There is abundant research being conducted on the use of artificial intelligence (AI) to improve diagnosis in dermatology. Recently, convolutional neural networks trained using large image libraries have achieved parity with dermatologists in discriminating between benign and malignant lesions.¹ There are expectations that these systems, as they improve and are implemented in mobile electronic devices, will revolutionize diagnosis. Substantially less attention has been given to the use of AI to guide management options following a diagnosis. There are several reasons this area lends itself to the application of AI.

In 2015, the National Library of Medicine indexed more than 800,000 articles.² Medical literature is growing at an overwhelming pace that makes it challenging for health care professionals to read, retain, and appropriately implement the latest research into their care. One survey found that physicians spend no more than 4 hours per week reading medical journals, and for the majority of articles, only the abstracts are read.³ Conversely, AI networks today are able to interpret millions of pages of data within seconds. It is worth investigating how AI can be used to improve treatment and management decisions made by physicians.

Cognitive computing is a modern approach to AI that incorporates natural language processing, machine learning, and other techniques to answer questions. One cognitive computing system developed by IBM research in 2007, Watson, can interpret a user’s query using natural language processing and then generate hypotheses. It searches data sources extensively to find and score evidence for each candidate hypothesis.⁴ This information is synthesized to provide a simple output: ranked answers with associated confidence scores. Machine learning is used to improve the answers with feedback, training, and repetition.^4,5

Watson Oncology, an ongoing collaboration between IBM and Memorial Sloan Kettering Cancer Center, is an application of cognitive computing to medicine. At Memorial Sloan Kettering, Watson has been trained by expert clinicians to provide an individualized, evidence-based list of therapeutic options for oncologists and patients to discuss. Furthermore, Watson is capable of taking patient preferences into consideration.⁴

In the near future, there also may be a role that cognitive computing could play in aiding dermatologists. Dermatologists manage a multitude of conditions requiring systemic therapies such as chemotherapeutics, biologics, and immunosuppressant medications. Frequently, the patient population has a complicated medical history with multiple comorbidities. Although current electronic health record (EHR) systems are able to assist physicians with structured numerical data such as vitals and laboratory results, cognitive computing systems could interpret the natural language of journal articles, textbooks, and published guidelines, as well as the narrative components of EHR notes. Outcomes from similar patients also could be used as inputs. With enough data, cognitive computing systems may be able to identify associations and epidemiologic trends that would not otherwise be noticed. As described by Miotto et al,⁶ one system, “deep patient,” was able to accurately predict the development of schizophrenia, diabetes mellitus, and various cancers based on EHR data. Patient genetic information also could one day be used to generate new insights into pharmacogenomics.

The benefit of a cognitive computing decision support system is that ineffective treatments and adverse reactions could be minimized, which may improve outcomes and reduce costs. Artificial intelligence also could help to decrease work burden so that physicians can spend more time with their patients, resulting in improved patient satisfaction and overall increased access to the specialty.

As with other clinical decision support systems, a number of challenges exist with the integration of cognitive computing into real care. One obstacle unique to machine learning algorithms is the black box problem. For instance, the skin lesion–identifying neural network cannot be questioned to determine which factors it used to arrive at its diagnosis. This shortcoming can lead to dangerous situations, such as the one reported by Caruana et al.⁷ A predictive model classified patients with pneumonia and a history of asthma as having a lower mortality risk than those with pneumonia alone because the model was unable to recognize the confounder that asthmatic patients were preemptively admitted to the intensive care unit and treated more aggressively, which is another reason that AI recommendations must always be evaluated by a physician.⁷ Physician and patient input also will be integral to incorporate contextual and qualitative information that may not be accessible to computers.⁸

As cognitive computing decision support systems are primarily used in oncology, they will need to be adjusted to optimize them for dermatologic conditions. It also will be up to health care providers to benchmark the performance of these systems.

Current clinical decision support systems that do not use AI have struggled to improve major patient outcomes such as mortality. These systems have been hobbled by poor usability and human-computer integration. Clinicians find their alerts and warnings to be a nuisance. The adoption of cognitive computing systems has the potential to give clinicians an intelligent partner. Their natural language processing, ability to comprehend questions, and easily understandable output give them an inherent ease of use that simplifies interactions with clinicians. Rather than replacing physicians, these systems will free clinicians to spend more of their time on the components of care that only a human can provide.

There is abundant research being conducted on the use of artificial intelligence (AI) to improve diagnosis in dermatology. Recently, convolutional neural networks trained using large image libraries have achieved parity with dermatologists in discriminating between benign and malignant lesions.¹ There are expectations that these systems, as they improve and are implemented in mobile electronic devices, will revolutionize diagnosis. Substantially less attention has been given to the use of AI to guide management options following a diagnosis. There are several reasons this area lends itself to the application of AI.

In 2015, the National Library of Medicine indexed more than 800,000 articles.² Medical literature is growing at an overwhelming pace that makes it challenging for health care professionals to read, retain, and appropriately implement the latest research into their care. One survey found that physicians spend no more than 4 hours per week reading medical journals, and for the majority of articles, only the abstracts are read.³ Conversely, AI networks today are able to interpret millions of pages of data within seconds. It is worth investigating how AI can be used to improve treatment and management decisions made by physicians.

Cognitive computing is a modern approach to AI that incorporates natural language processing, machine learning, and other techniques to answer questions. One cognitive computing system developed by IBM research in 2007, Watson, can interpret a user’s query using natural language processing and then generate hypotheses. It searches data sources extensively to find and score evidence for each candidate hypothesis.⁴ This information is synthesized to provide a simple output: ranked answers with associated confidence scores. Machine learning is used to improve the answers with feedback, training, and repetition.^4,5

Watson Oncology, an ongoing collaboration between IBM and Memorial Sloan Kettering Cancer Center, is an application of cognitive computing to medicine. At Memorial Sloan Kettering, Watson has been trained by expert clinicians to provide an individualized, evidence-based list of therapeutic options for oncologists and patients to discuss. Furthermore, Watson is capable of taking patient preferences into consideration.⁴

In the near future, there also may be a role that cognitive computing could play in aiding dermatologists. Dermatologists manage a multitude of conditions requiring systemic therapies such as chemotherapeutics, biologics, and immunosuppressant medications. Frequently, the patient population has a complicated medical history with multiple comorbidities. Although current electronic health record (EHR) systems are able to assist physicians with structured numerical data such as vitals and laboratory results, cognitive computing systems could interpret the natural language of journal articles, textbooks, and published guidelines, as well as the narrative components of EHR notes. Outcomes from similar patients also could be used as inputs. With enough data, cognitive computing systems may be able to identify associations and epidemiologic trends that would not otherwise be noticed. As described by Miotto et al,⁶ one system, “deep patient,” was able to accurately predict the development of schizophrenia, diabetes mellitus, and various cancers based on EHR data. Patient genetic information also could one day be used to generate new insights into pharmacogenomics.

The benefit of a cognitive computing decision support system is that ineffective treatments and adverse reactions could be minimized, which may improve outcomes and reduce costs. Artificial intelligence also could help to decrease work burden so that physicians can spend more time with their patients, resulting in improved patient satisfaction and overall increased access to the specialty.

As with other clinical decision support systems, a number of challenges exist with the integration of cognitive computing into real care. One obstacle unique to machine learning algorithms is the black box problem. For instance, the skin lesion–identifying neural network cannot be questioned to determine which factors it used to arrive at its diagnosis. This shortcoming can lead to dangerous situations, such as the one reported by Caruana et al.⁷ A predictive model classified patients with pneumonia and a history of asthma as having a lower mortality risk than those with pneumonia alone because the model was unable to recognize the confounder that asthmatic patients were preemptively admitted to the intensive care unit and treated more aggressively, which is another reason that AI recommendations must always be evaluated by a physician.⁷ Physician and patient input also will be integral to incorporate contextual and qualitative information that may not be accessible to computers.⁸

As cognitive computing decision support systems are primarily used in oncology, they will need to be adjusted to optimize them for dermatologic conditions. It also will be up to health care providers to benchmark the performance of these systems.

Current clinical decision support systems that do not use AI have struggled to improve major patient outcomes such as mortality. These systems have been hobbled by poor usability and human-computer integration. Clinicians find their alerts and warnings to be a nuisance. The adoption of cognitive computing systems has the potential to give clinicians an intelligent partner. Their natural language processing, ability to comprehend questions, and easily understandable output give them an inherent ease of use that simplifies interactions with clinicians. Rather than replacing physicians, these systems will free clinicians to spend more of their time on the components of care that only a human can provide.

There is abundant research being conducted on the use of artificial intelligence (AI) to improve diagnosis in dermatology. Recently, convolutional neural networks trained using large image libraries have achieved parity with dermatologists in discriminating between benign and malignant lesions.¹ There are expectations that these systems, as they improve and are implemented in mobile electronic devices, will revolutionize diagnosis. Substantially less attention has been given to the use of AI to guide management options following a diagnosis. There are several reasons this area lends itself to the application of AI.

In 2015, the National Library of Medicine indexed more than 800,000 articles.² Medical literature is growing at an overwhelming pace that makes it challenging for health care professionals to read, retain, and appropriately implement the latest research into their care. One survey found that physicians spend no more than 4 hours per week reading medical journals, and for the majority of articles, only the abstracts are read.³ Conversely, AI networks today are able to interpret millions of pages of data within seconds. It is worth investigating how AI can be used to improve treatment and management decisions made by physicians.

Cognitive computing is a modern approach to AI that incorporates natural language processing, machine learning, and other techniques to answer questions. One cognitive computing system developed by IBM research in 2007, Watson, can interpret a user’s query using natural language processing and then generate hypotheses. It searches data sources extensively to find and score evidence for each candidate hypothesis.⁴ This information is synthesized to provide a simple output: ranked answers with associated confidence scores. Machine learning is used to improve the answers with feedback, training, and repetition.^4,5

Watson Oncology, an ongoing collaboration between IBM and Memorial Sloan Kettering Cancer Center, is an application of cognitive computing to medicine. At Memorial Sloan Kettering, Watson has been trained by expert clinicians to provide an individualized, evidence-based list of therapeutic options for oncologists and patients to discuss. Furthermore, Watson is capable of taking patient preferences into consideration.⁴

In the near future, there also may be a role that cognitive computing could play in aiding dermatologists. Dermatologists manage a multitude of conditions requiring systemic therapies such as chemotherapeutics, biologics, and immunosuppressant medications. Frequently, the patient population has a complicated medical history with multiple comorbidities. Although current electronic health record (EHR) systems are able to assist physicians with structured numerical data such as vitals and laboratory results, cognitive computing systems could interpret the natural language of journal articles, textbooks, and published guidelines, as well as the narrative components of EHR notes. Outcomes from similar patients also could be used as inputs. With enough data, cognitive computing systems may be able to identify associations and epidemiologic trends that would not otherwise be noticed. As described by Miotto et al,⁶ one system, “deep patient,” was able to accurately predict the development of schizophrenia, diabetes mellitus, and various cancers based on EHR data. Patient genetic information also could one day be used to generate new insights into pharmacogenomics.

The benefit of a cognitive computing decision support system is that ineffective treatments and adverse reactions could be minimized, which may improve outcomes and reduce costs. Artificial intelligence also could help to decrease work burden so that physicians can spend more time with their patients, resulting in improved patient satisfaction and overall increased access to the specialty.

As with other clinical decision support systems, a number of challenges exist with the integration of cognitive computing into real care. One obstacle unique to machine learning algorithms is the black box problem. For instance, the skin lesion–identifying neural network cannot be questioned to determine which factors it used to arrive at its diagnosis. This shortcoming can lead to dangerous situations, such as the one reported by Caruana et al.⁷ A predictive model classified patients with pneumonia and a history of asthma as having a lower mortality risk than those with pneumonia alone because the model was unable to recognize the confounder that asthmatic patients were preemptively admitted to the intensive care unit and treated more aggressively, which is another reason that AI recommendations must always be evaluated by a physician.⁷ Physician and patient input also will be integral to incorporate contextual and qualitative information that may not be accessible to computers.⁸

As cognitive computing decision support systems are primarily used in oncology, they will need to be adjusted to optimize them for dermatologic conditions. It also will be up to health care providers to benchmark the performance of these systems.

Current clinical decision support systems that do not use AI have struggled to improve major patient outcomes such as mortality. These systems have been hobbled by poor usability and human-computer integration. Clinicians find their alerts and warnings to be a nuisance. The adoption of cognitive computing systems has the potential to give clinicians an intelligent partner. Their natural language processing, ability to comprehend questions, and easily understandable output give them an inherent ease of use that simplifies interactions with clinicians. Rather than replacing physicians, these systems will free clinicians to spend more of their time on the components of care that only a human can provide.

Atopic dermatitis (AD) is most often treated with mid-potency topical corticosteroids.^1,2 Although this option is effective, not all patients respond to treatment, and those who do may lose efficacy over time, a phenomenon known as tachyphylaxis. The pathophysiology of tachyphylaxis to topical corticosteroids has been ascribed to loss of corticosteroid receptor function,³ but the evidence is weak.^3,4 Patients with severe treatment-resistant AD improve when treated with mid-potency topical steroids in an inpatient setting; therefore, treatment resistance to topical corticosteroids may be largely due to poor adherence.⁵

Patients with treatment-resistant AD generally improve when treated with topical corticosteroids under conditions designed to promote treatment adherence, but this improvement often is reported for study groups, not individual patients. Focusing on group data may not give a clear picture of what is happening at the individual level. In this study, we evaluated changes at an individual level to determine how frequently AD patients who were previously treated with topical corticosteroids unsuccessfully would respond to desoximetasone spray 0.25% under conditions designed to promote good adherence over a 7-day period.

Methods

This open-label, randomized, single-center clinical study included 12 patients with AD who were previously unsuccessfully treated with topical corticosteroids in the Department of Dermatology at Wake Forest Baptist Medical Center (Winston-Salem, North Carolina)(Table 1). The study was approved by the local institutional review board.

Inclusion criteria included men and women 18 years or older at baseline who had AD that was considered amenable to therapy with topical corticosteroids by the clinician and were able to comply with the study protocol (Figure). Written informed consent also was obtained from each patient. Women who were pregnant, breastfeeding, or unwilling to practice birth control during participation in the study were excluded. Other exclusion criteria included presence of a condition that in the opinion of the investigator would compromise the safety of the patient or quality of data as well as patients with no access to a telephone throughout the day. Patients diagnosed with conditions affecting adherence to treatment (eg, dementia, Alzheimer disease), those with a history of allergy or sensitivity to corticosteroids, and those with a history of drug hypersensitivity were excluded from the study.

Results

Twelve AD patients who were previously unsuccessfully treated with topical corticosteroids were recruited for the study. Six patients were randomized to the intervention group and 6 were randomized to the control group. Fifty percent of patients were black, 50% were women, and the average age was 50.4 years. All 12 patients completed the study.

At the end of the study, most patients showed improvement in all evaluation parameters (eFigure). All 12 patients showed improvement in pruritus visual analog scores; 83.3% (10/12) showed improved EASI scores, 75.0% (9/12) showed improved TLSS scores, and 58.3% (7/12) showed improved IGA scores (Tables 2–5). Patients who received telephone calls in the intervention group showed greater improvement compared to those in the control group, except for pruritus; the mean reduction in pruritus was 76.9% in the intervention group versus 87.0% in the control group. The mean improvement in EASI score was 46.9% in the intervention group versus 21.1% in the control group. The mean improvement in TLSS score was 38.3% in the intervention group versus 9.7% in the control group. The mean improvement in IGA score was 45.8% in the intervention group versus 4.2% in the control group. Only one patient in the control group (patient 8) showed lower EASI, TLSS, and IGA scores at baseline.

Comment

Although topical corticosteroids are the mainstay for treatment of AD, many patients report treatment resistance after a period of a few doses or longer.^6-9 There is strong evidence demonstrating rapid corticosteroid receptor downregulation in tissues after corticosteroid therapy, which is the accepted mechanism for tachyphylaxis, but the timing of this effect does not match up with clinical experiences. The physiologic significance of corticosteroid agonist-induced receptor downregulation is unknown and may not have any considerable effect on corticosteroid efficacy.³ A systematic review by Taheri et al³ on the development of resistance to topical corticosteroids proposed 2 theories for the underlying pathogenesis of tachyphylaxis: (1) long-term patient nonadherence, and (2) the initial maximal response during the first few weeks of therapy eventually plateaus. Because corticosteroids may plateau after a certain number of doses, natural disease flare-ups during this period may give the wrong impression of tachyphylaxis.¹⁰ The treatment “resistance” reported by the patients in our study may have been due to this plateau effect or to poor adherence.

