In patients preparing for elective surgery in which respiratory, gastrointestinal, or genitourinary tracts will be entered, biologics may be discontinued at least 3 half-lives (Table) prior to surgery if the dermatologist and surgeon collaboratively deem that risk of infection outweighs benefit of continued therapy.¹⁸ Therapy may be resumed within 1 to 2 weeks postoperatively if there are no surgical complications.

Switching Biologics

Changing therapy to another biologic should be considered if there is no response to treatment or the patient experiences adverse effects while taking a particular biologic. Because evidence is limited regarding the ideal time frame between discontinuation of a prior medication and initiation of a new biologic, this interval should be determined at the discretion of the provider based on the patient’s disease severity and response to prior treatment. For individuals who experience primary or secondary treatment failure while maintaining appropriate dosing and treatment compliance, switching to a different biologic is recommended to maximize treatment response.¹⁹ Changing therapy to a biologic within the same class is generally effective,²⁰ and switching to a biologic with another mechanism of action should be considered if a class-specific adverse effect is the major reason for altering the regimen. Nonetheless, some patients may be unresponsive to biologic changes. Further research is necessary to determine which biologics may be most effective when previously used biologics have failed and particular factors that may predispose patients to biologic unresponsiveness.

Resuming Biologic Treatment Following Cessation

In cases where therapy is discontinued for any reason, it may be necessary to repeat initiation dosing when resuming treatment. In patients with severe or flaring disease or if more than 3 to 4 half-lives have passed since the most recent dose, it may be necessary to restart therapy with the loading dose (Table). Unfortunately, restarting therapy may preclude some patients from experiencing the maximal response that they attained prior to cessation. In such cases, switching biologic therapy to a different class may prove beneficial.

Final Thoughts

These recommendations contain valuable information that will assist dermatologists when initiating biologics and managing outcomes of their psoriasis patients. It is, however, crucial to bear in mind that these guidelines serve as merely a tool. Given the paucity of comprehensive research, particularly regarding some of the more recently approved therapies, there are many questions that are unanswered within the guidelines. Their utility for each individual patient situation is therefore limited, and clinical judgement may outweigh the information presented. The recommendations nevertheless provide a pivotal and unprecedented framework that promotes discourse among patients, dermatologists, and other providers to optimize the efficacy of biologic therapy for psoriasis.

AUSTIN, TEX. – Adolescents with moderate to severe atopic dermatitis who used dupilumab experienced significant improvements in signs and symptoms of the condition, with minimal safety concerns, according to results of a phase 3 study.

Doug Brunk/MDedge News

“Dupilumab works as effectively in adolescents as in adults,” Randy Prescilla, MD, one of the study authors, said in an interview at the annual meeting of the Society for Pediatric Dermatology. “It gives us promise that we could go into other age groups with the same optimism. We are enrolling patients in even younger age groups.”

The double-blind, placebo-controlled study analyzed the efficacy and safety of dupilumab monotherapy in patients between the ages of 12 and 17 years with moderate to severe atopic dermatitis (AD) inadequately controlled with topical therapies. In the United States, dupilumab is approved for those aged 12 years and older with moderate to severe disease inadequately controlled by topical prescription treatments or when those therapies are not advisable.

For the 16-week study, Dr. Prescilla, global medical affairs director of pediatric dermatology for Sanofi Genzyme, and colleagues randomized 251 patients to one of three groups: dupilumab every 2 weeks (200 mg if baseline weight was less than 60 kg; 300 mg if that weight was 60 kg or more); 300 mg dupilumab every 4 weeks; or placebo every 2 weeks.

At week 16, a significantly higher proportion of patients in the two drug treatment groups had Investigator’s Global Assessment scores of 0/1, compared with those in the placebo group (24.4%, 17.9%, and 2.4%) as well as a significantly higher percentage of patients who achieved at least a 75% improvement in the Eczema Area and Severity Index (EASI-75) score (41.5%, 38.1%, and 8.2%).

In addition, patients in the two drug treatment groups experienced improved percent change in least square-means on the EASI from baseline to week 16, compared with those in the placebo group (–65.9%, –64.8%, and –23.6%), the Peak Pruritus Numerical Rating Scale (–47.9%, –45.5%, and –19.0%), body surface area affected by AD (–30.1%, –33.4%, and –11.7%), and in the SCORing AD clinical tool (P less than .001 for all comparisons).


Between baseline and week 16, scores on the Children’s Dermatology Life Quality Index and Patient-Oriented Eczema Measure improved significantly in the two dupilumab groups, compared with the placebo group. The rate of skin infection was higher in the placebo group (20%), compared with 11% in the group that received dupilumab every 2 weeks and 13.3% in the group receiving the drug every 4 weeks.

Conjunctivitis occurred more frequently with dupilumab treatment (9.8% in the every-2-weeks dupilumab group, 10.8% in the every-4-weeks dupilumab group, and 4.7% in the placebo group) as did injection site reactions (8.5%, 6.0%, and 3.5%). Two adverse events, one of which was serious, occurred in the placebo group.

Dr. Prescilla acknowledged certain limitations of the study, including its small sample size and the fact that it was limited to 16 weeks. “However, smaller sample size and duration are typical for this type of study and in line with the study design of the SOLO 1 and SOLO 2 studies in adults,” he said.

On Aug. 6, the European Commission extended the marketing authorization for dupilumab in the European Union to include adolescents 12-17 years of age with moderate to severe atopic dermatitis who are candidates for systemic therapy. On the same day, Sanofi Genzyme and Regeneron announced positive topline results in a phase 3 trial in children aged 6-11 years with severe AD.

The study’s principal investigator was Amy S. Paller, MD. The study was funded by Sanofi Genzyme and Regeneron. Dr. Prescilla is an employee of Sanofi Genzyme.

[email protected]

AUSTIN, TEX. – Adolescents with moderate to severe atopic dermatitis who used dupilumab experienced significant improvements in signs and symptoms of the condition, with minimal safety concerns, according to results of a phase 3 study.

Doug Brunk/MDedge News

“Dupilumab works as effectively in adolescents as in adults,” Randy Prescilla, MD, one of the study authors, said in an interview at the annual meeting of the Society for Pediatric Dermatology. “It gives us promise that we could go into other age groups with the same optimism. We are enrolling patients in even younger age groups.”

The double-blind, placebo-controlled study analyzed the efficacy and safety of dupilumab monotherapy in patients between the ages of 12 and 17 years with moderate to severe atopic dermatitis (AD) inadequately controlled with topical therapies. In the United States, dupilumab is approved for those aged 12 years and older with moderate to severe disease inadequately controlled by topical prescription treatments or when those therapies are not advisable.

For the 16-week study, Dr. Prescilla, global medical affairs director of pediatric dermatology for Sanofi Genzyme, and colleagues randomized 251 patients to one of three groups: dupilumab every 2 weeks (200 mg if baseline weight was less than 60 kg; 300 mg if that weight was 60 kg or more); 300 mg dupilumab every 4 weeks; or placebo every 2 weeks.

At week 16, a significantly higher proportion of patients in the two drug treatment groups had Investigator’s Global Assessment scores of 0/1, compared with those in the placebo group (24.4%, 17.9%, and 2.4%) as well as a significantly higher percentage of patients who achieved at least a 75% improvement in the Eczema Area and Severity Index (EASI-75) score (41.5%, 38.1%, and 8.2%).

In addition, patients in the two drug treatment groups experienced improved percent change in least square-means on the EASI from baseline to week 16, compared with those in the placebo group (–65.9%, –64.8%, and –23.6%), the Peak Pruritus Numerical Rating Scale (–47.9%, –45.5%, and –19.0%), body surface area affected by AD (–30.1%, –33.4%, and –11.7%), and in the SCORing AD clinical tool (P less than .001 for all comparisons).


Between baseline and week 16, scores on the Children’s Dermatology Life Quality Index and Patient-Oriented Eczema Measure improved significantly in the two dupilumab groups, compared with the placebo group. The rate of skin infection was higher in the placebo group (20%), compared with 11% in the group that received dupilumab every 2 weeks and 13.3% in the group receiving the drug every 4 weeks.

Conjunctivitis occurred more frequently with dupilumab treatment (9.8% in the every-2-weeks dupilumab group, 10.8% in the every-4-weeks dupilumab group, and 4.7% in the placebo group) as did injection site reactions (8.5%, 6.0%, and 3.5%). Two adverse events, one of which was serious, occurred in the placebo group.