Our finding that nearly all patients had rapid improvement of AD with the topical corticosteroid is not definitive proof but supports the notion that tachyphylaxis is largely mediated by poor adherence to treatment. Patients rapidly improved over the short study period. The short duration of treatment and multiple visits over the study period were designed to help ensure patient adherence. Rapid improvement in AD when topical corticosteroids are used should be expected, as AD patients have rapid improvement with application of topical corticosteroids in inpatient settings.^11,12

Poor adherence to topical medication is common. In a Danish study, 99 of 322 patients (31%) did not redeem their AD prescriptions.¹³ In a single-center, 5-day, prospective study evaluating the use of fluocinonide cream 0.1% for treatment of children and adults with AD, the median percentage of prescribed doses taken was 40%, according to objective electronic monitors, even though patients reported 100% adherence in their medication diaries.Better adherence was seen on day 1 of treatment in which 66.6% (6/9) of patients adhered to their treatment strategy versus day 5 in which only 11.1% (1/9) of patients used their medication.¹

Topical corticosteroids are safe and efficacious if used appropriately; however, patients commonly express fear and anxiety about using them. Topical corticosteroid phobia may stem from a misconception that these products carry the same adverse effects as their oral and systemic counterparts, which may be perpetuated by the media.¹ Of 200 dermatology patients surveyed, 72.5% expressed concern about using topical corticosteroids on themselves or their children’s skin, and 24% of these patients stated they were noncompliant with their medication because of these worries. Almost 50% of patients requested prescriptions for corticosteroid-sparing medications such as tacrolimus.¹ Patient education is important to help ensure treatment adherence. Other factors that can affect treatment adherence include forgetfulness; the chronic nature of AD; the need for ongoing application of topical treatments; prohibitive costs of some topical agents; and complexities in coordinating school, work, and family plans with the treatment regimen.²

We attempted to ensure good treatment adherence in our study by calling the patients in the intervention group twice daily. The mean improvement in EASI, TLSS, and IGA scores was higher in the intervention group versus the control group, which suggests that patient reminders have at least some benefit. Because AD treatment resistance appears more closely tied to nonadherence rather than loss of medication efficacy, it seems prudent to focus on interventions that would improve treatment adherence; however, such interventions generally are not well tested. Recommended interventions have included educating patients about the side effects of topical corticosteroids, avoiding use of medical jargon, and taking patient vehicle preference into account when prescribing treatments.⁸ Patients should be scheduled for a return visit within 1 to 2 weeks, as early return visits can augment treatment adherence.¹⁴ At the return visit, there can be a more detailed discussion of long-term management and side effects.⁸

Limitations of our study included a small sample size and brief treatment duration. Even though the patients had previously reported treatment failure with topical corticosteroids, all demonstrated improvement in only 1 week with a potent topical corticosteroid. The treatment resistance that initially was reported likely was due to poor adherence, but it is possible for AD patients to be resistant to treatment with topical corticosteroids due to allergic contact dermatitis. Patients could theoretically be allergic to components of the vehicle used in topical corticosteroids, which could aggravate their dermatitis; however, this effect seems unlikely in our patient population, as all the patients in our study showed improvement following treatment. Another study limitation was that adherence was not measured. The frequent follow-up visits were designed to encourage treatment adherence, but adherence was not specifically assessed. Although patients were encouraged to only use the desoximetasone spray during the study, it is not known whether patients used other products.

Conclusion

Some AD patients exhibit apparent decreased efficacy of topical corticosteroids over time, but this tachyphylaxis phenomenon is more likely due to poor treatment adherence than to loss of corticosteroid responsiveness. In our study, AD patients who reported treatment failure with topical corticosteroids improved rapidly with topical corticosteroids under conditions designed to promote good adherence to treatment. The majority of patients improved in all 4 parameters used for evaluating disease severity, with 100% of patients reporting improvement in pruritus. Intervention to improve treatment adherence may lead to better health outcomes. When AD appears resistant to topical corticosteroids, addressing adherence issues may be critical.

Atopic dermatitis (AD) is most often treated with mid-potency topical corticosteroids.^1,2 Although this option is effective, not all patients respond to treatment, and those who do may lose efficacy over time, a phenomenon known as tachyphylaxis. The pathophysiology of tachyphylaxis to topical corticosteroids has been ascribed to loss of corticosteroid receptor function,³ but the evidence is weak.^3,4 Patients with severe treatment-resistant AD improve when treated with mid-potency topical steroids in an inpatient setting; therefore, treatment resistance to topical corticosteroids may be largely due to poor adherence.⁵

Patients with treatment-resistant AD generally improve when treated with topical corticosteroids under conditions designed to promote treatment adherence, but this improvement often is reported for study groups, not individual patients. Focusing on group data may not give a clear picture of what is happening at the individual level. In this study, we evaluated changes at an individual level to determine how frequently AD patients who were previously treated with topical corticosteroids unsuccessfully would respond to desoximetasone spray 0.25% under conditions designed to promote good adherence over a 7-day period.

Methods

This open-label, randomized, single-center clinical study included 12 patients with AD who were previously unsuccessfully treated with topical corticosteroids in the Department of Dermatology at Wake Forest Baptist Medical Center (Winston-Salem, North Carolina)(Table 1). The study was approved by the local institutional review board.

Inclusion criteria included men and women 18 years or older at baseline who had AD that was considered amenable to therapy with topical corticosteroids by the clinician and were able to comply with the study protocol (Figure). Written informed consent also was obtained from each patient. Women who were pregnant, breastfeeding, or unwilling to practice birth control during participation in the study were excluded. Other exclusion criteria included presence of a condition that in the opinion of the investigator would compromise the safety of the patient or quality of data as well as patients with no access to a telephone throughout the day. Patients diagnosed with conditions affecting adherence to treatment (eg, dementia, Alzheimer disease), those with a history of allergy or sensitivity to corticosteroids, and those with a history of drug hypersensitivity were excluded from the study.

Results

Twelve AD patients who were previously unsuccessfully treated with topical corticosteroids were recruited for the study. Six patients were randomized to the intervention group and 6 were randomized to the control group. Fifty percent of patients were black, 50% were women, and the average age was 50.4 years. All 12 patients completed the study.

At the end of the study, most patients showed improvement in all evaluation parameters (eFigure). All 12 patients showed improvement in pruritus visual analog scores; 83.3% (10/12) showed improved EASI scores, 75.0% (9/12) showed improved TLSS scores, and 58.3% (7/12) showed improved IGA scores (Tables 2–5). Patients who received telephone calls in the intervention group showed greater improvement compared to those in the control group, except for pruritus; the mean reduction in pruritus was 76.9% in the intervention group versus 87.0% in the control group. The mean improvement in EASI score was 46.9% in the intervention group versus 21.1% in the control group. The mean improvement in TLSS score was 38.3% in the intervention group versus 9.7% in the control group. The mean improvement in IGA score was 45.8% in the intervention group versus 4.2% in the control group. Only one patient in the control group (patient 8) showed lower EASI, TLSS, and IGA scores at baseline.

Comment

Although topical corticosteroids are the mainstay for treatment of AD, many patients report treatment resistance after a period of a few doses or longer.^6-9 There is strong evidence demonstrating rapid corticosteroid receptor downregulation in tissues after corticosteroid therapy, which is the accepted mechanism for tachyphylaxis, but the timing of this effect does not match up with clinical experiences. The physiologic significance of corticosteroid agonist-induced receptor downregulation is unknown and may not have any considerable effect on corticosteroid efficacy.³ A systematic review by Taheri et al³ on the development of resistance to topical corticosteroids proposed 2 theories for the underlying pathogenesis of tachyphylaxis: (1) long-term patient nonadherence, and (2) the initial maximal response during the first few weeks of therapy eventually plateaus. Because corticosteroids may plateau after a certain number of doses, natural disease flare-ups during this period may give the wrong impression of tachyphylaxis.¹⁰ The treatment “resistance” reported by the patients in our study may have been due to this plateau effect or to poor adherence.

Our finding that nearly all patients had rapid improvement of AD with the topical corticosteroid is not definitive proof but supports the notion that tachyphylaxis is largely mediated by poor adherence to treatment. Patients rapidly improved over the short study period. The short duration of treatment and multiple visits over the study period were designed to help ensure patient adherence. Rapid improvement in AD when topical corticosteroids are used should be expected, as AD patients have rapid improvement with application of topical corticosteroids in inpatient settings.^11,12

Poor adherence to topical medication is common. In a Danish study, 99 of 322 patients (31%) did not redeem their AD prescriptions.¹³ In a single-center, 5-day, prospective study evaluating the use of fluocinonide cream 0.1% for treatment of children and adults with AD, the median percentage of prescribed doses taken was 40%, according to objective electronic monitors, even though patients reported 100% adherence in their medication diaries.Better adherence was seen on day 1 of treatment in which 66.6% (6/9) of patients adhered to their treatment strategy versus day 5 in which only 11.1% (1/9) of patients used their medication.¹

Topical corticosteroids are safe and efficacious if used appropriately; however, patients commonly express fear and anxiety about using them. Topical corticosteroid phobia may stem from a misconception that these products carry the same adverse effects as their oral and systemic counterparts, which may be perpetuated by the media.¹ Of 200 dermatology patients surveyed, 72.5% expressed concern about using topical corticosteroids on themselves or their children’s skin, and 24% of these patients stated they were noncompliant with their medication because of these worries. Almost 50% of patients requested prescriptions for corticosteroid-sparing medications such as tacrolimus.¹ Patient education is important to help ensure treatment adherence. Other factors that can affect treatment adherence include forgetfulness; the chronic nature of AD; the need for ongoing application of topical treatments; prohibitive costs of some topical agents; and complexities in coordinating school, work, and family plans with the treatment regimen.²

We attempted to ensure good treatment adherence in our study by calling the patients in the intervention group twice daily. The mean improvement in EASI, TLSS, and IGA scores was higher in the intervention group versus the control group, which suggests that patient reminders have at least some benefit. Because AD treatment resistance appears more closely tied to nonadherence rather than loss of medication efficacy, it seems prudent to focus on interventions that would improve treatment adherence; however, such interventions generally are not well tested. Recommended interventions have included educating patients about the side effects of topical corticosteroids, avoiding use of medical jargon, and taking patient vehicle preference into account when prescribing treatments.⁸ Patients should be scheduled for a return visit within 1 to 2 weeks, as early return visits can augment treatment adherence.¹⁴ At the return visit, there can be a more detailed discussion of long-term management and side effects.⁸

Limitations of our study included a small sample size and brief treatment duration. Even though the patients had previously reported treatment failure with topical corticosteroids, all demonstrated improvement in only 1 week with a potent topical corticosteroid. The treatment resistance that initially was reported likely was due to poor adherence, but it is possible for AD patients to be resistant to treatment with topical corticosteroids due to allergic contact dermatitis. Patients could theoretically be allergic to components of the vehicle used in topical corticosteroids, which could aggravate their dermatitis; however, this effect seems unlikely in our patient population, as all the patients in our study showed improvement following treatment. Another study limitation was that adherence was not measured. The frequent follow-up visits were designed to encourage treatment adherence, but adherence was not specifically assessed. Although patients were encouraged to only use the desoximetasone spray during the study, it is not known whether patients used other products.

Conclusion

Some AD patients exhibit apparent decreased efficacy of topical corticosteroids over time, but this tachyphylaxis phenomenon is more likely due to poor treatment adherence than to loss of corticosteroid responsiveness. In our study, AD patients who reported treatment failure with topical corticosteroids improved rapidly with topical corticosteroids under conditions designed to promote good adherence to treatment. The majority of patients improved in all 4 parameters used for evaluating disease severity, with 100% of patients reporting improvement in pruritus. Intervention to improve treatment adherence may lead to better health outcomes. When AD appears resistant to topical corticosteroids, addressing adherence issues may be critical.

Atopic dermatitis (AD) is most often treated with mid-potency topical corticosteroids.^1,2 Although this option is effective, not all patients respond to treatment, and those who do may lose efficacy over time, a phenomenon known as tachyphylaxis. The pathophysiology of tachyphylaxis to topical corticosteroids has been ascribed to loss of corticosteroid receptor function,³ but the evidence is weak.^3,4 Patients with severe treatment-resistant AD improve when treated with mid-potency topical steroids in an inpatient setting; therefore, treatment resistance to topical corticosteroids may be largely due to poor adherence.⁵

Patients with treatment-resistant AD generally improve when treated with topical corticosteroids under conditions designed to promote treatment adherence, but this improvement often is reported for study groups, not individual patients. Focusing on group data may not give a clear picture of what is happening at the individual level. In this study, we evaluated changes at an individual level to determine how frequently AD patients who were previously treated with topical corticosteroids unsuccessfully would respond to desoximetasone spray 0.25% under conditions designed to promote good adherence over a 7-day period.

Methods

This open-label, randomized, single-center clinical study included 12 patients with AD who were previously unsuccessfully treated with topical corticosteroids in the Department of Dermatology at Wake Forest Baptist Medical Center (Winston-Salem, North Carolina)(Table 1). The study was approved by the local institutional review board.

Inclusion criteria included men and women 18 years or older at baseline who had AD that was considered amenable to therapy with topical corticosteroids by the clinician and were able to comply with the study protocol (Figure). Written informed consent also was obtained from each patient. Women who were pregnant, breastfeeding, or unwilling to practice birth control during participation in the study were excluded. Other exclusion criteria included presence of a condition that in the opinion of the investigator would compromise the safety of the patient or quality of data as well as patients with no access to a telephone throughout the day. Patients diagnosed with conditions affecting adherence to treatment (eg, dementia, Alzheimer disease), those with a history of allergy or sensitivity to corticosteroids, and those with a history of drug hypersensitivity were excluded from the study.

Results

Twelve AD patients who were previously unsuccessfully treated with topical corticosteroids were recruited for the study. Six patients were randomized to the intervention group and 6 were randomized to the control group. Fifty percent of patients were black, 50% were women, and the average age was 50.4 years. All 12 patients completed the study.

At the end of the study, most patients showed improvement in all evaluation parameters (eFigure). All 12 patients showed improvement in pruritus visual analog scores; 83.3% (10/12) showed improved EASI scores, 75.0% (9/12) showed improved TLSS scores, and 58.3% (7/12) showed improved IGA scores (Tables 2–5). Patients who received telephone calls in the intervention group showed greater improvement compared to those in the control group, except for pruritus; the mean reduction in pruritus was 76.9% in the intervention group versus 87.0% in the control group. The mean improvement in EASI score was 46.9% in the intervention group versus 21.1% in the control group. The mean improvement in TLSS score was 38.3% in the intervention group versus 9.7% in the control group. The mean improvement in IGA score was 45.8% in the intervention group versus 4.2% in the control group. Only one patient in the control group (patient 8) showed lower EASI, TLSS, and IGA scores at baseline.

Comment

Although topical corticosteroids are the mainstay for treatment of AD, many patients report treatment resistance after a period of a few doses or longer.^6-9 There is strong evidence demonstrating rapid corticosteroid receptor downregulation in tissues after corticosteroid therapy, which is the accepted mechanism for tachyphylaxis, but the timing of this effect does not match up with clinical experiences. The physiologic significance of corticosteroid agonist-induced receptor downregulation is unknown and may not have any considerable effect on corticosteroid efficacy.³ A systematic review by Taheri et al³ on the development of resistance to topical corticosteroids proposed 2 theories for the underlying pathogenesis of tachyphylaxis: (1) long-term patient nonadherence, and (2) the initial maximal response during the first few weeks of therapy eventually plateaus. Because corticosteroids may plateau after a certain number of doses, natural disease flare-ups during this period may give the wrong impression of tachyphylaxis.¹⁰ The treatment “resistance” reported by the patients in our study may have been due to this plateau effect or to poor adherence.

Our finding that nearly all patients had rapid improvement of AD with the topical corticosteroid is not definitive proof but supports the notion that tachyphylaxis is largely mediated by poor adherence to treatment. Patients rapidly improved over the short study period. The short duration of treatment and multiple visits over the study period were designed to help ensure patient adherence. Rapid improvement in AD when topical corticosteroids are used should be expected, as AD patients have rapid improvement with application of topical corticosteroids in inpatient settings.^11,12

Poor adherence to topical medication is common. In a Danish study, 99 of 322 patients (31%) did not redeem their AD prescriptions.¹³ In a single-center, 5-day, prospective study evaluating the use of fluocinonide cream 0.1% for treatment of children and adults with AD, the median percentage of prescribed doses taken was 40%, according to objective electronic monitors, even though patients reported 100% adherence in their medication diaries.Better adherence was seen on day 1 of treatment in which 66.6% (6/9) of patients adhered to their treatment strategy versus day 5 in which only 11.1% (1/9) of patients used their medication.¹

Topical corticosteroids are safe and efficacious if used appropriately; however, patients commonly express fear and anxiety about using them. Topical corticosteroid phobia may stem from a misconception that these products carry the same adverse effects as their oral and systemic counterparts, which may be perpetuated by the media.¹ Of 200 dermatology patients surveyed, 72.5% expressed concern about using topical corticosteroids on themselves or their children’s skin, and 24% of these patients stated they were noncompliant with their medication because of these worries. Almost 50% of patients requested prescriptions for corticosteroid-sparing medications such as tacrolimus.¹ Patient education is important to help ensure treatment adherence. Other factors that can affect treatment adherence include forgetfulness; the chronic nature of AD; the need for ongoing application of topical treatments; prohibitive costs of some topical agents; and complexities in coordinating school, work, and family plans with the treatment regimen.²

We attempted to ensure good treatment adherence in our study by calling the patients in the intervention group twice daily. The mean improvement in EASI, TLSS, and IGA scores was higher in the intervention group versus the control group, which suggests that patient reminders have at least some benefit. Because AD treatment resistance appears more closely tied to nonadherence rather than loss of medication efficacy, it seems prudent to focus on interventions that would improve treatment adherence; however, such interventions generally are not well tested. Recommended interventions have included educating patients about the side effects of topical corticosteroids, avoiding use of medical jargon, and taking patient vehicle preference into account when prescribing treatments.⁸ Patients should be scheduled for a return visit within 1 to 2 weeks, as early return visits can augment treatment adherence.¹⁴ At the return visit, there can be a more detailed discussion of long-term management and side effects.⁸

Limitations of our study included a small sample size and brief treatment duration. Even though the patients had previously reported treatment failure with topical corticosteroids, all demonstrated improvement in only 1 week with a potent topical corticosteroid. The treatment resistance that initially was reported likely was due to poor adherence, but it is possible for AD patients to be resistant to treatment with topical corticosteroids due to allergic contact dermatitis. Patients could theoretically be allergic to components of the vehicle used in topical corticosteroids, which could aggravate their dermatitis; however, this effect seems unlikely in our patient population, as all the patients in our study showed improvement following treatment. Another study limitation was that adherence was not measured. The frequent follow-up visits were designed to encourage treatment adherence, but adherence was not specifically assessed. Although patients were encouraged to only use the desoximetasone spray during the study, it is not known whether patients used other products.