Dr. Prescilla acknowledged certain limitations of the study, including its small sample size and the fact that it was limited to 16 weeks. “However, smaller sample size and duration are typical for this type of study and in line with the study design of the SOLO 1 and SOLO 2 studies in adults,” he said.

On Aug. 6, the European Commission extended the marketing authorization for dupilumab in the European Union to include adolescents 12-17 years of age with moderate to severe atopic dermatitis who are candidates for systemic therapy. On the same day, Sanofi Genzyme and Regeneron announced positive topline results in a phase 3 trial in children aged 6-11 years with severe AD.

The study’s principal investigator was Amy S. Paller, MD. The study was funded by Sanofi Genzyme and Regeneron. Dr. Prescilla is an employee of Sanofi Genzyme.

[email protected]

AUSTIN, TEX. – Adolescents with moderate to severe atopic dermatitis who used dupilumab experienced significant improvements in signs and symptoms of the condition, with minimal safety concerns, according to results of a phase 3 study.

Doug Brunk/MDedge News

“Dupilumab works as effectively in adolescents as in adults,” Randy Prescilla, MD, one of the study authors, said in an interview at the annual meeting of the Society for Pediatric Dermatology. “It gives us promise that we could go into other age groups with the same optimism. We are enrolling patients in even younger age groups.”

The double-blind, placebo-controlled study analyzed the efficacy and safety of dupilumab monotherapy in patients between the ages of 12 and 17 years with moderate to severe atopic dermatitis (AD) inadequately controlled with topical therapies. In the United States, dupilumab is approved for those aged 12 years and older with moderate to severe disease inadequately controlled by topical prescription treatments or when those therapies are not advisable.

For the 16-week study, Dr. Prescilla, global medical affairs director of pediatric dermatology for Sanofi Genzyme, and colleagues randomized 251 patients to one of three groups: dupilumab every 2 weeks (200 mg if baseline weight was less than 60 kg; 300 mg if that weight was 60 kg or more); 300 mg dupilumab every 4 weeks; or placebo every 2 weeks.

At week 16, a significantly higher proportion of patients in the two drug treatment groups had Investigator’s Global Assessment scores of 0/1, compared with those in the placebo group (24.4%, 17.9%, and 2.4%) as well as a significantly higher percentage of patients who achieved at least a 75% improvement in the Eczema Area and Severity Index (EASI-75) score (41.5%, 38.1%, and 8.2%).

In addition, patients in the two drug treatment groups experienced improved percent change in least square-means on the EASI from baseline to week 16, compared with those in the placebo group (–65.9%, –64.8%, and –23.6%), the Peak Pruritus Numerical Rating Scale (–47.9%, –45.5%, and –19.0%), body surface area affected by AD (–30.1%, –33.4%, and –11.7%), and in the SCORing AD clinical tool (P less than .001 for all comparisons).


Between baseline and week 16, scores on the Children’s Dermatology Life Quality Index and Patient-Oriented Eczema Measure improved significantly in the two dupilumab groups, compared with the placebo group. The rate of skin infection was higher in the placebo group (20%), compared with 11% in the group that received dupilumab every 2 weeks and 13.3% in the group receiving the drug every 4 weeks.

Conjunctivitis occurred more frequently with dupilumab treatment (9.8% in the every-2-weeks dupilumab group, 10.8% in the every-4-weeks dupilumab group, and 4.7% in the placebo group) as did injection site reactions (8.5%, 6.0%, and 3.5%). Two adverse events, one of which was serious, occurred in the placebo group.

Dr. Prescilla acknowledged certain limitations of the study, including its small sample size and the fact that it was limited to 16 weeks. “However, smaller sample size and duration are typical for this type of study and in line with the study design of the SOLO 1 and SOLO 2 studies in adults,” he said.

On Aug. 6, the European Commission extended the marketing authorization for dupilumab in the European Union to include adolescents 12-17 years of age with moderate to severe atopic dermatitis who are candidates for systemic therapy. On the same day, Sanofi Genzyme and Regeneron announced positive topline results in a phase 3 trial in children aged 6-11 years with severe AD.

The study’s principal investigator was Amy S. Paller, MD. The study was funded by Sanofi Genzyme and Regeneron. Dr. Prescilla is an employee of Sanofi Genzyme.

[email protected]

Psoriasis is associated with systemic inflammation, which heightens the risk of blood vessel disease and diabetes. Therefore, the finding, while notable, may not have been entirely unexpected. Biologic therapy (BT) for psoriasis was already found to be favorably associated with luminal coronary plaque, the researchers say, but it was not clear whether those associations were attributable to direct anti-inflammatory effects on the coronary arteries. They wanted to find out whether the perivascular fat attenuation index (FAI) would offer clues. FAI is a new method of analyzing CT scans by assessing whether the fat tissue surrounding arteries becomes attenuated, or less fatty.

The researchers investigated their premise in 134 participants from an ongoing NIH study, the Psoriasis Atherosclerosis Cardiometabolic Initiative cohort. Of the participants, 82 had been receiving anti-tumor necrosis factor α, anti-interleukin (IL) 12/23, or anti-IL-17 for 1 year. The remaining 52 had not received any BT, and given topical or light therapy. The patients underwent CT scans at the start of the study and 1 year later. All of the patients had low cardiovascular risk. At baseline, 27 in the treated group and 19 in the untreated group had a focal coronary atherosclerotic plaque.

The study found that an abnormal perivascular FAI was linked to a 6- to 9-fold increased risk of major adverse cardiovascular events, study coauthor Charalambos Antoniades, MD, says. Patients on BT had a significant decrease in FAI at 1 year, as well as improved psoriasis symptoms. Even patients with preexisting coronary artery plaque had a reduction in coronary inflammation after BT. No change was seen in the untreated patients. The associations with FAI were independent of the presence of coronary plaque and were consistent among patients receiving different biologic agents.

The researchers say their findings have implications for other chronic inflammatory diseases, such as lupus and rheumatoid arthritis, which are known to raise the risk for heart attacks and stroke.

Psoriasis is associated with systemic inflammation, which heightens the risk of blood vessel disease and diabetes. Therefore, the finding, while notable, may not have been entirely unexpected. Biologic therapy (BT) for psoriasis was already found to be favorably associated with luminal coronary plaque, the researchers say, but it was not clear whether those associations were attributable to direct anti-inflammatory effects on the coronary arteries. They wanted to find out whether the perivascular fat attenuation index (FAI) would offer clues. FAI is a new method of analyzing CT scans by assessing whether the fat tissue surrounding arteries becomes attenuated, or less fatty.

The researchers investigated their premise in 134 participants from an ongoing NIH study, the Psoriasis Atherosclerosis Cardiometabolic Initiative cohort. Of the participants, 82 had been receiving anti-tumor necrosis factor α, anti-interleukin (IL) 12/23, or anti-IL-17 for 1 year. The remaining 52 had not received any BT, and given topical or light therapy. The patients underwent CT scans at the start of the study and 1 year later. All of the patients had low cardiovascular risk. At baseline, 27 in the treated group and 19 in the untreated group had a focal coronary atherosclerotic plaque.

The study found that an abnormal perivascular FAI was linked to a 6- to 9-fold increased risk of major adverse cardiovascular events, study coauthor Charalambos Antoniades, MD, says. Patients on BT had a significant decrease in FAI at 1 year, as well as improved psoriasis symptoms. Even patients with preexisting coronary artery plaque had a reduction in coronary inflammation after BT. No change was seen in the untreated patients. The associations with FAI were independent of the presence of coronary plaque and were consistent among patients receiving different biologic agents.

The researchers say their findings have implications for other chronic inflammatory diseases, such as lupus and rheumatoid arthritis, which are known to raise the risk for heart attacks and stroke.

Psoriasis is associated with systemic inflammation, which heightens the risk of blood vessel disease and diabetes. Therefore, the finding, while notable, may not have been entirely unexpected. Biologic therapy (BT) for psoriasis was already found to be favorably associated with luminal coronary plaque, the researchers say, but it was not clear whether those associations were attributable to direct anti-inflammatory effects on the coronary arteries. They wanted to find out whether the perivascular fat attenuation index (FAI) would offer clues. FAI is a new method of analyzing CT scans by assessing whether the fat tissue surrounding arteries becomes attenuated, or less fatty.