Conclusion

Some AD patients exhibit apparent decreased efficacy of topical corticosteroids over time, but this tachyphylaxis phenomenon is more likely due to poor treatment adherence than to loss of corticosteroid responsiveness. In our study, AD patients who reported treatment failure with topical corticosteroids improved rapidly with topical corticosteroids under conditions designed to promote good adherence to treatment. The majority of patients improved in all 4 parameters used for evaluating disease severity, with 100% of patients reporting improvement in pruritus. Intervention to improve treatment adherence may lead to better health outcomes. When AD appears resistant to topical corticosteroids, addressing adherence issues may be critical.

Case Report

A 7-year-old boy with a history of shellfish anaphylaxis, pollen allergy, asthma, rhinoconjunctivitis, frequent headaches and ear infections, sinusitis, bronchitis, vitiligo, warts, and cold sores presented to our dermatology clinic for evaluation of a widespread crusting, cracking, red rash that had been present since 6 months of age. The patient’s mother reported that he had many sleepless nights from uncontrolled itching. His medications included albuterol solution for nebulization, loratadine, and montelukast. Prior to the current presentation he had been treated with triamcinolone and betamethasone creams by the pediatrician. Despite compliance with topical therapy, his mother stated the itching persisted and lesions lingered with minimal improvement. He also was treated with oral corticosteroids for episodic sinusitis and bronchitis, which was beneficial to the skin lesions for only a short duration. The patient was adopted and therefore his family history was unavailable.

During physical examination, the patient was in the fetal position on the examination table and appeared uncomfortable, scratching himself. The patient admitted to severe widespread itching and burning. On skin examination, multiple thick, lichenified, highly pruritic plaques coalesced on the knees, ankles, arms, and wrists, and very discreet scaly patches were present on the scalp. Annular patches covered 50% of the patient’s body, with highly inflamed lesions concentrated in skin folds (Figure 1), leading to diagnosis of atopic dermatitis (AD).

Five days after treatment with a 300-mg SQ dupilumab injection, the patient returned to clinic for evaluation of a vesicular rash with subsequent peeling confined to the shoulders (Figure 2). He and his mother denied any UV exposure, citing he had been completely out of the sun. He denied constitutional symptoms including fever, malaise, swelling, joint pain, headache, muscle pain, nausea, vomiting, diarrhea, enlarged lymph glands, difficulty urinating, breathing, or neurological disturbance. Upon physical examination, the rash was not considered to be a drug eruption. Had a mild drug reaction been suspected, a careful rechallenge, weighing the risks and benefits, would have been considered and was discussed with the mother and patient. New-onset or worsening eye symptoms should be reported; therefore, a referral to ophthalmology was prompted due to our patient’s history of rhinoconjunctivitis and persistent conjunctival injection observed early after initiating dupilumab therapy. Nothing remarkable was found.

Comment

Prevalence and Pathogenesis
Atopic dermatitis affects 31.6 million individuals in the United States, with 17.8 million experiencing moderate to severe lesions.¹ The current prevalence of AD in the pediatric population ranges from 10% to 30% compared to 2% to 10% in adults. Fortunately, up to 70% of young children enter remission or improve by 12 years of age. Atopic diatheses may simultaneously occur, which includes asthma and rhinoconjunctivitis.²

Complications from AD include bacterial and viral infections and ocular disease. Furthermore, impaired growth in stature has been correlated with individuals who have extensive disease.² Of interest, our 7-year-old patient gained 7 lb and grew almost 3 in within 6 months of being on immunosuppressant therapy. Children with AD have poorer sleep efficiency in contrast to children without AD.³ Eczema is associated with more frequent headaches in childhood, especially in those with sleep disturbances,⁴ as our patient had experienced prior to systemic therapy.

The pathogenesis of AD is complex, and one must take into consideration the multiple cellular activities including inflammatory mechanics in the absence of IgE-mediated sensitization, epidermal barrier changes, epicutaneous sensitization, dendritic cell roles, T-cell responses and cytokine orchestrations, actions of microbial colonization, and involvement of autoimmunity.⁵ Select patients with AD have IgE antibodies focused against self-proteins. Disease severity correlates with ubiquity of these antibodies. Moreover, certain autoallergens induce helper T cell (T_H1) responses.⁵ Circulating T_H2 cytokines and chemokines IL-4, IL4ra, and IL-13 also have been linked to AD pathogenesis. Additionally, nonlesional skin abnormalities have been observed.⁶ Most recently, researchers have identified a caspase recruitment domain family member 11 (CARD11) gene mutation possibly leading to AD.⁷ Clinically, our patient responded favorably to dupilumab, which inhibits T_H2 cytokines IL-4 and IL13. He experienced a considerable decrease in itching and inflammation and reduced lesion count after 1 month of treatment with dupilumab. No skin lesions were identified on visual examination at week 17 and inevitably the patient discontinued messy topicals.

Treatment Options
Because AD is characterized by episodes of remission and relapse, management generally is comprised of trigger avoidance, including known allergens and irritants; a skin care regimen that promotes healthy epidermal barrier function; anti-inflammatory therapies to control both flares and subclinical inflammation; and adjunctive therapy for additional symptomatic control (eg, phototherapy, stabilized hypochlorous acid, topical antibiotic treatment) when needed. Avoidance of excessive washing or irritants, food provocation, and emotional stress, as well as toleration of body temperature fluctuations and humidity, is recommended to amend exacerbations.⁵

Current topical therapies include emollients; corticosteroids; calcineurin inhibitors; and crisaborole, a newer phosphodiesterase 4 inhibitor. There are a number of emollients and moisturizers available, and one over-the-counter preparation showed tolerability and improved skin hydration in AD patients and demonstrated less transepidermal water loss than the control group.⁸ Ointments such as petrolatum usually do not include ingredients such as preservatives, gelling agents, or humectants that can promote stinging or burning.⁹ Topical corticosteroids, which ameliorate inflammation by subduing proinflammatory cytokine expression, have been the mainstay of treatment for more than 60 years; however, caution should be used due to the potential for side effects, mainly but not limited to systemic absorption in children, development of striae, and skin atrophy. Calcineurin inhibitors prohibit T-cell activity, modify mast cell response, and decrease dendritic cells in the epidermis. Since 2000, calcineurin inhibitors have been utilized as steroid-sparing agents¹⁰; however, prior authorization is still necessary with some insurance providers. Crisaborole ointment 2%, the newest topical agent for AD treatment in the market, has shown improvement of erythema, exudation, and pruritus. Approved for patients aged 2 years and older, twice-daily application of topical crisaborole as a steroid-sparing agent has rendered AD symptom relief.¹¹ It has been reported that 4% of patients encounter stinging or burning with topical crisaborole application, whereas up to 50% of calcineurin inhibitors induce these adverse effects.¹² Stabilized hypochlorous acid spray or gel acts as an antipruritic and antimicrobial agent, relieving pain associated with skin irritations. Topical antimicrobial preparations such as mupirocin 2% antibiotic ointment can reduce Staphylococcus colonization when applied in the nasal passage as well as to affected skin lesions.²

In children, UVA and UVB phototherapy has proven safe and effective and can be utilized in AD when suitable.¹³ When patients inadequately respond to topical therapies and phototherapy, systemic immunomodulatory agents have been recommended as treatment options.A child’s developing immune system indeed may be sensitive to systemic therapies as the innate immune system fully matures in adolescence and his/her adaptive immune system is undergoing vigorous definition.¹⁴ Systemic immunomodulatory agents such as cyclosporine, azathioprine, mycophenolate mofetil, and methotrexate have been used off label for years and pose certain challenges in being identified as durable therapies due to potential side effects. Cyclosporine is effective for the treatment of AD; however, long-term administration should be dosed up to a 12-month period and then stopped to decrease cumulative exposure to the drug. Therefore, further treatment options must be considered. For children, cyclosporine should be administered in a dose of 3 to 6 mg/kg daily. Fluctuations in blood pressure and renal function should be monitored. The recommended pediatric dose for azathioprine is 1 to 4 mg/kg daily with laboratory monitoring, particularly of liver enzymes and complete blood cell count. Obtaining the patient’s thiopurine methyltransferase level may aid in dosing. Gastrointestinal tract symptoms such as nausea, vomiting, and diarrhea are common. Phototherapy is not advised in conjunction with azathioprine due to an increased risk of photocarcinogenicity.¹³ The literature supporting mycophenolate mofetil in children with AD is limited. In one single retrospective case series, 14 children were treated at a mean dose of 38 mg/kg once daily for 2 to 24 months with 57% (8/14) of children demonstrating almost complete to complete clearance.Thirty-six percent (5/14) of children showed 60% to 90% improvement.¹⁵ Gastrointestinal tract side effects along with hematologic symptoms have been reported. Methotrexate is dosed at 0.2 to 0.7 mg/kg weekly, with 10 weeks being the average time to greatest efficacy.¹³ Gastrointestinal tract symptoms, pancytopenia, pneumonitis, and possibly pulmonary fibrosis can occur. To reduce the risk of pancytopenia during methotrexate therapy, routine administration of folic acid 1 to 5 mg once daily is prudent.¹⁶

Biologic therapies targeting IgE, B-lymphocyte antigen CD20, IL-5, thymic stromal lymphopoietin, T_H17 cells, IL-12, IL-23, interferon gamma, IL-6 receptors, tumor necrosis factor, phosphodiesterase 4, Janus kinase, chymase, and nuclear receptors expressed on adipocytes and immune cells have undergone investigation for treatment of AD.¹⁷ Additionally, biologic agents targeting IL-31, IL-13, and IL-22 also have been evaluated.¹ Currently, there are no US Food and Drug Administration–approved biologic agents for moderate to severe childhood AD.

Dupilumab, an IL-4Rα and IL-13Rα antagonist, recently has been approved for treatment of moderate to severe AD in adults but not yet for children. Potential side effects include nasopharyngitis, headache, hypersensitivity reactions, and ocular symptoms,¹¹ namely keratitis and conjunctivitis.¹⁸ Less than 1% of patients experienced keratitis in clinical trials, while conjunctivitis was reported in 4% of patients taking dupilumab with topical corticosteroids at 52 weeks.¹⁸ However, possible ocular findings on slit-lamp examination in AD patients include atopic keratoconjunctivitis, blepharitis, palpebral conjunctival scarring, papillary conjunctival reaction, Horner-Trantas dots, keratoconus, and atopic cataracts. Spontaneous retinal detachment is seen more commonly in individuals with AD than in the general population.¹⁹

In clinical trials, hypersensitivity reactions included urticaria and serum sickness or serum sickness–like reactions in less than 1% of patients taking dupilumab.¹⁸ Most monoclonal antibody reactions are immediate; however, 10% to 30% are delayed and may recur in a subsequent rechallenge of the drug.²⁰

Conclusion

Childhood AD can be debilitating, and affected individuals often lead a poorer quality of life if left untreated. Embarrassment and isolation are commonly experienced. Increased responsibility and work in tending for a child with eczema may result in parental exhaustion.²¹ As with psoriasis, AD can impair activity and productivity.²² Currently, dupilumab has proven to positively impact health-related quality of life for adults.²³ Pending the outcome of ongoing pediatric clinical trials, dupilumab may become a benchmark therapy for children younger than 18 years.

Case Report

A 7-year-old boy with a history of shellfish anaphylaxis, pollen allergy, asthma, rhinoconjunctivitis, frequent headaches and ear infections, sinusitis, bronchitis, vitiligo, warts, and cold sores presented to our dermatology clinic for evaluation of a widespread crusting, cracking, red rash that had been present since 6 months of age. The patient’s mother reported that he had many sleepless nights from uncontrolled itching. His medications included albuterol solution for nebulization, loratadine, and montelukast. Prior to the current presentation he had been treated with triamcinolone and betamethasone creams by the pediatrician. Despite compliance with topical therapy, his mother stated the itching persisted and lesions lingered with minimal improvement. He also was treated with oral corticosteroids for episodic sinusitis and bronchitis, which was beneficial to the skin lesions for only a short duration. The patient was adopted and therefore his family history was unavailable.

During physical examination, the patient was in the fetal position on the examination table and appeared uncomfortable, scratching himself. The patient admitted to severe widespread itching and burning. On skin examination, multiple thick, lichenified, highly pruritic plaques coalesced on the knees, ankles, arms, and wrists, and very discreet scaly patches were present on the scalp. Annular patches covered 50% of the patient’s body, with highly inflamed lesions concentrated in skin folds (Figure 1), leading to diagnosis of atopic dermatitis (AD).

Five days after treatment with a 300-mg SQ dupilumab injection, the patient returned to clinic for evaluation of a vesicular rash with subsequent peeling confined to the shoulders (Figure 2). He and his mother denied any UV exposure, citing he had been completely out of the sun. He denied constitutional symptoms including fever, malaise, swelling, joint pain, headache, muscle pain, nausea, vomiting, diarrhea, enlarged lymph glands, difficulty urinating, breathing, or neurological disturbance. Upon physical examination, the rash was not considered to be a drug eruption. Had a mild drug reaction been suspected, a careful rechallenge, weighing the risks and benefits, would have been considered and was discussed with the mother and patient. New-onset or worsening eye symptoms should be reported; therefore, a referral to ophthalmology was prompted due to our patient’s history of rhinoconjunctivitis and persistent conjunctival injection observed early after initiating dupilumab therapy. Nothing remarkable was found.

Comment

Prevalence and Pathogenesis
Atopic dermatitis affects 31.6 million individuals in the United States, with 17.8 million experiencing moderate to severe lesions.¹ The current prevalence of AD in the pediatric population ranges from 10% to 30% compared to 2% to 10% in adults. Fortunately, up to 70% of young children enter remission or improve by 12 years of age. Atopic diatheses may simultaneously occur, which includes asthma and rhinoconjunctivitis.²

Complications from AD include bacterial and viral infections and ocular disease. Furthermore, impaired growth in stature has been correlated with individuals who have extensive disease.² Of interest, our 7-year-old patient gained 7 lb and grew almost 3 in within 6 months of being on immunosuppressant therapy. Children with AD have poorer sleep efficiency in contrast to children without AD.³ Eczema is associated with more frequent headaches in childhood, especially in those with sleep disturbances,⁴ as our patient had experienced prior to systemic therapy.

The pathogenesis of AD is complex, and one must take into consideration the multiple cellular activities including inflammatory mechanics in the absence of IgE-mediated sensitization, epidermal barrier changes, epicutaneous sensitization, dendritic cell roles, T-cell responses and cytokine orchestrations, actions of microbial colonization, and involvement of autoimmunity.⁵ Select patients with AD have IgE antibodies focused against self-proteins. Disease severity correlates with ubiquity of these antibodies. Moreover, certain autoallergens induce helper T cell (T_H1) responses.⁵ Circulating T_H2 cytokines and chemokines IL-4, IL4ra, and IL-13 also have been linked to AD pathogenesis. Additionally, nonlesional skin abnormalities have been observed.⁶ Most recently, researchers have identified a caspase recruitment domain family member 11 (CARD11) gene mutation possibly leading to AD.⁷ Clinically, our patient responded favorably to dupilumab, which inhibits T_H2 cytokines IL-4 and IL13. He experienced a considerable decrease in itching and inflammation and reduced lesion count after 1 month of treatment with dupilumab. No skin lesions were identified on visual examination at week 17 and inevitably the patient discontinued messy topicals.

Treatment Options
Because AD is characterized by episodes of remission and relapse, management generally is comprised of trigger avoidance, including known allergens and irritants; a skin care regimen that promotes healthy epidermal barrier function; anti-inflammatory therapies to control both flares and subclinical inflammation; and adjunctive therapy for additional symptomatic control (eg, phototherapy, stabilized hypochlorous acid, topical antibiotic treatment) when needed. Avoidance of excessive washing or irritants, food provocation, and emotional stress, as well as toleration of body temperature fluctuations and humidity, is recommended to amend exacerbations.⁵

Current topical therapies include emollients; corticosteroids; calcineurin inhibitors; and crisaborole, a newer phosphodiesterase 4 inhibitor. There are a number of emollients and moisturizers available, and one over-the-counter preparation showed tolerability and improved skin hydration in AD patients and demonstrated less transepidermal water loss than the control group.⁸ Ointments such as petrolatum usually do not include ingredients such as preservatives, gelling agents, or humectants that can promote stinging or burning.⁹ Topical corticosteroids, which ameliorate inflammation by subduing proinflammatory cytokine expression, have been the mainstay of treatment for more than 60 years; however, caution should be used due to the potential for side effects, mainly but not limited to systemic absorption in children, development of striae, and skin atrophy. Calcineurin inhibitors prohibit T-cell activity, modify mast cell response, and decrease dendritic cells in the epidermis. Since 2000, calcineurin inhibitors have been utilized as steroid-sparing agents¹⁰; however, prior authorization is still necessary with some insurance providers. Crisaborole ointment 2%, the newest topical agent for AD treatment in the market, has shown improvement of erythema, exudation, and pruritus. Approved for patients aged 2 years and older, twice-daily application of topical crisaborole as a steroid-sparing agent has rendered AD symptom relief.¹¹ It has been reported that 4% of patients encounter stinging or burning with topical crisaborole application, whereas up to 50% of calcineurin inhibitors induce these adverse effects.¹² Stabilized hypochlorous acid spray or gel acts as an antipruritic and antimicrobial agent, relieving pain associated with skin irritations. Topical antimicrobial preparations such as mupirocin 2% antibiotic ointment can reduce Staphylococcus colonization when applied in the nasal passage as well as to affected skin lesions.²

In children, UVA and UVB phototherapy has proven safe and effective and can be utilized in AD when suitable.¹³ When patients inadequately respond to topical therapies and phototherapy, systemic immunomodulatory agents have been recommended as treatment options.A child’s developing immune system indeed may be sensitive to systemic therapies as the innate immune system fully matures in adolescence and his/her adaptive immune system is undergoing vigorous definition.¹⁴ Systemic immunomodulatory agents such as cyclosporine, azathioprine, mycophenolate mofetil, and methotrexate have been used off label for years and pose certain challenges in being identified as durable therapies due to potential side effects. Cyclosporine is effective for the treatment of AD; however, long-term administration should be dosed up to a 12-month period and then stopped to decrease cumulative exposure to the drug. Therefore, further treatment options must be considered. For children, cyclosporine should be administered in a dose of 3 to 6 mg/kg daily. Fluctuations in blood pressure and renal function should be monitored. The recommended pediatric dose for azathioprine is 1 to 4 mg/kg daily with laboratory monitoring, particularly of liver enzymes and complete blood cell count. Obtaining the patient’s thiopurine methyltransferase level may aid in dosing. Gastrointestinal tract symptoms such as nausea, vomiting, and diarrhea are common. Phototherapy is not advised in conjunction with azathioprine due to an increased risk of photocarcinogenicity.¹³ The literature supporting mycophenolate mofetil in children with AD is limited. In one single retrospective case series, 14 children were treated at a mean dose of 38 mg/kg once daily for 2 to 24 months with 57% (8/14) of children demonstrating almost complete to complete clearance.Thirty-six percent (5/14) of children showed 60% to 90% improvement.¹⁵ Gastrointestinal tract side effects along with hematologic symptoms have been reported. Methotrexate is dosed at 0.2 to 0.7 mg/kg weekly, with 10 weeks being the average time to greatest efficacy.¹³ Gastrointestinal tract symptoms, pancytopenia, pneumonitis, and possibly pulmonary fibrosis can occur. To reduce the risk of pancytopenia during methotrexate therapy, routine administration of folic acid 1 to 5 mg once daily is prudent.¹⁶

Biologic therapies targeting IgE, B-lymphocyte antigen CD20, IL-5, thymic stromal lymphopoietin, T_H17 cells, IL-12, IL-23, interferon gamma, IL-6 receptors, tumor necrosis factor, phosphodiesterase 4, Janus kinase, chymase, and nuclear receptors expressed on adipocytes and immune cells have undergone investigation for treatment of AD.¹⁷ Additionally, biologic agents targeting IL-31, IL-13, and IL-22 also have been evaluated.¹ Currently, there are no US Food and Drug Administration–approved biologic agents for moderate to severe childhood AD.

Dupilumab, an IL-4Rα and IL-13Rα antagonist, recently has been approved for treatment of moderate to severe AD in adults but not yet for children. Potential side effects include nasopharyngitis, headache, hypersensitivity reactions, and ocular symptoms,¹¹ namely keratitis and conjunctivitis.¹⁸ Less than 1% of patients experienced keratitis in clinical trials, while conjunctivitis was reported in 4% of patients taking dupilumab with topical corticosteroids at 52 weeks.¹⁸ However, possible ocular findings on slit-lamp examination in AD patients include atopic keratoconjunctivitis, blepharitis, palpebral conjunctival scarring, papillary conjunctival reaction, Horner-Trantas dots, keratoconus, and atopic cataracts. Spontaneous retinal detachment is seen more commonly in individuals with AD than in the general population.¹⁹

In clinical trials, hypersensitivity reactions included urticaria and serum sickness or serum sickness–like reactions in less than 1% of patients taking dupilumab.¹⁸ Most monoclonal antibody reactions are immediate; however, 10% to 30% are delayed and may recur in a subsequent rechallenge of the drug.²⁰

Conclusion

Childhood AD can be debilitating, and affected individuals often lead a poorer quality of life if left untreated. Embarrassment and isolation are commonly experienced. Increased responsibility and work in tending for a child with eczema may result in parental exhaustion.²¹ As with psoriasis, AD can impair activity and productivity.²² Currently, dupilumab has proven to positively impact health-related quality of life for adults.²³ Pending the outcome of ongoing pediatric clinical trials, dupilumab may become a benchmark therapy for children younger than 18 years.

Case Report

A 7-year-old boy with a history of shellfish anaphylaxis, pollen allergy, asthma, rhinoconjunctivitis, frequent headaches and ear infections, sinusitis, bronchitis, vitiligo, warts, and cold sores presented to our dermatology clinic for evaluation of a widespread crusting, cracking, red rash that had been present since 6 months of age. The patient’s mother reported that he had many sleepless nights from uncontrolled itching. His medications included albuterol solution for nebulization, loratadine, and montelukast. Prior to the current presentation he had been treated with triamcinolone and betamethasone creams by the pediatrician. Despite compliance with topical therapy, his mother stated the itching persisted and lesions lingered with minimal improvement. He also was treated with oral corticosteroids for episodic sinusitis and bronchitis, which was beneficial to the skin lesions for only a short duration. The patient was adopted and therefore his family history was unavailable.

During physical examination, the patient was in the fetal position on the examination table and appeared uncomfortable, scratching himself. The patient admitted to severe widespread itching and burning. On skin examination, multiple thick, lichenified, highly pruritic plaques coalesced on the knees, ankles, arms, and wrists, and very discreet scaly patches were present on the scalp. Annular patches covered 50% of the patient’s body, with highly inflamed lesions concentrated in skin folds (Figure 1), leading to diagnosis of atopic dermatitis (AD).

Five days after treatment with a 300-mg SQ dupilumab injection, the patient returned to clinic for evaluation of a vesicular rash with subsequent peeling confined to the shoulders (Figure 2). He and his mother denied any UV exposure, citing he had been completely out of the sun. He denied constitutional symptoms including fever, malaise, swelling, joint pain, headache, muscle pain, nausea, vomiting, diarrhea, enlarged lymph glands, difficulty urinating, breathing, or neurological disturbance. Upon physical examination, the rash was not considered to be a drug eruption. Had a mild drug reaction been suspected, a careful rechallenge, weighing the risks and benefits, would have been considered and was discussed with the mother and patient. New-onset or worsening eye symptoms should be reported; therefore, a referral to ophthalmology was prompted due to our patient’s history of rhinoconjunctivitis and persistent conjunctival injection observed early after initiating dupilumab therapy. Nothing remarkable was found.

Comment

Prevalence and Pathogenesis
Atopic dermatitis affects 31.6 million individuals in the United States, with 17.8 million experiencing moderate to severe lesions.¹ The current prevalence of AD in the pediatric population ranges from 10% to 30% compared to 2% to 10% in adults. Fortunately, up to 70% of young children enter remission or improve by 12 years of age. Atopic diatheses may simultaneously occur, which includes asthma and rhinoconjunctivitis.²

Complications from AD include bacterial and viral infections and ocular disease. Furthermore, impaired growth in stature has been correlated with individuals who have extensive disease.² Of interest, our 7-year-old patient gained 7 lb and grew almost 3 in within 6 months of being on immunosuppressant therapy. Children with AD have poorer sleep efficiency in contrast to children without AD.³ Eczema is associated with more frequent headaches in childhood, especially in those with sleep disturbances,⁴ as our patient had experienced prior to systemic therapy.

The pathogenesis of AD is complex, and one must take into consideration the multiple cellular activities including inflammatory mechanics in the absence of IgE-mediated sensitization, epidermal barrier changes, epicutaneous sensitization, dendritic cell roles, T-cell responses and cytokine orchestrations, actions of microbial colonization, and involvement of autoimmunity.⁵ Select patients with AD have IgE antibodies focused against self-proteins. Disease severity correlates with ubiquity of these antibodies. Moreover, certain autoallergens induce helper T cell (T_H1) responses.⁵ Circulating T_H2 cytokines and chemokines IL-4, IL4ra, and IL-13 also have been linked to AD pathogenesis. Additionally, nonlesional skin abnormalities have been observed.⁶ Most recently, researchers have identified a caspase recruitment domain family member 11 (CARD11) gene mutation possibly leading to AD.⁷ Clinically, our patient responded favorably to dupilumab, which inhibits T_H2 cytokines IL-4 and IL13. He experienced a considerable decrease in itching and inflammation and reduced lesion count after 1 month of treatment with dupilumab. No skin lesions were identified on visual examination at week 17 and inevitably the patient discontinued messy topicals.

Treatment Options
Because AD is characterized by episodes of remission and relapse, management generally is comprised of trigger avoidance, including known allergens and irritants; a skin care regimen that promotes healthy epidermal barrier function; anti-inflammatory therapies to control both flares and subclinical inflammation; and adjunctive therapy for additional symptomatic control (eg, phototherapy, stabilized hypochlorous acid, topical antibiotic treatment) when needed. Avoidance of excessive washing or irritants, food provocation, and emotional stress, as well as toleration of body temperature fluctuations and humidity, is recommended to amend exacerbations.⁵

Current topical therapies include emollients; corticosteroids; calcineurin inhibitors; and crisaborole, a newer phosphodiesterase 4 inhibitor. There are a number of emollients and moisturizers available, and one over-the-counter preparation showed tolerability and improved skin hydration in AD patients and demonstrated less transepidermal water loss than the control group.⁸ Ointments such as petrolatum usually do not include ingredients such as preservatives, gelling agents, or humectants that can promote stinging or burning.⁹ Topical corticosteroids, which ameliorate inflammation by subduing proinflammatory cytokine expression, have been the mainstay of treatment for more than 60 years; however, caution should be used due to the potential for side effects, mainly but not limited to systemic absorption in children, development of striae, and skin atrophy. Calcineurin inhibitors prohibit T-cell activity, modify mast cell response, and decrease dendritic cells in the epidermis. Since 2000, calcineurin inhibitors have been utilized as steroid-sparing agents¹⁰; however, prior authorization is still necessary with some insurance providers. Crisaborole ointment 2%, the newest topical agent for AD treatment in the market, has shown improvement of erythema, exudation, and pruritus. Approved for patients aged 2 years and older, twice-daily application of topical crisaborole as a steroid-sparing agent has rendered AD symptom relief.¹¹ It has been reported that 4% of patients encounter stinging or burning with topical crisaborole application, whereas up to 50% of calcineurin inhibitors induce these adverse effects.¹² Stabilized hypochlorous acid spray or gel acts as an antipruritic and antimicrobial agent, relieving pain associated with skin irritations. Topical antimicrobial preparations such as mupirocin 2% antibiotic ointment can reduce Staphylococcus colonization when applied in the nasal passage as well as to affected skin lesions.²

In children, UVA and UVB phototherapy has proven safe and effective and can be utilized in AD when suitable.¹³ When patients inadequately respond to topical therapies and phototherapy, systemic immunomodulatory agents have been recommended as treatment options.A child’s developing immune system indeed may be sensitive to systemic therapies as the innate immune system fully matures in adolescence and his/her adaptive immune system is undergoing vigorous definition.¹⁴ Systemic immunomodulatory agents such as cyclosporine, azathioprine, mycophenolate mofetil, and methotrexate have been used off label for years and pose certain challenges in being identified as durable therapies due to potential side effects. Cyclosporine is effective for the treatment of AD; however, long-term administration should be dosed up to a 12-month period and then stopped to decrease cumulative exposure to the drug. Therefore, further treatment options must be considered. For children, cyclosporine should be administered in a dose of 3 to 6 mg/kg daily. Fluctuations in blood pressure and renal function should be monitored. The recommended pediatric dose for azathioprine is 1 to 4 mg/kg daily with laboratory monitoring, particularly of liver enzymes and complete blood cell count. Obtaining the patient’s thiopurine methyltransferase level may aid in dosing. Gastrointestinal tract symptoms such as nausea, vomiting, and diarrhea are common. Phototherapy is not advised in conjunction with azathioprine due to an increased risk of photocarcinogenicity.¹³ The literature supporting mycophenolate mofetil in children with AD is limited. In one single retrospective case series, 14 children were treated at a mean dose of 38 mg/kg once daily for 2 to 24 months with 57% (8/14) of children demonstrating almost complete to complete clearance.Thirty-six percent (5/14) of children showed 60% to 90% improvement.¹⁵ Gastrointestinal tract side effects along with hematologic symptoms have been reported. Methotrexate is dosed at 0.2 to 0.7 mg/kg weekly, with 10 weeks being the average time to greatest efficacy.¹³ Gastrointestinal tract symptoms, pancytopenia, pneumonitis, and possibly pulmonary fibrosis can occur. To reduce the risk of pancytopenia during methotrexate therapy, routine administration of folic acid 1 to 5 mg once daily is prudent.¹⁶

Biologic therapies targeting IgE, B-lymphocyte antigen CD20, IL-5, thymic stromal lymphopoietin, T_H17 cells, IL-12, IL-23, interferon gamma, IL-6 receptors, tumor necrosis factor, phosphodiesterase 4, Janus kinase, chymase, and nuclear receptors expressed on adipocytes and immune cells have undergone investigation for treatment of AD.¹⁷ Additionally, biologic agents targeting IL-31, IL-13, and IL-22 also have been evaluated.¹ Currently, there are no US Food and Drug Administration–approved biologic agents for moderate to severe childhood AD.

Dupilumab, an IL-4Rα and IL-13Rα antagonist, recently has been approved for treatment of moderate to severe AD in adults but not yet for children. Potential side effects include nasopharyngitis, headache, hypersensitivity reactions, and ocular symptoms,¹¹ namely keratitis and conjunctivitis.¹⁸ Less than 1% of patients experienced keratitis in clinical trials, while conjunctivitis was reported in 4% of patients taking dupilumab with topical corticosteroids at 52 weeks.¹⁸ However, possible ocular findings on slit-lamp examination in AD patients include atopic keratoconjunctivitis, blepharitis, palpebral conjunctival scarring, papillary conjunctival reaction, Horner-Trantas dots, keratoconus, and atopic cataracts. Spontaneous retinal detachment is seen more commonly in individuals with AD than in the general population.¹⁹

In clinical trials, hypersensitivity reactions included urticaria and serum sickness or serum sickness–like reactions in less than 1% of patients taking dupilumab.¹⁸ Most monoclonal antibody reactions are immediate; however, 10% to 30% are delayed and may recur in a subsequent rechallenge of the drug.²⁰

Conclusion

Childhood AD can be debilitating, and affected individuals often lead a poorer quality of life if left untreated. Embarrassment and isolation are commonly experienced. Increased responsibility and work in tending for a child with eczema may result in parental exhaustion.²¹ As with psoriasis, AD can impair activity and productivity.²² Currently, dupilumab has proven to positively impact health-related quality of life for adults.²³ Pending the outcome of ongoing pediatric clinical trials, dupilumab may become a benchmark therapy for children younger than 18 years.

BALTIMORE—Multiple dimensions of sleep may temporally precede acute risk of migraine attack among patients with episodic migraine, according to a study presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies. While some aspects of sleep appear to protect against next-day headache, “these novel pilot data support the hypothesis that self-reported fragmented sleep is associated with higher risk of migraine two days later,” said Suzanne M. Bertisch, MD, MPH, and colleagues. Dr. Bertisch is an Assistant Professor of Medicine at Harvard Medical School and a Director of Behavioral Sleep Medicine at Brigham and Women’s Hospital in Boston.

Retrospective studies have indicated that nearly half of patients with migraine identify too little or too much sleep as a migraine trigger. One prospective study reported a higher incidence of headache, both migraine and tension type, after two consecutive nights of four or fewer hours of sleep, as measured by self-report. This study accounted for daily stress but not other potential triggers of migraine. “To date, there have been no prospective studies on the association between objectively assessed sleep parameters and migraine incidence while accounting for other potential triggers of migraine,” Dr. Bertisch said.

A Cohort Study of Migraine Triggers

She and her colleagues assessed the independent contribution of sleep characteristics as temporal precedents of migraine. “We were particularly interested … in sleep duration, fragmentation, and self-reported quality.” To examine these factors, they developed a cohort study of migraine triggers that they conducted from March 2016 to August 2017.

The researchers enrolled 101 adults with episodic migraine from the greater Boston area. Inclusion criteria included at least two migraines per month but fewer than 15 headache days per month, a history of migraine for at least three years, and fulfillment of ICHD-3 criteria for episodic migraine. Exclusion criteria included untreated obstructive sleep apnea, pregnancy, and current opioid use.

Data were collected for six weeks. Study participants were prompted to complete morning and evening diaries that recorded information on sleep, including the pattern, fragmentation, and sleep quality; physical activity and daily mood; medications; and headache characteristics. Patients also wore wrist actigraphs for the duration of the six-week study. Each patient had about 40 days of diary and actigraphy data.