The researchers investigated their premise in 134 participants from an ongoing NIH study, the Psoriasis Atherosclerosis Cardiometabolic Initiative cohort. Of the participants, 82 had been receiving anti-tumor necrosis factor α, anti-interleukin (IL) 12/23, or anti-IL-17 for 1 year. The remaining 52 had not received any BT, and given topical or light therapy. The patients underwent CT scans at the start of the study and 1 year later. All of the patients had low cardiovascular risk. At baseline, 27 in the treated group and 19 in the untreated group had a focal coronary atherosclerotic plaque.

The study found that an abnormal perivascular FAI was linked to a 6- to 9-fold increased risk of major adverse cardiovascular events, study coauthor Charalambos Antoniades, MD, says. Patients on BT had a significant decrease in FAI at 1 year, as well as improved psoriasis symptoms. Even patients with preexisting coronary artery plaque had a reduction in coronary inflammation after BT. No change was seen in the untreated patients. The associations with FAI were independent of the presence of coronary plaque and were consistent among patients receiving different biologic agents.

The researchers say their findings have implications for other chronic inflammatory diseases, such as lupus and rheumatoid arthritis, which are known to raise the risk for heart attacks and stroke.

The physician thought that this was most likely toxic epidermal necrolysis (TEN). He was in a small hospital without a burn unit, so he drew baseline labs and blood cultures, and started to give intravenous fluids to treat the dehydration.

TEN is on the most severe side of a spectrum of disorders that includes erythema multiforme and Stevens-Johnson syndrome (SJS). Erythema multiforme is diagnosed when < 10% of the body surface area is involved, SJS/TEN when between 10% and 30% is involved, and TEN when >30% is involved. Drugs that are most commonly known to cause SJS and TEN include sulfonamide antibiotics, allopurinol, nonsteroidal anti-inflammatory agents, amine antiepileptic drugs (phenytoin and carbamazepine), and lamotrigine. In this case, the amoxicillin was the likely culprit.

The physician waited until the patient was hemodynamically stable before transferring her to the closest city hospital where a dermatologist could manage her care. The dermatologist agreed with the diagnosis of TEN and continued supportive care. While the hospital did not have intravenous immunoglobulin or cyclosporine on hand, the health care team was able to provide the necessary supportive care. The patient survived, and she was warned to never take any type of penicillin again.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Milana C, Smith M. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1161-1168.

To learn more about the 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com

The physician thought that this was most likely toxic epidermal necrolysis (TEN). He was in a small hospital without a burn unit, so he drew baseline labs and blood cultures, and started to give intravenous fluids to treat the dehydration.

TEN is on the most severe side of a spectrum of disorders that includes erythema multiforme and Stevens-Johnson syndrome (SJS). Erythema multiforme is diagnosed when < 10% of the body surface area is involved, SJS/TEN when between 10% and 30% is involved, and TEN when >30% is involved. Drugs that are most commonly known to cause SJS and TEN include sulfonamide antibiotics, allopurinol, nonsteroidal anti-inflammatory agents, amine antiepileptic drugs (phenytoin and carbamazepine), and lamotrigine. In this case, the amoxicillin was the likely culprit.

The physician waited until the patient was hemodynamically stable before transferring her to the closest city hospital where a dermatologist could manage her care. The dermatologist agreed with the diagnosis of TEN and continued supportive care. While the hospital did not have intravenous immunoglobulin or cyclosporine on hand, the health care team was able to provide the necessary supportive care. The patient survived, and she was warned to never take any type of penicillin again.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Milana C, Smith M. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1161-1168.

To learn more about the 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com

The physician thought that this was most likely toxic epidermal necrolysis (TEN). He was in a small hospital without a burn unit, so he drew baseline labs and blood cultures, and started to give intravenous fluids to treat the dehydration.

TEN is on the most severe side of a spectrum of disorders that includes erythema multiforme and Stevens-Johnson syndrome (SJS). Erythema multiforme is diagnosed when < 10% of the body surface area is involved, SJS/TEN when between 10% and 30% is involved, and TEN when >30% is involved. Drugs that are most commonly known to cause SJS and TEN include sulfonamide antibiotics, allopurinol, nonsteroidal anti-inflammatory agents, amine antiepileptic drugs (phenytoin and carbamazepine), and lamotrigine. In this case, the amoxicillin was the likely culprit.

The physician waited until the patient was hemodynamically stable before transferring her to the closest city hospital where a dermatologist could manage her care. The dermatologist agreed with the diagnosis of TEN and continued supportive care. While the hospital did not have intravenous immunoglobulin or cyclosporine on hand, the health care team was able to provide the necessary supportive care. The patient survived, and she was warned to never take any type of penicillin again.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Milana C, Smith M. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1161-1168.

To learn more about the 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com

A 73-year-old male veteran with a history of ischemic stroke with left-sided deficits and edema, falls, poorly controlled hypertension, active tobacco use, obesity, and prediabetes was assessed on a routine visit by our home-based primary care team and found to have a new, unilateral, asymptomatic rash. He reported feeling no pain in the affected area or any significant increase in the baseline left lower extremity edema and weakness resulting from his stroke 2 years prior.

On the left lateral leg from mid-thigh to mid-calf, there was a nontender, flat, reticulated rash with pigmentary alteration ranging from light brown to dark brown (Figure).

On further questioning, the patient reported regular use of a space heater because his gas furnace had been destroyed in an earthquake more than 20 years before. He would place this heater close to his left leg when using the computer or while sleeping in his wheelchair.

• What is your diagnosis?
• How would you treat this patient?

Our Diagnosis

Erythema ab igne, also called hot water bottle rash, is a clinical diagnosis based on characteristic cutaneous findings and a clear history of chronic, moderate heat or infrared exposure.¹ Although exposure to space heaters, open fire, radiators, hot water bottles, and heating pads are the classic causes, recently there have been reports of laptop computers, cell phones, infrared food lamps, automobile seat heaters, and heated recliners causing the same type of skin reaction.²

With chronic moderate heat or infrared exposure, the rash usually progresses over days to months. It begins as a mild, transient, reticulated, erythematous rash, which follows the pattern of the cutaneous venous plexus and resolves minutes to hours after removal of the offending source as vasodilation resolves. After months of continued exposure, the dermis around the affected vasculature eventually becomes hyperpigmented due to the deposition of melanin and sometimes hemosiderin.

The rash is usually asymptomatic but has been associated with pain, pruritis, and/or tingling. Once the diagnosis is made, treatment involves removal of the offending source. The discoloration may resolve over months to years, but permanent hyperpigmentation is not uncommon. There are a few case reports on treatment using Nd-Yag laser therapy, topical hydroquinone and tretinoin, 5-fluorouracil, and systemic mesoglycan with topical bioflavonoids.^2-4

While the prognosis of erythema ab igne is excellent if detected early, failure to recognize this condition and remove the offending source can lead to sequalae, such as squamous cell carcinoma, poorly differentiated carcinoma, cutaneous marginal zone lymphoma, and Merkel cell carcinoma.^5-8 Development of malignancy typically has a latency period of > 30 years. Patients should have periodic surveillance of their skin and any suspicious lesion in the involved area should be considered for biopsy.

Rashes may represent systemic or more localized pathology (Table). In contrast to erythema ab igne, the rash associated with a vasculitic process (autoimmune, drug-induced, or infectious) tends to be more generalized and bilateral but still follows the pattern of the cutaneous venous plexus. An example of this would be livedo reticularis. Although this rash is reticular, it is not hyperpigmented.⁹ A variant of livedo reticularis is cutis marmorata, which develops in response to cold exposure, particularly in infants or in the setting of hypothyroidism.Cutis marmorata is erythematous, blanchable, and reversible with rewarming. Unlike erythema ab igne, there is no hyperpigmentation and tends to be more diffuse.¹⁰ 

When evaluating a reticular rash, consider local and systemic etiologies. If more localized and hyperpigmented, ask about heat or infrared exposure. This may point to a diagnosis of erythema ab igne.

A 73-year-old male veteran with a history of ischemic stroke with left-sided deficits and edema, falls, poorly controlled hypertension, active tobacco use, obesity, and prediabetes was assessed on a routine visit by our home-based primary care team and found to have a new, unilateral, asymptomatic rash. He reported feeling no pain in the affected area or any significant increase in the baseline left lower extremity edema and weakness resulting from his stroke 2 years prior.

On the left lateral leg from mid-thigh to mid-calf, there was a nontender, flat, reticulated rash with pigmentary alteration ranging from light brown to dark brown (Figure).

On further questioning, the patient reported regular use of a space heater because his gas furnace had been destroyed in an earthquake more than 20 years before. He would place this heater close to his left leg when using the computer or while sleeping in his wheelchair.

• What is your diagnosis?
• How would you treat this patient?

Our Diagnosis

Erythema ab igne, also called hot water bottle rash, is a clinical diagnosis based on characteristic cutaneous findings and a clear history of chronic, moderate heat or infrared exposure.¹ Although exposure to space heaters, open fire, radiators, hot water bottles, and heating pads are the classic causes, recently there have been reports of laptop computers, cell phones, infrared food lamps, automobile seat heaters, and heated recliners causing the same type of skin reaction.²

With chronic moderate heat or infrared exposure, the rash usually progresses over days to months. It begins as a mild, transient, reticulated, erythematous rash, which follows the pattern of the cutaneous venous plexus and resolves minutes to hours after removal of the offending source as vasodilation resolves. After months of continued exposure, the dermis around the affected vasculature eventually becomes hyperpigmented due to the deposition of melanin and sometimes hemosiderin.

The rash is usually asymptomatic but has been associated with pain, pruritis, and/or tingling. Once the diagnosis is made, treatment involves removal of the offending source. The discoloration may resolve over months to years, but permanent hyperpigmentation is not uncommon. There are a few case reports on treatment using Nd-Yag laser therapy, topical hydroquinone and tretinoin, 5-fluorouracil, and systemic mesoglycan with topical bioflavonoids.^2-4

While the prognosis of erythema ab igne is excellent if detected early, failure to recognize this condition and remove the offending source can lead to sequalae, such as squamous cell carcinoma, poorly differentiated carcinoma, cutaneous marginal zone lymphoma, and Merkel cell carcinoma.^5-8 Development of malignancy typically has a latency period of > 30 years. Patients should have periodic surveillance of their skin and any suspicious lesion in the involved area should be considered for biopsy.

Rashes may represent systemic or more localized pathology (Table). In contrast to erythema ab igne, the rash associated with a vasculitic process (autoimmune, drug-induced, or infectious) tends to be more generalized and bilateral but still follows the pattern of the cutaneous venous plexus. An example of this would be livedo reticularis. Although this rash is reticular, it is not hyperpigmented.⁹ A variant of livedo reticularis is cutis marmorata, which develops in response to cold exposure, particularly in infants or in the setting of hypothyroidism.Cutis marmorata is erythematous, blanchable, and reversible with rewarming. Unlike erythema ab igne, there is no hyperpigmentation and tends to be more diffuse.¹⁰ 

When evaluating a reticular rash, consider local and systemic etiologies. If more localized and hyperpigmented, ask about heat or infrared exposure. This may point to a diagnosis of erythema ab igne.

A 73-year-old male veteran with a history of ischemic stroke with left-sided deficits and edema, falls, poorly controlled hypertension, active tobacco use, obesity, and prediabetes was assessed on a routine visit by our home-based primary care team and found to have a new, unilateral, asymptomatic rash. He reported feeling no pain in the affected area or any significant increase in the baseline left lower extremity edema and weakness resulting from his stroke 2 years prior.

On the left lateral leg from mid-thigh to mid-calf, there was a nontender, flat, reticulated rash with pigmentary alteration ranging from light brown to dark brown (Figure).

On further questioning, the patient reported regular use of a space heater because his gas furnace had been destroyed in an earthquake more than 20 years before. He would place this heater close to his left leg when using the computer or while sleeping in his wheelchair.

• What is your diagnosis?
• How would you treat this patient?

Our Diagnosis

Erythema ab igne, also called hot water bottle rash, is a clinical diagnosis based on characteristic cutaneous findings and a clear history of chronic, moderate heat or infrared exposure.¹ Although exposure to space heaters, open fire, radiators, hot water bottles, and heating pads are the classic causes, recently there have been reports of laptop computers, cell phones, infrared food lamps, automobile seat heaters, and heated recliners causing the same type of skin reaction.²

With chronic moderate heat or infrared exposure, the rash usually progresses over days to months. It begins as a mild, transient, reticulated, erythematous rash, which follows the pattern of the cutaneous venous plexus and resolves minutes to hours after removal of the offending source as vasodilation resolves. After months of continued exposure, the dermis around the affected vasculature eventually becomes hyperpigmented due to the deposition of melanin and sometimes hemosiderin.

The rash is usually asymptomatic but has been associated with pain, pruritis, and/or tingling. Once the diagnosis is made, treatment involves removal of the offending source. The discoloration may resolve over months to years, but permanent hyperpigmentation is not uncommon. There are a few case reports on treatment using Nd-Yag laser therapy, topical hydroquinone and tretinoin, 5-fluorouracil, and systemic mesoglycan with topical bioflavonoids.^2-4

While the prognosis of erythema ab igne is excellent if detected early, failure to recognize this condition and remove the offending source can lead to sequalae, such as squamous cell carcinoma, poorly differentiated carcinoma, cutaneous marginal zone lymphoma, and Merkel cell carcinoma.^5-8 Development of malignancy typically has a latency period of > 30 years. Patients should have periodic surveillance of their skin and any suspicious lesion in the involved area should be considered for biopsy.

Rashes may represent systemic or more localized pathology (Table). In contrast to erythema ab igne, the rash associated with a vasculitic process (autoimmune, drug-induced, or infectious) tends to be more generalized and bilateral but still follows the pattern of the cutaneous venous plexus. An example of this would be livedo reticularis. Although this rash is reticular, it is not hyperpigmented.⁹ A variant of livedo reticularis is cutis marmorata, which develops in response to cold exposure, particularly in infants or in the setting of hypothyroidism.Cutis marmorata is erythematous, blanchable, and reversible with rewarming. Unlike erythema ab igne, there is no hyperpigmentation and tends to be more diffuse.¹⁰ 

When evaluating a reticular rash, consider local and systemic etiologies. If more localized and hyperpigmented, ask about heat or infrared exposure. This may point to a diagnosis of erythema ab igne.

SEATTLE – Blood cultures were ordered for over half of pediatric skin infection encounters across 38 children’s hospitals, with rates varying from about 20% to 80% between hospitals, according to a review of almost 50,000 encounters in the Pediatric Health Information System database.

M. Alexander Otto/MDedge News

It was a surprising finding, because current guidelines from the Infectious Diseases Society of America do not recommend blood cultures as part of the routine evaluation of uncomplicated pediatric skin and soft-tissue infections (SSTIs), meaning infections in children who are otherwise healthy without neutropenia or other complicating factors.

Just 0.6% of the cultures were positive in the review, and it’s likely some of those were caused by contamination. After adjustment for demographics, complex chronic conditions, and severity of illness, culture draws were associated with a 20% increase in hospital length of stay (LOS), hospital costs, and 30-day readmission rates.

“Our data provide more evidence that [routine] blood cultures for children with SSTI represents low-value practice and should be avoided,” said lead investigator John Stephens, MD, a pediatrics professor and hospitalist at the University of North Carolina at Chapel Hill.

Dr. Stephens became curious about how common the practice was across hospitals after he and a friend penned an article about the issue for the Journal of Hospital Medicine’s “Things We Do for No Reason” series. The single-center studies they reviewed showed similarly high rates of both testing and negative cultures (J Hosp Med. 2018 Jul;13[7]:496-9).

Dr. Stephens and his team queried the Pediatric Health Information System database for encounters in children aged 2 months to 18 years with the diagnostic code 383, “cellulitis and other skin infections,” from 2012 to 2017, during which time “there really wasn’t a change” in IDSA guidance, he noted. Transfers, encounters with ICU care, and immunocompromised children were excluded.

Hospital admissions were included in the review if they had an additional code for erysipelas, cellulitis, impetigo, or other localized skin infection. The rate of positive cultures was inferred from subsequent codes for bacteremia or septicemia.

Across 49,291 encounters, the median rate of blood culture for skin infection was 51.6%, with tremendous variation between hospitals. With blood cultures, the hospital LOS was about 1.9 days, the hospital cost was $4,030, and the 30-day readmission rate was 1.3%. Without cultures, LOS was 1.6 days, the cost was $3,291, and the readmission rate was 1%.

Although infrequent, it’s likely that positive cultures triggered additional work-up, time in the hospital, and other measures, which might help account for the increase in LOS and costs.