Patients reported the onset and duration of headaches, associated symptoms, whether their pain was a headache or a migraine, maximum pain intensity, and any abortive medications used. Data on daily covariates such as alcohol and caffeine consumption, self-reported physical activity, menstrual cycle, stress, and mood prior to bedtime also were collected.

Dr. Bertisch and colleagues used self-matched case–crossover analyses. “Each person served as [his or her] own control. This approach accounts for time-invariant confounders, including sex, genetics, and usual migraine frequency. We used a conditional logistic regression model that was self-matched by day of the week, because there might be an influence of weekend versus weekday sleep patterns, as well as migraine, and we adjusted for time-dependent covariates, including daily alcohol and caffeine use.”

High WASO Protected Against Next-Day Headache

The 98 participants included in the analyses reflected the known migraine prevalence. “They were generally younger women with an average age of 35, and generally a healthy population,” Dr. Bertisch said. “About one-third reported a history of migraine with aura, and about one-quarter used daily medications to prevent migraines. About 60% reported that sleeping too little triggered their migraines.”

The researchers collected data by actigraphy and diary during approximately 4,500 nights and found that their cohort’s sleep was relatively healthy. “They slept over seven hours per night, they had few sleep problems, they had high sleep efficiency, and they had modest alcohol or caffeine consumption during the study,” Dr. Bertisch said.

In an analysis of diary data, there was no association between odds of a next-day headache and sleep duration, wake after sleep onset (WASO), sleep efficiency, or sleep quality. “However, when we looked at the actigraphy measures, we did find associations with lower sleep efficiency and higher WASO, each associated with lower risk of next-day headache,” Dr. Bertisch said.

“When we looked at odds of headache two days later, we did find that a low sleep efficiency based on self-report was associated with a higher risk of migraine. We also noted a similar trend with self-reported short sleep duration. For actigraphy data, we found a somewhat similar pattern. We also found that sleep duration greater than 8.5 hours was associated with lower risk of migraine two days later.”

In summary, sleep efficiency and high WASO may be associated with lower odds of next-day headache. For sleep two nights before the headache, low sleep efficiency was associated with higher odds of headache. Long sleep duration, as assessed by actigraphy, was associated with lower odds of headache two days later.

—Glenn S. Williams

BALTIMORE—Multiple dimensions of sleep may temporally precede acute risk of migraine attack among patients with episodic migraine, according to a study presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies. While some aspects of sleep appear to protect against next-day headache, “these novel pilot data support the hypothesis that self-reported fragmented sleep is associated with higher risk of migraine two days later,” said Suzanne M. Bertisch, MD, MPH, and colleagues. Dr. Bertisch is an Assistant Professor of Medicine at Harvard Medical School and a Director of Behavioral Sleep Medicine at Brigham and Women’s Hospital in Boston.

Retrospective studies have indicated that nearly half of patients with migraine identify too little or too much sleep as a migraine trigger. One prospective study reported a higher incidence of headache, both migraine and tension type, after two consecutive nights of four or fewer hours of sleep, as measured by self-report. This study accounted for daily stress but not other potential triggers of migraine. “To date, there have been no prospective studies on the association between objectively assessed sleep parameters and migraine incidence while accounting for other potential triggers of migraine,” Dr. Bertisch said.

A Cohort Study of Migraine Triggers

She and her colleagues assessed the independent contribution of sleep characteristics as temporal precedents of migraine. “We were particularly interested … in sleep duration, fragmentation, and self-reported quality.” To examine these factors, they developed a cohort study of migraine triggers that they conducted from March 2016 to August 2017.

The researchers enrolled 101 adults with episodic migraine from the greater Boston area. Inclusion criteria included at least two migraines per month but fewer than 15 headache days per month, a history of migraine for at least three years, and fulfillment of ICHD-3 criteria for episodic migraine. Exclusion criteria included untreated obstructive sleep apnea, pregnancy, and current opioid use.

Data were collected for six weeks. Study participants were prompted to complete morning and evening diaries that recorded information on sleep, including the pattern, fragmentation, and sleep quality; physical activity and daily mood; medications; and headache characteristics. Patients also wore wrist actigraphs for the duration of the six-week study. Each patient had about 40 days of diary and actigraphy data.

Patients reported the onset and duration of headaches, associated symptoms, whether their pain was a headache or a migraine, maximum pain intensity, and any abortive medications used. Data on daily covariates such as alcohol and caffeine consumption, self-reported physical activity, menstrual cycle, stress, and mood prior to bedtime also were collected.

Dr. Bertisch and colleagues used self-matched case–crossover analyses. “Each person served as [his or her] own control. This approach accounts for time-invariant confounders, including sex, genetics, and usual migraine frequency. We used a conditional logistic regression model that was self-matched by day of the week, because there might be an influence of weekend versus weekday sleep patterns, as well as migraine, and we adjusted for time-dependent covariates, including daily alcohol and caffeine use.”

High WASO Protected Against Next-Day Headache

The 98 participants included in the analyses reflected the known migraine prevalence. “They were generally younger women with an average age of 35, and generally a healthy population,” Dr. Bertisch said. “About one-third reported a history of migraine with aura, and about one-quarter used daily medications to prevent migraines. About 60% reported that sleeping too little triggered their migraines.”

The researchers collected data by actigraphy and diary during approximately 4,500 nights and found that their cohort’s sleep was relatively healthy. “They slept over seven hours per night, they had few sleep problems, they had high sleep efficiency, and they had modest alcohol or caffeine consumption during the study,” Dr. Bertisch said.

In an analysis of diary data, there was no association between odds of a next-day headache and sleep duration, wake after sleep onset (WASO), sleep efficiency, or sleep quality. “However, when we looked at the actigraphy measures, we did find associations with lower sleep efficiency and higher WASO, each associated with lower risk of next-day headache,” Dr. Bertisch said.

“When we looked at odds of headache two days later, we did find that a low sleep efficiency based on self-report was associated with a higher risk of migraine. We also noted a similar trend with self-reported short sleep duration. For actigraphy data, we found a somewhat similar pattern. We also found that sleep duration greater than 8.5 hours was associated with lower risk of migraine two days later.”

In summary, sleep efficiency and high WASO may be associated with lower odds of next-day headache. For sleep two nights before the headache, low sleep efficiency was associated with higher odds of headache. Long sleep duration, as assessed by actigraphy, was associated with lower odds of headache two days later.

—Glenn S. Williams

BALTIMORE—Multiple dimensions of sleep may temporally precede acute risk of migraine attack among patients with episodic migraine, according to a study presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies. While some aspects of sleep appear to protect against next-day headache, “these novel pilot data support the hypothesis that self-reported fragmented sleep is associated with higher risk of migraine two days later,” said Suzanne M. Bertisch, MD, MPH, and colleagues. Dr. Bertisch is an Assistant Professor of Medicine at Harvard Medical School and a Director of Behavioral Sleep Medicine at Brigham and Women’s Hospital in Boston.

Retrospective studies have indicated that nearly half of patients with migraine identify too little or too much sleep as a migraine trigger. One prospective study reported a higher incidence of headache, both migraine and tension type, after two consecutive nights of four or fewer hours of sleep, as measured by self-report. This study accounted for daily stress but not other potential triggers of migraine. “To date, there have been no prospective studies on the association between objectively assessed sleep parameters and migraine incidence while accounting for other potential triggers of migraine,” Dr. Bertisch said.

A Cohort Study of Migraine Triggers

She and her colleagues assessed the independent contribution of sleep characteristics as temporal precedents of migraine. “We were particularly interested … in sleep duration, fragmentation, and self-reported quality.” To examine these factors, they developed a cohort study of migraine triggers that they conducted from March 2016 to August 2017.

The researchers enrolled 101 adults with episodic migraine from the greater Boston area. Inclusion criteria included at least two migraines per month but fewer than 15 headache days per month, a history of migraine for at least three years, and fulfillment of ICHD-3 criteria for episodic migraine. Exclusion criteria included untreated obstructive sleep apnea, pregnancy, and current opioid use.

Data were collected for six weeks. Study participants were prompted to complete morning and evening diaries that recorded information on sleep, including the pattern, fragmentation, and sleep quality; physical activity and daily mood; medications; and headache characteristics. Patients also wore wrist actigraphs for the duration of the six-week study. Each patient had about 40 days of diary and actigraphy data.

Patients reported the onset and duration of headaches, associated symptoms, whether their pain was a headache or a migraine, maximum pain intensity, and any abortive medications used. Data on daily covariates such as alcohol and caffeine consumption, self-reported physical activity, menstrual cycle, stress, and mood prior to bedtime also were collected.

Dr. Bertisch and colleagues used self-matched case–crossover analyses. “Each person served as [his or her] own control. This approach accounts for time-invariant confounders, including sex, genetics, and usual migraine frequency. We used a conditional logistic regression model that was self-matched by day of the week, because there might be an influence of weekend versus weekday sleep patterns, as well as migraine, and we adjusted for time-dependent covariates, including daily alcohol and caffeine use.”

High WASO Protected Against Next-Day Headache

The 98 participants included in the analyses reflected the known migraine prevalence. “They were generally younger women with an average age of 35, and generally a healthy population,” Dr. Bertisch said. “About one-third reported a history of migraine with aura, and about one-quarter used daily medications to prevent migraines. About 60% reported that sleeping too little triggered their migraines.”

The researchers collected data by actigraphy and diary during approximately 4,500 nights and found that their cohort’s sleep was relatively healthy. “They slept over seven hours per night, they had few sleep problems, they had high sleep efficiency, and they had modest alcohol or caffeine consumption during the study,” Dr. Bertisch said.

In an analysis of diary data, there was no association between odds of a next-day headache and sleep duration, wake after sleep onset (WASO), sleep efficiency, or sleep quality. “However, when we looked at the actigraphy measures, we did find associations with lower sleep efficiency and higher WASO, each associated with lower risk of next-day headache,” Dr. Bertisch said.

“When we looked at odds of headache two days later, we did find that a low sleep efficiency based on self-report was associated with a higher risk of migraine. We also noted a similar trend with self-reported short sleep duration. For actigraphy data, we found a somewhat similar pattern. We also found that sleep duration greater than 8.5 hours was associated with lower risk of migraine two days later.”

In summary, sleep efficiency and high WASO may be associated with lower odds of next-day headache. For sleep two nights before the headache, low sleep efficiency was associated with higher odds of headache. Long sleep duration, as assessed by actigraphy, was associated with lower odds of headache two days later.

—Glenn S. Williams

Almirall Acquires 5 Products From Allergan

Almirall, SA, announces the acquisition of 5 products from Allergan: Aczone (dapsone), Tazorac (tazarotene), Azelex (azelaic acid), Cordran Tape (flurandrenolide), and Seysara (sarecycline). Seysara is a tetracycline-derived antibiotic with anti-inflammatory properties for the treatment of acne vulgaris in patients aged 9 years and older. Approval for Seysara is anticipated later in 2018. For more information, visit www.almirall.com.

Aspire Higher Scholarship Honorees Selected

Ortho Dermatologics announces the 2018 honorees of the Aspire Higher scholarship program. Nine students—3 pursuing undergraduate degrees, 3 pursuing graduate degrees, and 3 who are mothers pursuing either degree—will receive scholarships of $10,000 each. The 2018 honorees were selected from nearly 1200 applicants who shared their experience of living with a dermatologic condition, as well as the role that a dermatologist, physician assistant, or nurse practitioner has played in helping treat it. The applications were judged by an independent panel of dermatologists from across the country. Since 2013 the program has granted more than $450,000 in scholarships to students who have been affected by dermatologic conditions. For more information, visit www.aspirehigherscholarships.com.

Duobrii NDA Resubmitted to FDA

Ortho Dermatologics resubmits a New Drug Application to the US Food and Drug Administration (FDA) for Duobrii (halobetasol propionate and tazarotene) for plaque psoriasis with additional pharmacokinetic data as requested by the FDA in June 2018. The unique formulation will allow for a potentially expanded duration of use if approved. For more information, visit www.ortho-dermatologics.com.

JubliApp Now Available for Onychomycosis Patients

Ortho Dermatologics launches JubliApp, a mobile application (app) designed to encourage patient adherence to long-term treatment with Jublia (efinaconazole topical solution 10%) for onychomycosis. The app offers treatment and refill reminders, as well as a game (Mission Plu-Toe) to keep patients engaged while the daily application is drying, helping to make the 48-week long therapy less intimidating. The app also includes efficacy tracking with side-by-side photographs that can be shared with health care providers to monitor progress. It is available in the Apple App Store and the Google Play store. For more information, visit www.jubliarx.com.

Qbrexza Receives FDA Approval for Hyperhidrosis

Dermira, Inc, receives US Food and Drug Administration approval of Qbrexza (glycopyrronium cloth 2.4%) for the topical treatment of primary axillary hyperhidrosis in patients 9 years and older. Qbrexza works by blocking receptors responsible for sweat gland activation and can be used once daily. Qbrexza is expected to be available in October 2018. For more information, visit www.qbrexza.com/hcp.

Rituxan Announces FDA Approval for Pemphigus Vulgaris

Genentech USA, Inc, announces US Food and Drug Administration approval of Rituxan (rituximab) for the treatment of adults with moderate to severe pemphigus vulgaris, making it the first approved treatment for the condition in more than 60 years. Rituxan also is indicated for the treatment of rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis. Clinical trials indicated that more Rituxan-treated patients had no lesions at 2 years versus those treated with steroids alone. For more information, visit www.rituxan.com.

Verrica Is Developing a Topical Treatment for Molluscum Contagiosum

Verrica Pharmaceuticals, a clinical-stage medical dermatology company committed to identifying, developing, and commercializing pharmaceutical products for underserved patients, is working on a novel therapy for molluscum contagiosum and verruca vulgaris (common warts). Verrica’s lead product VP-102 is a proprietary drug-device combination of a topical solution of cantharidin administered through a single-use precision applicator. Top-line phase 3 trial results are expected in 2019. For more information, visit www.verrica.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at cutis@mdedge.com.

Almirall Acquires 5 Products From Allergan

Almirall, SA, announces the acquisition of 5 products from Allergan: Aczone (dapsone), Tazorac (tazarotene), Azelex (azelaic acid), Cordran Tape (flurandrenolide), and Seysara (sarecycline). Seysara is a tetracycline-derived antibiotic with anti-inflammatory properties for the treatment of acne vulgaris in patients aged 9 years and older. Approval for Seysara is anticipated later in 2018. For more information, visit www.almirall.com.

Aspire Higher Scholarship Honorees Selected

Ortho Dermatologics announces the 2018 honorees of the Aspire Higher scholarship program. Nine students—3 pursuing undergraduate degrees, 3 pursuing graduate degrees, and 3 who are mothers pursuing either degree—will receive scholarships of $10,000 each. The 2018 honorees were selected from nearly 1200 applicants who shared their experience of living with a dermatologic condition, as well as the role that a dermatologist, physician assistant, or nurse practitioner has played in helping treat it. The applications were judged by an independent panel of dermatologists from across the country. Since 2013 the program has granted more than $450,000 in scholarships to students who have been affected by dermatologic conditions. For more information, visit www.aspirehigherscholarships.com.

Duobrii NDA Resubmitted to FDA

Ortho Dermatologics resubmits a New Drug Application to the US Food and Drug Administration (FDA) for Duobrii (halobetasol propionate and tazarotene) for plaque psoriasis with additional pharmacokinetic data as requested by the FDA in June 2018. The unique formulation will allow for a potentially expanded duration of use if approved. For more information, visit www.ortho-dermatologics.com.

JubliApp Now Available for Onychomycosis Patients

Ortho Dermatologics launches JubliApp, a mobile application (app) designed to encourage patient adherence to long-term treatment with Jublia (efinaconazole topical solution 10%) for onychomycosis. The app offers treatment and refill reminders, as well as a game (Mission Plu-Toe) to keep patients engaged while the daily application is drying, helping to make the 48-week long therapy less intimidating. The app also includes efficacy tracking with side-by-side photographs that can be shared with health care providers to monitor progress. It is available in the Apple App Store and the Google Play store. For more information, visit www.jubliarx.com.

Qbrexza Receives FDA Approval for Hyperhidrosis

Dermira, Inc, receives US Food and Drug Administration approval of Qbrexza (glycopyrronium cloth 2.4%) for the topical treatment of primary axillary hyperhidrosis in patients 9 years and older. Qbrexza works by blocking receptors responsible for sweat gland activation and can be used once daily. Qbrexza is expected to be available in October 2018. For more information, visit www.qbrexza.com/hcp.

Rituxan Announces FDA Approval for Pemphigus Vulgaris

Genentech USA, Inc, announces US Food and Drug Administration approval of Rituxan (rituximab) for the treatment of adults with moderate to severe pemphigus vulgaris, making it the first approved treatment for the condition in more than 60 years. Rituxan also is indicated for the treatment of rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis. Clinical trials indicated that more Rituxan-treated patients had no lesions at 2 years versus those treated with steroids alone. For more information, visit www.rituxan.com.

Verrica Is Developing a Topical Treatment for Molluscum Contagiosum

Verrica Pharmaceuticals, a clinical-stage medical dermatology company committed to identifying, developing, and commercializing pharmaceutical products for underserved patients, is working on a novel therapy for molluscum contagiosum and verruca vulgaris (common warts). Verrica’s lead product VP-102 is a proprietary drug-device combination of a topical solution of cantharidin administered through a single-use precision applicator. Top-line phase 3 trial results are expected in 2019. For more information, visit www.verrica.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at cutis@mdedge.com.