As for why blood testing was so common, especially in some hospitals, “I think it’s just institutional culture. No amount of clinical variation in patient population could explain” a 20%-80% “variation across hospitals. It’s really just ingrained habits,” Dr. Stephens said at Pediatric Hospital Medicine.

“The rate of positive blood culture was really low, and the association was for higher cost and utilization. I think this really reinforces the IDSA guidelines. We need to focus on quality improvement efforts to do this better,” he said, noting that he hopes to do so at his own institution.

“I’d also like to know more on the positives. In the single center studies, we know more than half of them are contaminants. Often, there’s more contamination than true positives,” he said at the meeting sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.

Instead of routine blood culture, Dr. Stephens recommended in his article to send pus for a Gram stain and culture and sensitivity, while noting that blood cultures remain reasonable for complicated infections, immunocompromised patients, and neonates.

There was no external funding, and Dr. Stephens didn’t report any disclosures.

[email protected]

SEATTLE – Blood cultures were ordered for over half of pediatric skin infection encounters across 38 children’s hospitals, with rates varying from about 20% to 80% between hospitals, according to a review of almost 50,000 encounters in the Pediatric Health Information System database.

M. Alexander Otto/MDedge News

It was a surprising finding, because current guidelines from the Infectious Diseases Society of America do not recommend blood cultures as part of the routine evaluation of uncomplicated pediatric skin and soft-tissue infections (SSTIs), meaning infections in children who are otherwise healthy without neutropenia or other complicating factors.

Just 0.6% of the cultures were positive in the review, and it’s likely some of those were caused by contamination. After adjustment for demographics, complex chronic conditions, and severity of illness, culture draws were associated with a 20% increase in hospital length of stay (LOS), hospital costs, and 30-day readmission rates.

“Our data provide more evidence that [routine] blood cultures for children with SSTI represents low-value practice and should be avoided,” said lead investigator John Stephens, MD, a pediatrics professor and hospitalist at the University of North Carolina at Chapel Hill.

Dr. Stephens became curious about how common the practice was across hospitals after he and a friend penned an article about the issue for the Journal of Hospital Medicine’s “Things We Do for No Reason” series. The single-center studies they reviewed showed similarly high rates of both testing and negative cultures (J Hosp Med. 2018 Jul;13[7]:496-9).

Dr. Stephens and his team queried the Pediatric Health Information System database for encounters in children aged 2 months to 18 years with the diagnostic code 383, “cellulitis and other skin infections,” from 2012 to 2017, during which time “there really wasn’t a change” in IDSA guidance, he noted. Transfers, encounters with ICU care, and immunocompromised children were excluded.

Hospital admissions were included in the review if they had an additional code for erysipelas, cellulitis, impetigo, or other localized skin infection. The rate of positive cultures was inferred from subsequent codes for bacteremia or septicemia.

Across 49,291 encounters, the median rate of blood culture for skin infection was 51.6%, with tremendous variation between hospitals. With blood cultures, the hospital LOS was about 1.9 days, the hospital cost was $4,030, and the 30-day readmission rate was 1.3%. Without cultures, LOS was 1.6 days, the cost was $3,291, and the readmission rate was 1%.

Although infrequent, it’s likely that positive cultures triggered additional work-up, time in the hospital, and other measures, which might help account for the increase in LOS and costs.

As for why blood testing was so common, especially in some hospitals, “I think it’s just institutional culture. No amount of clinical variation in patient population could explain” a 20%-80% “variation across hospitals. It’s really just ingrained habits,” Dr. Stephens said at Pediatric Hospital Medicine.

“The rate of positive blood culture was really low, and the association was for higher cost and utilization. I think this really reinforces the IDSA guidelines. We need to focus on quality improvement efforts to do this better,” he said, noting that he hopes to do so at his own institution.

“I’d also like to know more on the positives. In the single center studies, we know more than half of them are contaminants. Often, there’s more contamination than true positives,” he said at the meeting sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.

Instead of routine blood culture, Dr. Stephens recommended in his article to send pus for a Gram stain and culture and sensitivity, while noting that blood cultures remain reasonable for complicated infections, immunocompromised patients, and neonates.

There was no external funding, and Dr. Stephens didn’t report any disclosures.

[email protected]

SEATTLE – Blood cultures were ordered for over half of pediatric skin infection encounters across 38 children’s hospitals, with rates varying from about 20% to 80% between hospitals, according to a review of almost 50,000 encounters in the Pediatric Health Information System database.

M. Alexander Otto/MDedge News

It was a surprising finding, because current guidelines from the Infectious Diseases Society of America do not recommend blood cultures as part of the routine evaluation of uncomplicated pediatric skin and soft-tissue infections (SSTIs), meaning infections in children who are otherwise healthy without neutropenia or other complicating factors.

Just 0.6% of the cultures were positive in the review, and it’s likely some of those were caused by contamination. After adjustment for demographics, complex chronic conditions, and severity of illness, culture draws were associated with a 20% increase in hospital length of stay (LOS), hospital costs, and 30-day readmission rates.

“Our data provide more evidence that [routine] blood cultures for children with SSTI represents low-value practice and should be avoided,” said lead investigator John Stephens, MD, a pediatrics professor and hospitalist at the University of North Carolina at Chapel Hill.

Dr. Stephens became curious about how common the practice was across hospitals after he and a friend penned an article about the issue for the Journal of Hospital Medicine’s “Things We Do for No Reason” series. The single-center studies they reviewed showed similarly high rates of both testing and negative cultures (J Hosp Med. 2018 Jul;13[7]:496-9).

Dr. Stephens and his team queried the Pediatric Health Information System database for encounters in children aged 2 months to 18 years with the diagnostic code 383, “cellulitis and other skin infections,” from 2012 to 2017, during which time “there really wasn’t a change” in IDSA guidance, he noted. Transfers, encounters with ICU care, and immunocompromised children were excluded.

Hospital admissions were included in the review if they had an additional code for erysipelas, cellulitis, impetigo, or other localized skin infection. The rate of positive cultures was inferred from subsequent codes for bacteremia or septicemia.

Across 49,291 encounters, the median rate of blood culture for skin infection was 51.6%, with tremendous variation between hospitals. With blood cultures, the hospital LOS was about 1.9 days, the hospital cost was $4,030, and the 30-day readmission rate was 1.3%. Without cultures, LOS was 1.6 days, the cost was $3,291, and the readmission rate was 1%.

Although infrequent, it’s likely that positive cultures triggered additional work-up, time in the hospital, and other measures, which might help account for the increase in LOS and costs.

As for why blood testing was so common, especially in some hospitals, “I think it’s just institutional culture. No amount of clinical variation in patient population could explain” a 20%-80% “variation across hospitals. It’s really just ingrained habits,” Dr. Stephens said at Pediatric Hospital Medicine.

“The rate of positive blood culture was really low, and the association was for higher cost and utilization. I think this really reinforces the IDSA guidelines. We need to focus on quality improvement efforts to do this better,” he said, noting that he hopes to do so at his own institution.

“I’d also like to know more on the positives. In the single center studies, we know more than half of them are contaminants. Often, there’s more contamination than true positives,” he said at the meeting sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.

Instead of routine blood culture, Dr. Stephens recommended in his article to send pus for a Gram stain and culture and sensitivity, while noting that blood cultures remain reasonable for complicated infections, immunocompromised patients, and neonates.

There was no external funding, and Dr. Stephens didn’t report any disclosures.

[email protected]

The FP diagnosed erythema multiforme (EM) in this patient based on the target lesions with central epithelial disruption on his palms. In this case, the EM was due to the herpes simplex outbreak on the patient’s lips (herpes labialis) that had occurred about a week earlier.

EM is a hypersensitivity reaction that is often secondary to infections or medications. Herpes simplex viruses (HSVI and HSV2) are the most common causative agents and have been implicated in ≥ 60% of cases.

The patient did not know that cold sores were due to herpes simplex and most oral HSV is due to HSV1 infection. He acknowledged that he experienced cold sores about every 2 months that were usually related to stress or exposure to intense sunlight. The FP recommended that the patient avoid intense sunlight (midday sun avoidance; wearing sunscreen and hats) and use lip protection with at least an SPF of 15. As the lip lesions were > 90% healed, there was no reason for the FP to prescribe an antiviral agent. The FP did, however, offer a prescription for valacyclovir to be used at the first signs of an oral herpes outbreak to avoid another case of EM (2000 mg by mouth every 12 hours x 2 doses). For symptomatic relief of the EM, the physician prescribed a 15 g tube of 0.1% triamcinolone cream to be applied to the lesions twice daily.