Almirall Acquires 5 Products From Allergan

Almirall, SA, announces the acquisition of 5 products from Allergan: Aczone (dapsone), Tazorac (tazarotene), Azelex (azelaic acid), Cordran Tape (flurandrenolide), and Seysara (sarecycline). Seysara is a tetracycline-derived antibiotic with anti-inflammatory properties for the treatment of acne vulgaris in patients aged 9 years and older. Approval for Seysara is anticipated later in 2018. For more information, visit www.almirall.com.

Aspire Higher Scholarship Honorees Selected

Ortho Dermatologics announces the 2018 honorees of the Aspire Higher scholarship program. Nine students—3 pursuing undergraduate degrees, 3 pursuing graduate degrees, and 3 who are mothers pursuing either degree—will receive scholarships of $10,000 each. The 2018 honorees were selected from nearly 1200 applicants who shared their experience of living with a dermatologic condition, as well as the role that a dermatologist, physician assistant, or nurse practitioner has played in helping treat it. The applications were judged by an independent panel of dermatologists from across the country. Since 2013 the program has granted more than $450,000 in scholarships to students who have been affected by dermatologic conditions. For more information, visit www.aspirehigherscholarships.com.

Duobrii NDA Resubmitted to FDA

Ortho Dermatologics resubmits a New Drug Application to the US Food and Drug Administration (FDA) for Duobrii (halobetasol propionate and tazarotene) for plaque psoriasis with additional pharmacokinetic data as requested by the FDA in June 2018. The unique formulation will allow for a potentially expanded duration of use if approved. For more information, visit www.ortho-dermatologics.com.

JubliApp Now Available for Onychomycosis Patients

Ortho Dermatologics launches JubliApp, a mobile application (app) designed to encourage patient adherence to long-term treatment with Jublia (efinaconazole topical solution 10%) for onychomycosis. The app offers treatment and refill reminders, as well as a game (Mission Plu-Toe) to keep patients engaged while the daily application is drying, helping to make the 48-week long therapy less intimidating. The app also includes efficacy tracking with side-by-side photographs that can be shared with health care providers to monitor progress. It is available in the Apple App Store and the Google Play store. For more information, visit www.jubliarx.com.

Qbrexza Receives FDA Approval for Hyperhidrosis

Dermira, Inc, receives US Food and Drug Administration approval of Qbrexza (glycopyrronium cloth 2.4%) for the topical treatment of primary axillary hyperhidrosis in patients 9 years and older. Qbrexza works by blocking receptors responsible for sweat gland activation and can be used once daily. Qbrexza is expected to be available in October 2018. For more information, visit www.qbrexza.com/hcp.

Rituxan Announces FDA Approval for Pemphigus Vulgaris

Genentech USA, Inc, announces US Food and Drug Administration approval of Rituxan (rituximab) for the treatment of adults with moderate to severe pemphigus vulgaris, making it the first approved treatment for the condition in more than 60 years. Rituxan also is indicated for the treatment of rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis. Clinical trials indicated that more Rituxan-treated patients had no lesions at 2 years versus those treated with steroids alone. For more information, visit www.rituxan.com.

Verrica Is Developing a Topical Treatment for Molluscum Contagiosum

Verrica Pharmaceuticals, a clinical-stage medical dermatology company committed to identifying, developing, and commercializing pharmaceutical products for underserved patients, is working on a novel therapy for molluscum contagiosum and verruca vulgaris (common warts). Verrica’s lead product VP-102 is a proprietary drug-device combination of a topical solution of cantharidin administered through a single-use precision applicator. Top-line phase 3 trial results are expected in 2019. For more information, visit www.verrica.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at cutis@mdedge.com.

Molluscum contagiosum virus (MCV) is a common pediatric viral infection of the skin and/or mucous membranes.¹ It has been noted in increasingly younger patient populations, ranging from congenital cases resulting from perinatal/vertical transmission to transmission from cobathing and pool usage.^2,3Adolescent cases of MCV infection presumed to be sexually transmitted also have been reported.¹

An association between MCV infection and atopic dermatitis (AD) has been reported to be caused by a predisposition to prolonged and severe cutaneous viral infections.⁴ However, the exact nature of the relationship between MCV and AD is unknown. It is not clear if there is a greater incidence of MCV infection in AD patients, a greater number of MCV lesions when MCV infection and AD co-occur,⁵ or just more associated dermatitis in the setting of the combination of AD and MCV.⁶

The purpose of this study was to identify pediatric patients with AD onset or flare of AD triggered by MCV infection as well as to characterize the setting under which MCV may trigger AD onset or flares in children.

Methods

Medical records for 50 children with prior or current MCV infection who presented sequentially to an outpatient pediatric dermatology practice over a 1-month period were identified. Institutional review board approval was obtained. Patients were categorized according to the following parameters, which were identified as available data entry points: age at examination (last available); age at onset of MCV infection; duration of MCV infection (months); history of cobathing and with whom as well as presence of MCV infection in the cobather; usage of pools just prior to onset of MCV infection; enrollment in daycare just prior to onset of MCV infection; family and/or personal history of AD and/or psoriasis; presence of AD prior to onset of MCV infection; persistence of AD after clearance of MCV (yes/no); duration of AD following resolution of MCV infection; location of AD; location of MCV infection; number of MCV lesions documented; presence of unusual MCV morphology; therapeutics received; and comorbidities. Statistics were run using spreadsheet software.

Results

The age range of the 50 patients with MCV infection was 1 to 13 years, with an average age of 3.6 years at the onset of infection (reported by parents/guardians) and 4.5 years at presentation to the pediatric dermatology office (Table 1). Children 3 years of age or younger were more likely to have MCV lesions below the waist (P<.05). The majority of patients were female, but AD onset or flares triggered by MCV infection were not associated with sex.

The role of cobathing is unknown; however, 62% (31/50) of patients previously or currently cobathed at home, suggesting it may be a risk factor for MCV infection. An association of MCV lesions in the popliteal region trended toward being more likely with cobathing, but the association was not statistically significant.

Children with AD onset triggered by MCV infection statistically were more likely to have flexural localization of MCV and AD lesions and were statistically more likely to have a family history of AD (P<.04)(Table 2). Children with AD flares triggered by MCV infection were more likely to have MCV and AD lesions of the popliteal region and legs (P<.05)(Figure) and family history of AD (P<.04)(Table 3). Location of MCV lesions on the upper and lower extremities, buttocks, and genitalia were more likely to be associated with presence of any dermatitis than facial and/or truncal lesions (P<.05). Treatment of the MCV infection did not appear to impact the course of AD when present, but prospective interventions would be needed to assess this issue.

Superinfection with methicillin-resistant and methicillin-sensitive Staphylococcus aureus as well as atypical giant lesions of the intertriginous neck, inner thighs, and buttocks also were noted, but AD was uncommon in these cases. Given the limited number of cases, statistical significance could not be assessed.

Comment

Cutaneous infections with Malassezia have been postulated to trigger AD in infancy,¹ while systemic viral infections such as varicella-zoster virus may be protective against AD when acquired in younger children.⁷ It appears that MCV infection in young children (eg, 3 years or younger) with specific localization to the flexural areas has the potential to trigger AD in susceptible hosts. Larger studies are needed to chart the long-term disease course of AD in these children. Due to the small size of this study, it is unclear if the rise of MCV infections since the 1980s has contributed to increased AD.⁸ Susceptible children appear to have a family history of AD and localization of MCV lesions on the legs, buttocks, and antecubital region. Atopic dermatitis risk appears to be highest when MCV lesions are localized to intertriginous or flexural locations.

In addition to triggering the onset of AD, MCV infection also can trigger persistent flaring of AD, especially in the popliteal region and legs. Atopic dermatitis flares can occur at any age, but they appear to cluster in preschoolers and typically are not prevented by AD or MCV treatments; however, randomized trials are needed to identify if early intervention of MCV has a preventive benefit on AD onset or flares, and longer-term observation is needed to identify true disease course modification. Reduction of the number of MCV lesions previously has been demonstrated with institution of topical corticosteroid therapy.⁶ Therefore, institution of atopic skin care generally is advisable in the setting of MCV infection. Future studies should address the potential use of interventions to prevent the triggering of AD onset or flares in the setting of MCV infection in children.⁵

Molluscum contagiosum virus (MCV) is a common pediatric viral infection of the skin and/or mucous membranes.¹ It has been noted in increasingly younger patient populations, ranging from congenital cases resulting from perinatal/vertical transmission to transmission from cobathing and pool usage.^2,3Adolescent cases of MCV infection presumed to be sexually transmitted also have been reported.¹

An association between MCV infection and atopic dermatitis (AD) has been reported to be caused by a predisposition to prolonged and severe cutaneous viral infections.⁴ However, the exact nature of the relationship between MCV and AD is unknown. It is not clear if there is a greater incidence of MCV infection in AD patients, a greater number of MCV lesions when MCV infection and AD co-occur,⁵ or just more associated dermatitis in the setting of the combination of AD and MCV.⁶

The purpose of this study was to identify pediatric patients with AD onset or flare of AD triggered by MCV infection as well as to characterize the setting under which MCV may trigger AD onset or flares in children.

Methods

Medical records for 50 children with prior or current MCV infection who presented sequentially to an outpatient pediatric dermatology practice over a 1-month period were identified. Institutional review board approval was obtained. Patients were categorized according to the following parameters, which were identified as available data entry points: age at examination (last available); age at onset of MCV infection; duration of MCV infection (months); history of cobathing and with whom as well as presence of MCV infection in the cobather; usage of pools just prior to onset of MCV infection; enrollment in daycare just prior to onset of MCV infection; family and/or personal history of AD and/or psoriasis; presence of AD prior to onset of MCV infection; persistence of AD after clearance of MCV (yes/no); duration of AD following resolution of MCV infection; location of AD; location of MCV infection; number of MCV lesions documented; presence of unusual MCV morphology; therapeutics received; and comorbidities. Statistics were run using spreadsheet software.

Results

The age range of the 50 patients with MCV infection was 1 to 13 years, with an average age of 3.6 years at the onset of infection (reported by parents/guardians) and 4.5 years at presentation to the pediatric dermatology office (Table 1). Children 3 years of age or younger were more likely to have MCV lesions below the waist (P<.05). The majority of patients were female, but AD onset or flares triggered by MCV infection were not associated with sex.

The role of cobathing is unknown; however, 62% (31/50) of patients previously or currently cobathed at home, suggesting it may be a risk factor for MCV infection. An association of MCV lesions in the popliteal region trended toward being more likely with cobathing, but the association was not statistically significant.

Children with AD onset triggered by MCV infection statistically were more likely to have flexural localization of MCV and AD lesions and were statistically more likely to have a family history of AD (P<.04)(Table 2). Children with AD flares triggered by MCV infection were more likely to have MCV and AD lesions of the popliteal region and legs (P<.05)(Figure) and family history of AD (P<.04)(Table 3). Location of MCV lesions on the upper and lower extremities, buttocks, and genitalia were more likely to be associated with presence of any dermatitis than facial and/or truncal lesions (P<.05). Treatment of the MCV infection did not appear to impact the course of AD when present, but prospective interventions would be needed to assess this issue.

Superinfection with methicillin-resistant and methicillin-sensitive Staphylococcus aureus as well as atypical giant lesions of the intertriginous neck, inner thighs, and buttocks also were noted, but AD was uncommon in these cases. Given the limited number of cases, statistical significance could not be assessed.

Comment

Cutaneous infections with Malassezia have been postulated to trigger AD in infancy,¹ while systemic viral infections such as varicella-zoster virus may be protective against AD when acquired in younger children.⁷ It appears that MCV infection in young children (eg, 3 years or younger) with specific localization to the flexural areas has the potential to trigger AD in susceptible hosts. Larger studies are needed to chart the long-term disease course of AD in these children. Due to the small size of this study, it is unclear if the rise of MCV infections since the 1980s has contributed to increased AD.⁸ Susceptible children appear to have a family history of AD and localization of MCV lesions on the legs, buttocks, and antecubital region. Atopic dermatitis risk appears to be highest when MCV lesions are localized to intertriginous or flexural locations.

In addition to triggering the onset of AD, MCV infection also can trigger persistent flaring of AD, especially in the popliteal region and legs. Atopic dermatitis flares can occur at any age, but they appear to cluster in preschoolers and typically are not prevented by AD or MCV treatments; however, randomized trials are needed to identify if early intervention of MCV has a preventive benefit on AD onset or flares, and longer-term observation is needed to identify true disease course modification. Reduction of the number of MCV lesions previously has been demonstrated with institution of topical corticosteroid therapy.⁶ Therefore, institution of atopic skin care generally is advisable in the setting of MCV infection. Future studies should address the potential use of interventions to prevent the triggering of AD onset or flares in the setting of MCV infection in children.⁵

Molluscum contagiosum virus (MCV) is a common pediatric viral infection of the skin and/or mucous membranes.¹ It has been noted in increasingly younger patient populations, ranging from congenital cases resulting from perinatal/vertical transmission to transmission from cobathing and pool usage.^2,3Adolescent cases of MCV infection presumed to be sexually transmitted also have been reported.¹

An association between MCV infection and atopic dermatitis (AD) has been reported to be caused by a predisposition to prolonged and severe cutaneous viral infections.⁴ However, the exact nature of the relationship between MCV and AD is unknown. It is not clear if there is a greater incidence of MCV infection in AD patients, a greater number of MCV lesions when MCV infection and AD co-occur,⁵ or just more associated dermatitis in the setting of the combination of AD and MCV.⁶

The purpose of this study was to identify pediatric patients with AD onset or flare of AD triggered by MCV infection as well as to characterize the setting under which MCV may trigger AD onset or flares in children.

Methods

Medical records for 50 children with prior or current MCV infection who presented sequentially to an outpatient pediatric dermatology practice over a 1-month period were identified. Institutional review board approval was obtained. Patients were categorized according to the following parameters, which were identified as available data entry points: age at examination (last available); age at onset of MCV infection; duration of MCV infection (months); history of cobathing and with whom as well as presence of MCV infection in the cobather; usage of pools just prior to onset of MCV infection; enrollment in daycare just prior to onset of MCV infection; family and/or personal history of AD and/or psoriasis; presence of AD prior to onset of MCV infection; persistence of AD after clearance of MCV (yes/no); duration of AD following resolution of MCV infection; location of AD; location of MCV infection; number of MCV lesions documented; presence of unusual MCV morphology; therapeutics received; and comorbidities. Statistics were run using spreadsheet software.

Results

The age range of the 50 patients with MCV infection was 1 to 13 years, with an average age of 3.6 years at the onset of infection (reported by parents/guardians) and 4.5 years at presentation to the pediatric dermatology office (Table 1). Children 3 years of age or younger were more likely to have MCV lesions below the waist (P<.05). The majority of patients were female, but AD onset or flares triggered by MCV infection were not associated with sex.

The role of cobathing is unknown; however, 62% (31/50) of patients previously or currently cobathed at home, suggesting it may be a risk factor for MCV infection. An association of MCV lesions in the popliteal region trended toward being more likely with cobathing, but the association was not statistically significant.

Children with AD onset triggered by MCV infection statistically were more likely to have flexural localization of MCV and AD lesions and were statistically more likely to have a family history of AD (P<.04)(Table 2). Children with AD flares triggered by MCV infection were more likely to have MCV and AD lesions of the popliteal region and legs (P<.05)(Figure) and family history of AD (P<.04)(Table 3). Location of MCV lesions on the upper and lower extremities, buttocks, and genitalia were more likely to be associated with presence of any dermatitis than facial and/or truncal lesions (P<.05). Treatment of the MCV infection did not appear to impact the course of AD when present, but prospective interventions would be needed to assess this issue.

Superinfection with methicillin-resistant and methicillin-sensitive Staphylococcus aureus as well as atypical giant lesions of the intertriginous neck, inner thighs, and buttocks also were noted, but AD was uncommon in these cases. Given the limited number of cases, statistical significance could not be assessed.

Comment

Cutaneous infections with Malassezia have been postulated to trigger AD in infancy,¹ while systemic viral infections such as varicella-zoster virus may be protective against AD when acquired in younger children.⁷ It appears that MCV infection in young children (eg, 3 years or younger) with specific localization to the flexural areas has the potential to trigger AD in susceptible hosts. Larger studies are needed to chart the long-term disease course of AD in these children. Due to the small size of this study, it is unclear if the rise of MCV infections since the 1980s has contributed to increased AD.⁸ Susceptible children appear to have a family history of AD and localization of MCV lesions on the legs, buttocks, and antecubital region. Atopic dermatitis risk appears to be highest when MCV lesions are localized to intertriginous or flexural locations.

In addition to triggering the onset of AD, MCV infection also can trigger persistent flaring of AD, especially in the popliteal region and legs. Atopic dermatitis flares can occur at any age, but they appear to cluster in preschoolers and typically are not prevented by AD or MCV treatments; however, randomized trials are needed to identify if early intervention of MCV has a preventive benefit on AD onset or flares, and longer-term observation is needed to identify true disease course modification. Reduction of the number of MCV lesions previously has been demonstrated with institution of topical corticosteroid therapy.⁶ Therefore, institution of atopic skin care generally is advisable in the setting of MCV infection. Future studies should address the potential use of interventions to prevent the triggering of AD onset or flares in the setting of MCV infection in children.⁵

Case Report

A 74-year-old man presented with persistent episodes of severe pruritus with exacerbations on the bilateral forearms, arms, and left side of the mid back of 4 years’ duration. He had a refractory and debilitating disease that had failed extensive therapies including topical antipruritics, antihistamines, oral hydroxyzine, capsaicin, potent topical steroids (ie, clobetasol, fluocinonide, triamcinolone), phototherapy with narrowband UVB, and various dietary modifications including a gluten-free trial. The patient reported he had exhausted all medical evaluation through care with more than 7 physicians and multiple dermatologists, including a university-based dermatology department for repeated consultations; he was seen by our dermatology center for an eighth opinion.