‌

Photo courtesy of the University of Texas Health Sciences Center, Division of Dermatology and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Milana C, Smith M. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1161-1168.

To learn more about the 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com

The FP diagnosed erythema multiforme (EM) in this patient based on the target lesions with central epithelial disruption on his palms. In this case, the EM was due to the herpes simplex outbreak on the patient’s lips (herpes labialis) that had occurred about a week earlier.

EM is a hypersensitivity reaction that is often secondary to infections or medications. Herpes simplex viruses (HSVI and HSV2) are the most common causative agents and have been implicated in ≥ 60% of cases.

The patient did not know that cold sores were due to herpes simplex and most oral HSV is due to HSV1 infection. He acknowledged that he experienced cold sores about every 2 months that were usually related to stress or exposure to intense sunlight. The FP recommended that the patient avoid intense sunlight (midday sun avoidance; wearing sunscreen and hats) and use lip protection with at least an SPF of 15. As the lip lesions were > 90% healed, there was no reason for the FP to prescribe an antiviral agent. The FP did, however, offer a prescription for valacyclovir to be used at the first signs of an oral herpes outbreak to avoid another case of EM (2000 mg by mouth every 12 hours x 2 doses). For symptomatic relief of the EM, the physician prescribed a 15 g tube of 0.1% triamcinolone cream to be applied to the lesions twice daily.

‌

Photo courtesy of the University of Texas Health Sciences Center, Division of Dermatology and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Milana C, Smith M. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1161-1168.

To learn more about the 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com

The FP diagnosed erythema multiforme (EM) in this patient based on the target lesions with central epithelial disruption on his palms. In this case, the EM was due to the herpes simplex outbreak on the patient’s lips (herpes labialis) that had occurred about a week earlier.

EM is a hypersensitivity reaction that is often secondary to infections or medications. Herpes simplex viruses (HSVI and HSV2) are the most common causative agents and have been implicated in ≥ 60% of cases.

The patient did not know that cold sores were due to herpes simplex and most oral HSV is due to HSV1 infection. He acknowledged that he experienced cold sores about every 2 months that were usually related to stress or exposure to intense sunlight. The FP recommended that the patient avoid intense sunlight (midday sun avoidance; wearing sunscreen and hats) and use lip protection with at least an SPF of 15. As the lip lesions were > 90% healed, there was no reason for the FP to prescribe an antiviral agent. The FP did, however, offer a prescription for valacyclovir to be used at the first signs of an oral herpes outbreak to avoid another case of EM (2000 mg by mouth every 12 hours x 2 doses). For symptomatic relief of the EM, the physician prescribed a 15 g tube of 0.1% triamcinolone cream to be applied to the lesions twice daily.

‌

Photo courtesy of the University of Texas Health Sciences Center, Division of Dermatology and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Milana C, Smith M. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1161-1168.

To learn more about the 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com

A 30-year-old woman with a history of chronic overexposure to UV light presents to dermatology for a routine skin exam. The patient has a history of poor toleration to UV light, especially as a child, but participated in regular tanning as a teen. However, she stopped tanning when her sister developed a melanoma.

Additionally, the patient has been experiencing upper back pain, for which she has seen a variety of providers. Most recently, she consulted a naturopath, who recommended cupping therapy. Although the patient believes the therapy is alleviating her pain, she is distressed by the subsequent formation of large blemishes on her back and asks about possible treatment.

EXAMINATION
There are 10 large round patches, each measuring 7 cm in diameter, on the patient’s back. These patches consist of multiple petechiae and brown hyperpigmentation. On palpation, there is no surface disturbance or tenderness. The discoloration is nonblanchable. The size, shape, and configuration of the lesions is consistent with the patient's description of the cupping procedures she has undergone on several occasions.

Notably, the patient's skin is categorized as type II on the Fitzpatrick scale, with advanced dermatoheliosis.

What’s the diagnosis?

DISCUSSION
"Cupping," as medical therapy, was first described in ancient texts 3000 to 4000 years ago. The application of cups to the patient’s skin was intended to draw out substances (eg, toxins and fluids) inside the body that were believed to cause a variety of ailments. Though its use has long since been discarded in mainstream medicine, it is still used routinely in both Chinese and alternative medicine.

Cupping has been evaluated by numerous medical individuals and organizations, who uniformly dismiss any benefit it might offer, even as a placebo. From a pathophysiologic standpoint, cupping causes localized dilation of blood and lymph vessels, thus creating telangiectasia that, as they resolve, leave behind postinflammatory hyperpigmentation and edema. (Excessive production of telangiectasia might indicate pathologic capillary fragility, possibly secondary to Rumpel-Leede phenomenon.)

The patient's skin type can affect the rate of resolution (longer for those with darker skin, shorter for those with fair skin); there is little we can do to speed up this process. Although the case patient was disappointed with the lack of available treatment for her blemishes, she was insistent about continuing the cupping therapy.

Interestingly, there is a differential diagnosis for such lesions; it includes injury from tennis balls, racquetballs, paintballs, or even baseballs—though the associated lesions are usually solitary.

TAKE-HOME LEARNING POINTS

• Cupping, as medical therapy, has been around for thousands of years and is still routinely used in both Chinese and alternative medicine.
• The intention of its use is to draw out noxious substances that purportedly cause the patient's complaint—however, according to numerous medical authorities, the practice is totally ineffective.
• The suction effect of cupping induces edema and telangiectasia, which in turn results in postinflammatory hyperpigmentation that clears slowly.
• Similar lesions can result from being struck by paintballs, racquetballs, tennis balls, and baseballs.

A 30-year-old woman with a history of chronic overexposure to UV light presents to dermatology for a routine skin exam. The patient has a history of poor toleration to UV light, especially as a child, but participated in regular tanning as a teen. However, she stopped tanning when her sister developed a melanoma.

Additionally, the patient has been experiencing upper back pain, for which she has seen a variety of providers. Most recently, she consulted a naturopath, who recommended cupping therapy. Although the patient believes the therapy is alleviating her pain, she is distressed by the subsequent formation of large blemishes on her back and asks about possible treatment.

EXAMINATION
There are 10 large round patches, each measuring 7 cm in diameter, on the patient’s back. These patches consist of multiple petechiae and brown hyperpigmentation. On palpation, there is no surface disturbance or tenderness. The discoloration is nonblanchable. The size, shape, and configuration of the lesions is consistent with the patient's description of the cupping procedures she has undergone on several occasions.

Notably, the patient's skin is categorized as type II on the Fitzpatrick scale, with advanced dermatoheliosis.

What’s the diagnosis?

DISCUSSION
"Cupping," as medical therapy, was first described in ancient texts 3000 to 4000 years ago. The application of cups to the patient’s skin was intended to draw out substances (eg, toxins and fluids) inside the body that were believed to cause a variety of ailments. Though its use has long since been discarded in mainstream medicine, it is still used routinely in both Chinese and alternative medicine.

Cupping has been evaluated by numerous medical individuals and organizations, who uniformly dismiss any benefit it might offer, even as a placebo. From a pathophysiologic standpoint, cupping causes localized dilation of blood and lymph vessels, thus creating telangiectasia that, as they resolve, leave behind postinflammatory hyperpigmentation and edema. (Excessive production of telangiectasia might indicate pathologic capillary fragility, possibly secondary to Rumpel-Leede phenomenon.)

The patient's skin type can affect the rate of resolution (longer for those with darker skin, shorter for those with fair skin); there is little we can do to speed up this process. Although the case patient was disappointed with the lack of available treatment for her blemishes, she was insistent about continuing the cupping therapy.

Interestingly, there is a differential diagnosis for such lesions; it includes injury from tennis balls, racquetballs, paintballs, or even baseballs—though the associated lesions are usually solitary.

TAKE-HOME LEARNING POINTS

• Cupping, as medical therapy, has been around for thousands of years and is still routinely used in both Chinese and alternative medicine.
• The intention of its use is to draw out noxious substances that purportedly cause the patient's complaint—however, according to numerous medical authorities, the practice is totally ineffective.
• The suction effect of cupping induces edema and telangiectasia, which in turn results in postinflammatory hyperpigmentation that clears slowly.
• Similar lesions can result from being struck by paintballs, racquetballs, tennis balls, and baseballs.