Initial dermatologic examination revealed multiple secondarily excoriated, hemorrhagic, hyperpigmented plaques and nodules on the right side of the mid upper back indicative of notalgia paresthetica (NP) with secondary chronic skin changes (Figure 1). Additional examination of the left arm and forearm revealed several open erosions, raised nodules, and lichenified skin plaques indicative of brachioradial pruritus (BP) with secondary skin changes (Figure 2). In addition, multiple lichenified plaques of the left side of the mid back were associated with decreased sensory alternations to light touch and pin prick. Of note, the localized pruritus pattern, particularly of the unilateral infrascapular back region, heralded the possibility of a neuropathic pruritus condition originating from the cervical spine. Examination confirmed decreased range of motion in the neck with associated marked palpable bilateral cervical muscle spasm and tenderness. Laboratory testing confirmed Staphylococcus aureus secondary skin infection that was treated empirically with chlorhexidine wash. General pruritus serology and imaging workup was ordered with contributory results. The patient’s medical history was notable for noninsulin-dependent diabetes mellitus, obesity, deep venous thrombosis, asthma, vein surgery, cardiovascular disease, atrial fibrillation, atopy, allergies, asthma, and keratosis pilaris, as well as drug intolerances of warfarin sodium, sitagliptin, and clopidogrel. His medications on presentation included glyburide, digoxin, prednisone, aspirin, cetirizine, cimetidine, and hydroxyzine. Based on the relatively classic localized pruritus symptoms and the anatomical distribution of skin findings, a clinical diagnosis of concurrent NP and BRP was made, and radiologic studies of the cervical spine were ordered.

Comment

NP Presentation
Notalgia paresthetica is a common, albeit heavily unrecognized and underdiagnosed, sensory neuropathic syndrome of the back, classically of the unilateral infrascapular region. Notalgia paresthetica is largely associated with a particular localized dysesthesia that often is described by many patients as an under-the-skin itch. In 1934, NP was named and described as a periodic itching or pain on a small patch of skin located along the mid back.

The dermatologic condition may consist of other symptoms that include but are not limited to localized burning, pain, tenderness, hyperalgesia, or dysesthesia. Notalgia paresthetica typically is associated with a poorly confined tan or hyperpigmented patch in the symptomatic area, though the skin may have no visible findings in many early cases. Notalgia paresthetica tends to be a chronic condition with periodic remissions and exacerbations. It is generally not associated with other comorbidities and is not life threatening; however, it does frequently decrease quality of life, causing much discomfort and annoyance to the affected patients.

Treatment
Topical therapies for NP have generally failed and are considered difficult because of the out-of-reach affected location. There is no uniformly effective treatment of NP.



Pathogenesis
The etiologies for NP and BRP are evolving and remain to be fully elucidated. Although the exact etiology remains uncertain, there are several possible mechanisms that have been proposed for NP: (1) neuropathy from degenerative cervicothoracic disc disease or direct nerve impingement,¹ and (2) localized increased sensory innervations of the affected skin areas.²

Differential and Workup
The differential diagnosis in NP may include allergic or irritant contact dermatitis, fixed drug eruption, dermatophytosis, neoplasm, lichen amyloidosis, arthropod reaction, lichenified skin reactions including lichen simplex chronicus, neurodermatitis, infection, and other hypersensitivity reaction.

It is important during the initial assessment of patients with NP and/or BRP to obtain a thorough history of osteoarthritis, neck trauma, motor vehicle accident(s), vertebral fracture, cervical neoplasm or malignancy, family history of NP or BRP, or cervical disc disease. Radiographs or MRIs of the cervical spine may aid in diagnosis and treatment, and perhaps more so if there is an absence of contributory medical history. Radiographic imaging also may be indicated if there is a positive family history of osteoarthritis or vertebral disc disease.

A full laboratory workup including complete blood cell count, chemistry panel including renal and liver functions, and other laboratory tests (eg, IgE levels) may be warranted if pruritus is generalized and persistent to exclude other causes. Proper management of NP and BRP may involve a multispecialty effort of dermatology with radiology; orthopedic surgery; neurosurgery; neurology; and adjunctive fields including acupuncture, massage, chiropractic, and physical therapy.

NP and BRB Overlap
Because NP and BRP often originate from varying degrees of cervical disease, particularly at the C5-C6 level, traditional topical therapies aimed at treating the affected skin of the mid back and forearms may be ineffectual or partially effective as basic emollients. Due to NP and BRP’s periodic spontaneous remissions and exacerbations, it may be reasonably difficult to accurately measure direct response to various therapies. Some topical therapies aimed at the mid back skin or forearms may appear partially effective from a placebo-type perspective.

Currently, uniformly effective treatment of NP and BRP include the following: (1) therapies aimed at the cervical spine at C5-C6, including TENS, cervical massage, physical therapy, and acupuncture; and (2) therapies targeting the underlying lowered pruritus threshold such as oral antihistamines and narrowband UVB. Although uniformly effective treatments in this space had been previously lacking, traditional therapeutic options for NP and BRP included capsaicin cream, eutectic mixture of local anesthetic cream, topical steroids, pramoxine cream, topical cooling, oral steroids, menthol creams, various commercially available topical mixtures of menthol and methyl salicylate, cordran tape, intralesional corticosteroid injections, botulinum toxin injections,³ oral antihistamines, hydroxyzine, doxepin, topiramate, carbamazepine, antidepressants, gabapentin, oxcarbazepine, topiramate, thalidomide,⁴ paravertebral local anesthetic block, cervical epidural injection, surgical resection of the rib, and many others. Some of the tried systemic therapies exert their effect through the spinal nerves and central nervous system, thereby supporting the neuropathic etiology of NP.

Cervical Disc Disease
Alai et al¹ reported a 37-year-old with documented NP on the right side of the back with MRI findings of disc disease at C5-C6 and mild nerve impingement that strongly suggest the association of cervical degenerative disc disease and NP.

Savk and Savk⁵ reported that 7 of 10 patients with NP demonstrated normal neurological examination and standard electrodiagnostic results. All had skin histopathology compatible with postinflammatory hyperpigmentation. There were no amyloid deposits or other described pathology on pathologic examination of the skin. Seven of 10 cases confirmed radiographic changes in the vertebra corresponding to the dermatome of the cutaneous lesion.⁵

An earlier study by Springall et al⁶ evaluating the mechanism of NP studied whether the cutaneous symptoms were caused by alternations on the cutaneous innervation of the involved infrascapular area. They postulated that the histology findings would show increased dermal innervation to the areas; however, no measurable change in the distribution of neuropeptide-immunoreactive axons was found. There was an increase in the number of intradermal protein gene product 9.5 immunoreactive nerve fibers and epidermal dendritic cells compared with unaffected areas from the same patients and normal controls. It was concluded that the symptoms of NP may be partially related to an increase in the sensory epidermal innervation in the affected skin areas.⁶

Histologic studies have shown cutaneous changes in a few cases including lichen amyloidosis that may be secondary to the localized chronic scratching and rubbing.⁷ Clinical observations in orthopedics have established a clear relationship between the upper thoracic and interscapular region and the lower cervical spine. Frequently, cervical disc disease presents as referred pain in the upper thoracic and interscapular area. Similarly, some tumors of the cervical medulla also have presented as interscapular pain.⁸

Some have speculated direct involvement and actual entrapment of the posterior rami of T2-T6 spinal nerves.⁹ However, there are referred symptoms from the cervical area directly to the interscapular back. Degenerative vertebral and disc changes corresponding to the affected dermatome may be observed in some cases. Radiographic imaging of cervical and thoracic spine will help to exclude disc disease and possible nerve compromise.⁸

With advances in radiography and availability of MRI, earlier detection and intervention of cervical disc disease is possible. Early recognition may promote timely intervention and treatment to prevent cervical spine disease progression. In addition to degenerative cervical discs, osteoarthritis, and cervical spine strain and muscle spasm, there may be neoplasms or other pathology of the cervical spine contributing to NP and BRP.

There is some thought that there may be a relationship between NP and BRP. The described association of many cases of BRP and cervical spine disease⁶ and description of these diseases as likely neuropathic/neurogenic pruritic conditions also support a probable association of these two conditions. In contrast, NP has classically been described as unilateral in distribution, while BRP may involve unilateral or bilateral dorsolateral forearms. Most recently, as seen in our case, there are increasing incidences of nonclassic presentations of both of these diseases that may involve additional skin areas and be a basis for diagnostic challenges to the clinician.

First-line therapies for NP and BRP with associated cervical spinal disease are currently evolving and may include nondermatologic and noninvasive treatments such as spinal manipulation, physical therapy, acupuncture, cervical soft collars, massage, cervical traction, cervical muscle strengthening and increased range on motion, oral nonsteroidal anti-inflammatory medications (eg, ibuprofen, celecoxib, ketorolac), and oral muscle relaxants (eg, carisoprodol, cyclobenzaprine, methocarbamol, metaxalone). Current standard therapies such as cervical vertebral fusion and disc replacement as well as other innovative treatment measures for degenerative disc disease that may be introduced in the future also can be considered.¹⁰

Conclusion

Notalgia paresthetica and BRP may not be solely skin diseases but rather cutaneous signs of an underlying cervical spine disease. The striking association of NP with BRP we present as well as the degenerative and/or traumatic cervicothoracic spine disease suggests that early spinal nerve impingement or cervical muscle spasm may contribute to the pathogenesis of these skin symptoms. Additional studies are needed to further assess the relationship of NP and BRP as well as the association of each disease entity independently with cervical spine disease, as it is unknown if these are causal or coincidental findings. Although topical therapies may seemingly help decrease the localized symptoms in NP and BRP in some cases, systemic or broader-scope cervical spinal evaluation may be warranted to fully evaluate refractory cases. Cervical spinal imaging and treatment, particularly at C5-C6 levels, may be appropriate as primary or first-line therapy in many cases of NP and BRP. The paradigm shift in thinking will more likely than not be to treat the cervical spine and the skin will follow.

Case Report

A 74-year-old man presented with persistent episodes of severe pruritus with exacerbations on the bilateral forearms, arms, and left side of the mid back of 4 years’ duration. He had a refractory and debilitating disease that had failed extensive therapies including topical antipruritics, antihistamines, oral hydroxyzine, capsaicin, potent topical steroids (ie, clobetasol, fluocinonide, triamcinolone), phototherapy with narrowband UVB, and various dietary modifications including a gluten-free trial. The patient reported he had exhausted all medical evaluation through care with more than 7 physicians and multiple dermatologists, including a university-based dermatology department for repeated consultations; he was seen by our dermatology center for an eighth opinion.

Initial dermatologic examination revealed multiple secondarily excoriated, hemorrhagic, hyperpigmented plaques and nodules on the right side of the mid upper back indicative of notalgia paresthetica (NP) with secondary chronic skin changes (Figure 1). Additional examination of the left arm and forearm revealed several open erosions, raised nodules, and lichenified skin plaques indicative of brachioradial pruritus (BP) with secondary skin changes (Figure 2). In addition, multiple lichenified plaques of the left side of the mid back were associated with decreased sensory alternations to light touch and pin prick. Of note, the localized pruritus pattern, particularly of the unilateral infrascapular back region, heralded the possibility of a neuropathic pruritus condition originating from the cervical spine. Examination confirmed decreased range of motion in the neck with associated marked palpable bilateral cervical muscle spasm and tenderness. Laboratory testing confirmed Staphylococcus aureus secondary skin infection that was treated empirically with chlorhexidine wash. General pruritus serology and imaging workup was ordered with contributory results. The patient’s medical history was notable for noninsulin-dependent diabetes mellitus, obesity, deep venous thrombosis, asthma, vein surgery, cardiovascular disease, atrial fibrillation, atopy, allergies, asthma, and keratosis pilaris, as well as drug intolerances of warfarin sodium, sitagliptin, and clopidogrel. His medications on presentation included glyburide, digoxin, prednisone, aspirin, cetirizine, cimetidine, and hydroxyzine. Based on the relatively classic localized pruritus symptoms and the anatomical distribution of skin findings, a clinical diagnosis of concurrent NP and BRP was made, and radiologic studies of the cervical spine were ordered.

Comment

NP Presentation
Notalgia paresthetica is a common, albeit heavily unrecognized and underdiagnosed, sensory neuropathic syndrome of the back, classically of the unilateral infrascapular region. Notalgia paresthetica is largely associated with a particular localized dysesthesia that often is described by many patients as an under-the-skin itch. In 1934, NP was named and described as a periodic itching or pain on a small patch of skin located along the mid back.

The dermatologic condition may consist of other symptoms that include but are not limited to localized burning, pain, tenderness, hyperalgesia, or dysesthesia. Notalgia paresthetica typically is associated with a poorly confined tan or hyperpigmented patch in the symptomatic area, though the skin may have no visible findings in many early cases. Notalgia paresthetica tends to be a chronic condition with periodic remissions and exacerbations. It is generally not associated with other comorbidities and is not life threatening; however, it does frequently decrease quality of life, causing much discomfort and annoyance to the affected patients.

Treatment
Topical therapies for NP have generally failed and are considered difficult because of the out-of-reach affected location. There is no uniformly effective treatment of NP.



Pathogenesis
The etiologies for NP and BRP are evolving and remain to be fully elucidated. Although the exact etiology remains uncertain, there are several possible mechanisms that have been proposed for NP: (1) neuropathy from degenerative cervicothoracic disc disease or direct nerve impingement,¹ and (2) localized increased sensory innervations of the affected skin areas.²

Differential and Workup
The differential diagnosis in NP may include allergic or irritant contact dermatitis, fixed drug eruption, dermatophytosis, neoplasm, lichen amyloidosis, arthropod reaction, lichenified skin reactions including lichen simplex chronicus, neurodermatitis, infection, and other hypersensitivity reaction.

It is important during the initial assessment of patients with NP and/or BRP to obtain a thorough history of osteoarthritis, neck trauma, motor vehicle accident(s), vertebral fracture, cervical neoplasm or malignancy, family history of NP or BRP, or cervical disc disease. Radiographs or MRIs of the cervical spine may aid in diagnosis and treatment, and perhaps more so if there is an absence of contributory medical history. Radiographic imaging also may be indicated if there is a positive family history of osteoarthritis or vertebral disc disease.

A full laboratory workup including complete blood cell count, chemistry panel including renal and liver functions, and other laboratory tests (eg, IgE levels) may be warranted if pruritus is generalized and persistent to exclude other causes. Proper management of NP and BRP may involve a multispecialty effort of dermatology with radiology; orthopedic surgery; neurosurgery; neurology; and adjunctive fields including acupuncture, massage, chiropractic, and physical therapy.

NP and BRB Overlap
Because NP and BRP often originate from varying degrees of cervical disease, particularly at the C5-C6 level, traditional topical therapies aimed at treating the affected skin of the mid back and forearms may be ineffectual or partially effective as basic emollients. Due to NP and BRP’s periodic spontaneous remissions and exacerbations, it may be reasonably difficult to accurately measure direct response to various therapies. Some topical therapies aimed at the mid back skin or forearms may appear partially effective from a placebo-type perspective.

Currently, uniformly effective treatment of NP and BRP include the following: (1) therapies aimed at the cervical spine at C5-C6, including TENS, cervical massage, physical therapy, and acupuncture; and (2) therapies targeting the underlying lowered pruritus threshold such as oral antihistamines and narrowband UVB. Although uniformly effective treatments in this space had been previously lacking, traditional therapeutic options for NP and BRP included capsaicin cream, eutectic mixture of local anesthetic cream, topical steroids, pramoxine cream, topical cooling, oral steroids, menthol creams, various commercially available topical mixtures of menthol and methyl salicylate, cordran tape, intralesional corticosteroid injections, botulinum toxin injections,³ oral antihistamines, hydroxyzine, doxepin, topiramate, carbamazepine, antidepressants, gabapentin, oxcarbazepine, topiramate, thalidomide,⁴ paravertebral local anesthetic block, cervical epidural injection, surgical resection of the rib, and many others. Some of the tried systemic therapies exert their effect through the spinal nerves and central nervous system, thereby supporting the neuropathic etiology of NP.

Cervical Disc Disease
Alai et al¹ reported a 37-year-old with documented NP on the right side of the back with MRI findings of disc disease at C5-C6 and mild nerve impingement that strongly suggest the association of cervical degenerative disc disease and NP.