A 30-year-old woman with a history of chronic overexposure to UV light presents to dermatology for a routine skin exam. The patient has a history of poor toleration to UV light, especially as a child, but participated in regular tanning as a teen. However, she stopped tanning when her sister developed a melanoma.

Additionally, the patient has been experiencing upper back pain, for which she has seen a variety of providers. Most recently, she consulted a naturopath, who recommended cupping therapy. Although the patient believes the therapy is alleviating her pain, she is distressed by the subsequent formation of large blemishes on her back and asks about possible treatment.

EXAMINATION
There are 10 large round patches, each measuring 7 cm in diameter, on the patient’s back. These patches consist of multiple petechiae and brown hyperpigmentation. On palpation, there is no surface disturbance or tenderness. The discoloration is nonblanchable. The size, shape, and configuration of the lesions is consistent with the patient's description of the cupping procedures she has undergone on several occasions.

Notably, the patient's skin is categorized as type II on the Fitzpatrick scale, with advanced dermatoheliosis.

What’s the diagnosis?

DISCUSSION
"Cupping," as medical therapy, was first described in ancient texts 3000 to 4000 years ago. The application of cups to the patient’s skin was intended to draw out substances (eg, toxins and fluids) inside the body that were believed to cause a variety of ailments. Though its use has long since been discarded in mainstream medicine, it is still used routinely in both Chinese and alternative medicine.

Cupping has been evaluated by numerous medical individuals and organizations, who uniformly dismiss any benefit it might offer, even as a placebo. From a pathophysiologic standpoint, cupping causes localized dilation of blood and lymph vessels, thus creating telangiectasia that, as they resolve, leave behind postinflammatory hyperpigmentation and edema. (Excessive production of telangiectasia might indicate pathologic capillary fragility, possibly secondary to Rumpel-Leede phenomenon.)

The patient's skin type can affect the rate of resolution (longer for those with darker skin, shorter for those with fair skin); there is little we can do to speed up this process. Although the case patient was disappointed with the lack of available treatment for her blemishes, she was insistent about continuing the cupping therapy.

Interestingly, there is a differential diagnosis for such lesions; it includes injury from tennis balls, racquetballs, paintballs, or even baseballs—though the associated lesions are usually solitary.

TAKE-HOME LEARNING POINTS

• Cupping, as medical therapy, has been around for thousands of years and is still routinely used in both Chinese and alternative medicine.
• The intention of its use is to draw out noxious substances that purportedly cause the patient's complaint—however, according to numerous medical authorities, the practice is totally ineffective.
• The suction effect of cupping induces edema and telangiectasia, which in turn results in postinflammatory hyperpigmentation that clears slowly.
• Similar lesions can result from being struck by paintballs, racquetballs, tennis balls, and baseballs.

A 16-year-old boy sought care at a rural hospital in Panama for facial swelling that began 3 months earlier. He was seen by a family physician (RU) and a team of medical students who were there as part of a volunteer effort. The patient had difficulty opening his left eye. He denied fever and chills, and said he felt well—other than his inability to see out of his left eye. He denied any changes to his vision when he held the swollen eyelids open. The patient lived on a ranch far outside of town, and he walked down a mountain road alone for 6 hours with one eye swollen shut to present for treatment. The patient was not taking any medications and had not received any health care since his last vaccine several years ago. On physical exam, his vital signs were normal, and the swelling under his left eye was somewhat tender and slightly warm to the touch. There were no lesions on his trunk and the remainder of the exam was normal.

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

The family physician (FP) diagnosed severe inflammatory nodulocystic acne in this patient. He initially was concerned about possible cellulitis or an abscess, but his clinical experience suggested the swelling was secondary to severe inflammation and not a bacterial infection. The FP noted that the patient was afebrile and lacked systemic symptoms. In addition, the presence of open and closed comedones on the face, as well as the patient’s age and sex, supported the diagnosis of acne. No tests were performed; the diagnosis was made clinically.

A case of acne, or a bacterial infection?

The FP considered acne conglobata, acne fulminans, and a bacterial infection as other possible causes of the patient’s facial swelling.

Acne conglobata is a form of severe inflammatory cystic acne that affects the face, chest, and back. It is characterized by nodules, cysts, large open comedones, and interconnecting sinuses.^1,2 Although this case of acne was severe, the young man did not have large open comedones or interconnecting sinus tracts. In addition, his trunk was unaffected.

Acne fulminans is a type of severe cystic acne with systemic symptoms, which is mainly seen in adolescent males. It may have a sudden onset and is characterized by ulcerated, nodular, and painful acne that bleeds, crusts, and results in severe scarring. Patients may present with fever, joint pain, and weight loss.^1,2 Our patient did not have systemic symptoms despite the severe facial swelling.

Bacterial infections of the skin usually are caused by Staphylococcus aureus (S aureus) or Streptococcus pyogenes and can lead to cellulitis and/or abscess formation.³ This process was considered as a complication of the severe acne, but the clinical picture was consistent with severe inflammation rather than a bacterial superinfection.

Continue to: Treatment of choice includes prednisone and doxycycline

The FP knew that the severe inflammation and swelling needed to be treated with a systemic steroid, so he started the patient on prednisone 60 mg orally once daily at the time of presentation. Additionally, the FP prescribed doxycycline 100 mg bid to treat the inflammation and to cover a possible superinfection.

Doxycycline is the oral antibiotic of choice for inflammatory acne.² It also is a good antibiotic for cutaneous methicillin-resistant S aureus infection.³ Although it is not the treatment of choice for a nonpurulent cellulitis, it is a good option for cellulitis with purulence.³

With the working diagnosis of severe inflammatory acne, it was expected that the prednisone and doxycycline would be effective. Treating with antibiotics alone (for fear of causing immunosuppression with steroids) would have likely been less effective. Since the patient lived 6 hours from the hospital by foot and was alone, he was admitted overnight for observation (with parental permission obtained over the phone).

The patient’s condition improved overnight. Marked improvement in the swelling and inflammation was noted the following morning (FIGURES 2A and 2B). The patient was pleased with the results and was discharged to return home (transportation provided by the hospital) with directions on how to continue the oral prednisone and doxycycline. He was given 1 month of doxycycline to continue (100 mg bid) and enough oral prednisone to take 40 mg/d for 1 week and 20 mg/d for another week. He was given a follow-up appointment for 2 weeks to assess his acne and his ability to tolerate the medications.

PHOTOS COURTESY OF RICHARD USATINE, MD

He was warned to avoid the sun as much as possible, as doxycycline is photosensitizing, and to use a large hat and sunscreen when the sun could not be avoided. (Another option would have been to prescribe minocycline 100 mg bid because it is equally effective for acne with a lower risk for photosensitization.²)

Continue to: Access to medical care was limited

Access to medical care was limited. Although this patient was a good candidate for oral isotretinoin treatment, he did not have access to this medication in rural Panama. Managing his acne was challenging because of the severity of the case and the patient’s sun exposure in this tropical country. Access to the full range of topical anti-acne treatments also is limited in rural Panama, but fortunately his response to the initial oral medications was good.

The future plan at the follow-up visit consisted of continuing the doxycycline, stopping the prednisone, and adding topical benzoyl peroxide. The purpose of the benzoyl peroxide was to prevent bacterial resistance to the antibiotic.²

CORRESPONDENCE
Richard Usatine, MD, Skin Clinic, 903 W Martin Ave, Historic Building, San Antonio, TX 78207; [email protected]

A 16-year-old boy sought care at a rural hospital in Panama for facial swelling that began 3 months earlier. He was seen by a family physician (RU) and a team of medical students who were there as part of a volunteer effort. The patient had difficulty opening his left eye. He denied fever and chills, and said he felt well—other than his inability to see out of his left eye. He denied any changes to his vision when he held the swollen eyelids open. The patient lived on a ranch far outside of town, and he walked down a mountain road alone for 6 hours with one eye swollen shut to present for treatment. The patient was not taking any medications and had not received any health care since his last vaccine several years ago. On physical exam, his vital signs were normal, and the swelling under his left eye was somewhat tender and slightly warm to the touch. There were no lesions on his trunk and the remainder of the exam was normal.

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

The family physician (FP) diagnosed severe inflammatory nodulocystic acne in this patient. He initially was concerned about possible cellulitis or an abscess, but his clinical experience suggested the swelling was secondary to severe inflammation and not a bacterial infection. The FP noted that the patient was afebrile and lacked systemic symptoms. In addition, the presence of open and closed comedones on the face, as well as the patient’s age and sex, supported the diagnosis of acne. No tests were performed; the diagnosis was made clinically.

A case of acne, or a bacterial infection?

The FP considered acne conglobata, acne fulminans, and a bacterial infection as other possible causes of the patient’s facial swelling.

Acne conglobata is a form of severe inflammatory cystic acne that affects the face, chest, and back. It is characterized by nodules, cysts, large open comedones, and interconnecting sinuses.^1,2 Although this case of acne was severe, the young man did not have large open comedones or interconnecting sinus tracts. In addition, his trunk was unaffected.

Acne fulminans is a type of severe cystic acne with systemic symptoms, which is mainly seen in adolescent males. It may have a sudden onset and is characterized by ulcerated, nodular, and painful acne that bleeds, crusts, and results in severe scarring. Patients may present with fever, joint pain, and weight loss.^1,2 Our patient did not have systemic symptoms despite the severe facial swelling.

Bacterial infections of the skin usually are caused by Staphylococcus aureus (S aureus) or Streptococcus pyogenes and can lead to cellulitis and/or abscess formation.³ This process was considered as a complication of the severe acne, but the clinical picture was consistent with severe inflammation rather than a bacterial superinfection.

Continue to: Treatment of choice includes prednisone and doxycycline

The FP knew that the severe inflammation and swelling needed to be treated with a systemic steroid, so he started the patient on prednisone 60 mg orally once daily at the time of presentation. Additionally, the FP prescribed doxycycline 100 mg bid to treat the inflammation and to cover a possible superinfection.

Doxycycline is the oral antibiotic of choice for inflammatory acne.² It also is a good antibiotic for cutaneous methicillin-resistant S aureus infection.³ Although it is not the treatment of choice for a nonpurulent cellulitis, it is a good option for cellulitis with purulence.³

With the working diagnosis of severe inflammatory acne, it was expected that the prednisone and doxycycline would be effective. Treating with antibiotics alone (for fear of causing immunosuppression with steroids) would have likely been less effective. Since the patient lived 6 hours from the hospital by foot and was alone, he was admitted overnight for observation (with parental permission obtained over the phone).

The patient’s condition improved overnight. Marked improvement in the swelling and inflammation was noted the following morning (FIGURES 2A and 2B). The patient was pleased with the results and was discharged to return home (transportation provided by the hospital) with directions on how to continue the oral prednisone and doxycycline. He was given 1 month of doxycycline to continue (100 mg bid) and enough oral prednisone to take 40 mg/d for 1 week and 20 mg/d for another week. He was given a follow-up appointment for 2 weeks to assess his acne and his ability to tolerate the medications.

PHOTOS COURTESY OF RICHARD USATINE, MD

He was warned to avoid the sun as much as possible, as doxycycline is photosensitizing, and to use a large hat and sunscreen when the sun could not be avoided. (Another option would have been to prescribe minocycline 100 mg bid because it is equally effective for acne with a lower risk for photosensitization.²)

Continue to: Access to medical care was limited

Access to medical care was limited. Although this patient was a good candidate for oral isotretinoin treatment, he did not have access to this medication in rural Panama. Managing his acne was challenging because of the severity of the case and the patient’s sun exposure in this tropical country. Access to the full range of topical anti-acne treatments also is limited in rural Panama, but fortunately his response to the initial oral medications was good.

The future plan at the follow-up visit consisted of continuing the doxycycline, stopping the prednisone, and adding topical benzoyl peroxide. The purpose of the benzoyl peroxide was to prevent bacterial resistance to the antibiotic.²

CORRESPONDENCE
Richard Usatine, MD, Skin Clinic, 903 W Martin Ave, Historic Building, San Antonio, TX 78207; [email protected]

A 16-year-old boy sought care at a rural hospital in Panama for facial swelling that began 3 months earlier. He was seen by a family physician (RU) and a team of medical students who were there as part of a volunteer effort. The patient had difficulty opening his left eye. He denied fever and chills, and said he felt well—other than his inability to see out of his left eye. He denied any changes to his vision when he held the swollen eyelids open. The patient lived on a ranch far outside of town, and he walked down a mountain road alone for 6 hours with one eye swollen shut to present for treatment. The patient was not taking any medications and had not received any health care since his last vaccine several years ago. On physical exam, his vital signs were normal, and the swelling under his left eye was somewhat tender and slightly warm to the touch. There were no lesions on his trunk and the remainder of the exam was normal.

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

The family physician (FP) diagnosed severe inflammatory nodulocystic acne in this patient. He initially was concerned about possible cellulitis or an abscess, but his clinical experience suggested the swelling was secondary to severe inflammation and not a bacterial infection. The FP noted that the patient was afebrile and lacked systemic symptoms. In addition, the presence of open and closed comedones on the face, as well as the patient’s age and sex, supported the diagnosis of acne. No tests were performed; the diagnosis was made clinically.

A case of acne, or a bacterial infection?

The FP considered acne conglobata, acne fulminans, and a bacterial infection as other possible causes of the patient’s facial swelling.

Acne conglobata is a form of severe inflammatory cystic acne that affects the face, chest, and back. It is characterized by nodules, cysts, large open comedones, and interconnecting sinuses.^1,2 Although this case of acne was severe, the young man did not have large open comedones or interconnecting sinus tracts. In addition, his trunk was unaffected.

Acne fulminans is a type of severe cystic acne with systemic symptoms, which is mainly seen in adolescent males. It may have a sudden onset and is characterized by ulcerated, nodular, and painful acne that bleeds, crusts, and results in severe scarring. Patients may present with fever, joint pain, and weight loss.^1,2 Our patient did not have systemic symptoms despite the severe facial swelling.

Bacterial infections of the skin usually are caused by Staphylococcus aureus (S aureus) or Streptococcus pyogenes and can lead to cellulitis and/or abscess formation.³ This process was considered as a complication of the severe acne, but the clinical picture was consistent with severe inflammation rather than a bacterial superinfection.

Continue to: Treatment of choice includes prednisone and doxycycline

The FP knew that the severe inflammation and swelling needed to be treated with a systemic steroid, so he started the patient on prednisone 60 mg orally once daily at the time of presentation. Additionally, the FP prescribed doxycycline 100 mg bid to treat the inflammation and to cover a possible superinfection.

Doxycycline is the oral antibiotic of choice for inflammatory acne.² It also is a good antibiotic for cutaneous methicillin-resistant S aureus infection.³ Although it is not the treatment of choice for a nonpurulent cellulitis, it is a good option for cellulitis with purulence.³

With the working diagnosis of severe inflammatory acne, it was expected that the prednisone and doxycycline would be effective. Treating with antibiotics alone (for fear of causing immunosuppression with steroids) would have likely been less effective. Since the patient lived 6 hours from the hospital by foot and was alone, he was admitted overnight for observation (with parental permission obtained over the phone).

The patient’s condition improved overnight. Marked improvement in the swelling and inflammation was noted the following morning (FIGURES 2A and 2B). The patient was pleased with the results and was discharged to return home (transportation provided by the hospital) with directions on how to continue the oral prednisone and doxycycline. He was given 1 month of doxycycline to continue (100 mg bid) and enough oral prednisone to take 40 mg/d for 1 week and 20 mg/d for another week. He was given a follow-up appointment for 2 weeks to assess his acne and his ability to tolerate the medications.

PHOTOS COURTESY OF RICHARD USATINE, MD

He was warned to avoid the sun as much as possible, as doxycycline is photosensitizing, and to use a large hat and sunscreen when the sun could not be avoided. (Another option would have been to prescribe minocycline 100 mg bid because it is equally effective for acne with a lower risk for photosensitization.²)

Continue to: Access to medical care was limited

Access to medical care was limited. Although this patient was a good candidate for oral isotretinoin treatment, he did not have access to this medication in rural Panama. Managing his acne was challenging because of the severity of the case and the patient’s sun exposure in this tropical country. Access to the full range of topical anti-acne treatments also is limited in rural Panama, but fortunately his response to the initial oral medications was good.

The future plan at the follow-up visit consisted of continuing the doxycycline, stopping the prednisone, and adding topical benzoyl peroxide. The purpose of the benzoyl peroxide was to prevent bacterial resistance to the antibiotic.²

CORRESPONDENCE
Richard Usatine, MD, Skin Clinic, 903 W Martin Ave, Historic Building, San Antonio, TX 78207; [email protected]