Savk and Savk⁵ reported that 7 of 10 patients with NP demonstrated normal neurological examination and standard electrodiagnostic results. All had skin histopathology compatible with postinflammatory hyperpigmentation. There were no amyloid deposits or other described pathology on pathologic examination of the skin. Seven of 10 cases confirmed radiographic changes in the vertebra corresponding to the dermatome of the cutaneous lesion.⁵

An earlier study by Springall et al⁶ evaluating the mechanism of NP studied whether the cutaneous symptoms were caused by alternations on the cutaneous innervation of the involved infrascapular area. They postulated that the histology findings would show increased dermal innervation to the areas; however, no measurable change in the distribution of neuropeptide-immunoreactive axons was found. There was an increase in the number of intradermal protein gene product 9.5 immunoreactive nerve fibers and epidermal dendritic cells compared with unaffected areas from the same patients and normal controls. It was concluded that the symptoms of NP may be partially related to an increase in the sensory epidermal innervation in the affected skin areas.⁶

Histologic studies have shown cutaneous changes in a few cases including lichen amyloidosis that may be secondary to the localized chronic scratching and rubbing.⁷ Clinical observations in orthopedics have established a clear relationship between the upper thoracic and interscapular region and the lower cervical spine. Frequently, cervical disc disease presents as referred pain in the upper thoracic and interscapular area. Similarly, some tumors of the cervical medulla also have presented as interscapular pain.⁸

Some have speculated direct involvement and actual entrapment of the posterior rami of T2-T6 spinal nerves.⁹ However, there are referred symptoms from the cervical area directly to the interscapular back. Degenerative vertebral and disc changes corresponding to the affected dermatome may be observed in some cases. Radiographic imaging of cervical and thoracic spine will help to exclude disc disease and possible nerve compromise.⁸

With advances in radiography and availability of MRI, earlier detection and intervention of cervical disc disease is possible. Early recognition may promote timely intervention and treatment to prevent cervical spine disease progression. In addition to degenerative cervical discs, osteoarthritis, and cervical spine strain and muscle spasm, there may be neoplasms or other pathology of the cervical spine contributing to NP and BRP.

There is some thought that there may be a relationship between NP and BRP. The described association of many cases of BRP and cervical spine disease⁶ and description of these diseases as likely neuropathic/neurogenic pruritic conditions also support a probable association of these two conditions. In contrast, NP has classically been described as unilateral in distribution, while BRP may involve unilateral or bilateral dorsolateral forearms. Most recently, as seen in our case, there are increasing incidences of nonclassic presentations of both of these diseases that may involve additional skin areas and be a basis for diagnostic challenges to the clinician.

First-line therapies for NP and BRP with associated cervical spinal disease are currently evolving and may include nondermatologic and noninvasive treatments such as spinal manipulation, physical therapy, acupuncture, cervical soft collars, massage, cervical traction, cervical muscle strengthening and increased range on motion, oral nonsteroidal anti-inflammatory medications (eg, ibuprofen, celecoxib, ketorolac), and oral muscle relaxants (eg, carisoprodol, cyclobenzaprine, methocarbamol, metaxalone). Current standard therapies such as cervical vertebral fusion and disc replacement as well as other innovative treatment measures for degenerative disc disease that may be introduced in the future also can be considered.¹⁰

Conclusion

Notalgia paresthetica and BRP may not be solely skin diseases but rather cutaneous signs of an underlying cervical spine disease. The striking association of NP with BRP we present as well as the degenerative and/or traumatic cervicothoracic spine disease suggests that early spinal nerve impingement or cervical muscle spasm may contribute to the pathogenesis of these skin symptoms. Additional studies are needed to further assess the relationship of NP and BRP as well as the association of each disease entity independently with cervical spine disease, as it is unknown if these are causal or coincidental findings. Although topical therapies may seemingly help decrease the localized symptoms in NP and BRP in some cases, systemic or broader-scope cervical spinal evaluation may be warranted to fully evaluate refractory cases. Cervical spinal imaging and treatment, particularly at C5-C6 levels, may be appropriate as primary or first-line therapy in many cases of NP and BRP. The paradigm shift in thinking will more likely than not be to treat the cervical spine and the skin will follow.

Case Report

A 74-year-old man presented with persistent episodes of severe pruritus with exacerbations on the bilateral forearms, arms, and left side of the mid back of 4 years’ duration. He had a refractory and debilitating disease that had failed extensive therapies including topical antipruritics, antihistamines, oral hydroxyzine, capsaicin, potent topical steroids (ie, clobetasol, fluocinonide, triamcinolone), phototherapy with narrowband UVB, and various dietary modifications including a gluten-free trial. The patient reported he had exhausted all medical evaluation through care with more than 7 physicians and multiple dermatologists, including a university-based dermatology department for repeated consultations; he was seen by our dermatology center for an eighth opinion.

Initial dermatologic examination revealed multiple secondarily excoriated, hemorrhagic, hyperpigmented plaques and nodules on the right side of the mid upper back indicative of notalgia paresthetica (NP) with secondary chronic skin changes (Figure 1). Additional examination of the left arm and forearm revealed several open erosions, raised nodules, and lichenified skin plaques indicative of brachioradial pruritus (BP) with secondary skin changes (Figure 2). In addition, multiple lichenified plaques of the left side of the mid back were associated with decreased sensory alternations to light touch and pin prick. Of note, the localized pruritus pattern, particularly of the unilateral infrascapular back region, heralded the possibility of a neuropathic pruritus condition originating from the cervical spine. Examination confirmed decreased range of motion in the neck with associated marked palpable bilateral cervical muscle spasm and tenderness. Laboratory testing confirmed Staphylococcus aureus secondary skin infection that was treated empirically with chlorhexidine wash. General pruritus serology and imaging workup was ordered with contributory results. The patient’s medical history was notable for noninsulin-dependent diabetes mellitus, obesity, deep venous thrombosis, asthma, vein surgery, cardiovascular disease, atrial fibrillation, atopy, allergies, asthma, and keratosis pilaris, as well as drug intolerances of warfarin sodium, sitagliptin, and clopidogrel. His medications on presentation included glyburide, digoxin, prednisone, aspirin, cetirizine, cimetidine, and hydroxyzine. Based on the relatively classic localized pruritus symptoms and the anatomical distribution of skin findings, a clinical diagnosis of concurrent NP and BRP was made, and radiologic studies of the cervical spine were ordered.

Comment

NP Presentation
Notalgia paresthetica is a common, albeit heavily unrecognized and underdiagnosed, sensory neuropathic syndrome of the back, classically of the unilateral infrascapular region. Notalgia paresthetica is largely associated with a particular localized dysesthesia that often is described by many patients as an under-the-skin itch. In 1934, NP was named and described as a periodic itching or pain on a small patch of skin located along the mid back.

The dermatologic condition may consist of other symptoms that include but are not limited to localized burning, pain, tenderness, hyperalgesia, or dysesthesia. Notalgia paresthetica typically is associated with a poorly confined tan or hyperpigmented patch in the symptomatic area, though the skin may have no visible findings in many early cases. Notalgia paresthetica tends to be a chronic condition with periodic remissions and exacerbations. It is generally not associated with other comorbidities and is not life threatening; however, it does frequently decrease quality of life, causing much discomfort and annoyance to the affected patients.

Treatment
Topical therapies for NP have generally failed and are considered difficult because of the out-of-reach affected location. There is no uniformly effective treatment of NP.



Pathogenesis
The etiologies for NP and BRP are evolving and remain to be fully elucidated. Although the exact etiology remains uncertain, there are several possible mechanisms that have been proposed for NP: (1) neuropathy from degenerative cervicothoracic disc disease or direct nerve impingement,¹ and (2) localized increased sensory innervations of the affected skin areas.²

Differential and Workup
The differential diagnosis in NP may include allergic or irritant contact dermatitis, fixed drug eruption, dermatophytosis, neoplasm, lichen amyloidosis, arthropod reaction, lichenified skin reactions including lichen simplex chronicus, neurodermatitis, infection, and other hypersensitivity reaction.

It is important during the initial assessment of patients with NP and/or BRP to obtain a thorough history of osteoarthritis, neck trauma, motor vehicle accident(s), vertebral fracture, cervical neoplasm or malignancy, family history of NP or BRP, or cervical disc disease. Radiographs or MRIs of the cervical spine may aid in diagnosis and treatment, and perhaps more so if there is an absence of contributory medical history. Radiographic imaging also may be indicated if there is a positive family history of osteoarthritis or vertebral disc disease.

A full laboratory workup including complete blood cell count, chemistry panel including renal and liver functions, and other laboratory tests (eg, IgE levels) may be warranted if pruritus is generalized and persistent to exclude other causes. Proper management of NP and BRP may involve a multispecialty effort of dermatology with radiology; orthopedic surgery; neurosurgery; neurology; and adjunctive fields including acupuncture, massage, chiropractic, and physical therapy.

NP and BRB Overlap
Because NP and BRP often originate from varying degrees of cervical disease, particularly at the C5-C6 level, traditional topical therapies aimed at treating the affected skin of the mid back and forearms may be ineffectual or partially effective as basic emollients. Due to NP and BRP’s periodic spontaneous remissions and exacerbations, it may be reasonably difficult to accurately measure direct response to various therapies. Some topical therapies aimed at the mid back skin or forearms may appear partially effective from a placebo-type perspective.

Currently, uniformly effective treatment of NP and BRP include the following: (1) therapies aimed at the cervical spine at C5-C6, including TENS, cervical massage, physical therapy, and acupuncture; and (2) therapies targeting the underlying lowered pruritus threshold such as oral antihistamines and narrowband UVB. Although uniformly effective treatments in this space had been previously lacking, traditional therapeutic options for NP and BRP included capsaicin cream, eutectic mixture of local anesthetic cream, topical steroids, pramoxine cream, topical cooling, oral steroids, menthol creams, various commercially available topical mixtures of menthol and methyl salicylate, cordran tape, intralesional corticosteroid injections, botulinum toxin injections,³ oral antihistamines, hydroxyzine, doxepin, topiramate, carbamazepine, antidepressants, gabapentin, oxcarbazepine, topiramate, thalidomide,⁴ paravertebral local anesthetic block, cervical epidural injection, surgical resection of the rib, and many others. Some of the tried systemic therapies exert their effect through the spinal nerves and central nervous system, thereby supporting the neuropathic etiology of NP.

Cervical Disc Disease
Alai et al¹ reported a 37-year-old with documented NP on the right side of the back with MRI findings of disc disease at C5-C6 and mild nerve impingement that strongly suggest the association of cervical degenerative disc disease and NP.

Savk and Savk⁵ reported that 7 of 10 patients with NP demonstrated normal neurological examination and standard electrodiagnostic results. All had skin histopathology compatible with postinflammatory hyperpigmentation. There were no amyloid deposits or other described pathology on pathologic examination of the skin. Seven of 10 cases confirmed radiographic changes in the vertebra corresponding to the dermatome of the cutaneous lesion.⁵

An earlier study by Springall et al⁶ evaluating the mechanism of NP studied whether the cutaneous symptoms were caused by alternations on the cutaneous innervation of the involved infrascapular area. They postulated that the histology findings would show increased dermal innervation to the areas; however, no measurable change in the distribution of neuropeptide-immunoreactive axons was found. There was an increase in the number of intradermal protein gene product 9.5 immunoreactive nerve fibers and epidermal dendritic cells compared with unaffected areas from the same patients and normal controls. It was concluded that the symptoms of NP may be partially related to an increase in the sensory epidermal innervation in the affected skin areas.⁶

Histologic studies have shown cutaneous changes in a few cases including lichen amyloidosis that may be secondary to the localized chronic scratching and rubbing.⁷ Clinical observations in orthopedics have established a clear relationship between the upper thoracic and interscapular region and the lower cervical spine. Frequently, cervical disc disease presents as referred pain in the upper thoracic and interscapular area. Similarly, some tumors of the cervical medulla also have presented as interscapular pain.⁸

Some have speculated direct involvement and actual entrapment of the posterior rami of T2-T6 spinal nerves.⁹ However, there are referred symptoms from the cervical area directly to the interscapular back. Degenerative vertebral and disc changes corresponding to the affected dermatome may be observed in some cases. Radiographic imaging of cervical and thoracic spine will help to exclude disc disease and possible nerve compromise.⁸

With advances in radiography and availability of MRI, earlier detection and intervention of cervical disc disease is possible. Early recognition may promote timely intervention and treatment to prevent cervical spine disease progression. In addition to degenerative cervical discs, osteoarthritis, and cervical spine strain and muscle spasm, there may be neoplasms or other pathology of the cervical spine contributing to NP and BRP.

There is some thought that there may be a relationship between NP and BRP. The described association of many cases of BRP and cervical spine disease⁶ and description of these diseases as likely neuropathic/neurogenic pruritic conditions also support a probable association of these two conditions. In contrast, NP has classically been described as unilateral in distribution, while BRP may involve unilateral or bilateral dorsolateral forearms. Most recently, as seen in our case, there are increasing incidences of nonclassic presentations of both of these diseases that may involve additional skin areas and be a basis for diagnostic challenges to the clinician.

First-line therapies for NP and BRP with associated cervical spinal disease are currently evolving and may include nondermatologic and noninvasive treatments such as spinal manipulation, physical therapy, acupuncture, cervical soft collars, massage, cervical traction, cervical muscle strengthening and increased range on motion, oral nonsteroidal anti-inflammatory medications (eg, ibuprofen, celecoxib, ketorolac), and oral muscle relaxants (eg, carisoprodol, cyclobenzaprine, methocarbamol, metaxalone). Current standard therapies such as cervical vertebral fusion and disc replacement as well as other innovative treatment measures for degenerative disc disease that may be introduced in the future also can be considered.¹⁰

Conclusion

Notalgia paresthetica and BRP may not be solely skin diseases but rather cutaneous signs of an underlying cervical spine disease. The striking association of NP with BRP we present as well as the degenerative and/or traumatic cervicothoracic spine disease suggests that early spinal nerve impingement or cervical muscle spasm may contribute to the pathogenesis of these skin symptoms. Additional studies are needed to further assess the relationship of NP and BRP as well as the association of each disease entity independently with cervical spine disease, as it is unknown if these are causal or coincidental findings. Although topical therapies may seemingly help decrease the localized symptoms in NP and BRP in some cases, systemic or broader-scope cervical spinal evaluation may be warranted to fully evaluate refractory cases. Cervical spinal imaging and treatment, particularly at C5-C6 levels, may be appropriate as primary or first-line therapy in many cases of NP and BRP. The paradigm shift in thinking will more likely than not be to treat the cervical spine and the skin will follow.

Achieving sustained minimal disease activity in psoriatic arthritis could slow or prevent the progression of carotid atherosclerosis and arterial stiffness, new research suggests.

designer491/iStock/Getty Images

A prospective cohort study, published online Aug. 25 in Arthritis & Rheumatology, involved 90 patients with psoriatic arthritis (PsA) who were followed for at least 24 months. High-resolution carotid ultrasound and arterial stiffness markers were assessed annually.

Overall, 57 patients (63%) achieved minimal disease activity (MDA) – defined as meeting five or more cutoffs for seven domains of disease activity – at 1 year of follow-up, 69% achieved it by 2 years, and 46% sustained MDA from the 1-year follow-up to the 2-year follow-up.

The 41 patients who sustained MDA over the follow-up points showed significantly lower odds of progression of atherosclerotic carotid plaques (odds ratio = 0.273; P = .024). They were also significantly less likely to show increases in total carotid plaque area, increased intima-media thickness, or increased measures of arterial stiffness. The researchers also noted a trend toward improvements in pulse wave velocity in this group.

Patients who achieved sustained MDA had lower disease activity at baseline, and a higher proportion of them were already in a state of MDA at baseline, compared with the group of patients who did not achieved sustained MDA.

Sustained MDA appeared to be key to reducing atherosclerosis, as researchers did not see any significant differences in measures of arterial stiffness between those who achieved MDA – sustained or otherwise – at 2 years and those who did not, after adjusting for baseline differences and use of disease-modifying antirheumatic drugs (DMARDs).

“The most important finding in this study is that long-term control of inflammation is important in preventing progression of subclinical atherosclerosis and arterial stiffness, independent of traditional CV risk factors,” wrote Isaac T. Cheng of Prince of Wales Hospital at The Chinese University of Hong Kong, and his coauthors. “These data suggest that low stable disease activity over a prolonged period of time may have a significant protective effect against CVD in PsA compared with those patients with intermittent flare-ups.”

The study also looked at treatment effect. More patients treated with biologic DMARDs achieved MDA, but the researchers saw no association between the use of conventional synthetic DMARDs and the likelihood of achieving MDA.

They noted that the protective effects of achieving sustained MDA seemed to be independent of biologic DMARDs, “suggesting that controlling disease activity using various combinations of conventional and biological DMARD may be useful in improving CV risk in these patients.”

However, the investigators noted that the study was conducted in Hong Kong, where biologics are not reimbursed by the government. Patients in the study had to pay for these medications themselves, and some could not afford them.

They raised the possibility that early initiation with biologic DMARDs might further improve cardiovascular outcomes, but said this needed to be addressed in future studies.

“These data support the EULAR recommendation that disease activity should be controlled optimally in order to lower CVD risk in patients with PsA,” the authors wrote. “Data from the current study confirm that using a treat-to-target strategy, MDA is indeed an achievable target even in a health care system with resource constrain.”

The Health and Medical Research Fund supported the study. No conflicts of interest were declared.

SOURCE: Cheng I et al. Arthritis Rheumatol. 2018 Aug 25. doi: 10.1002/art.40695.

Achieving sustained minimal disease activity in psoriatic arthritis could slow or prevent the progression of carotid atherosclerosis and arterial stiffness, new research suggests.

designer491/iStock/Getty Images

A prospective cohort study, published online Aug. 25 in Arthritis & Rheumatology, involved 90 patients with psoriatic arthritis (PsA) who were followed for at least 24 months. High-resolution carotid ultrasound and arterial stiffness markers were assessed annually.

Overall, 57 patients (63%) achieved minimal disease activity (MDA) – defined as meeting five or more cutoffs for seven domains of disease activity – at 1 year of follow-up, 69% achieved it by 2 years, and 46% sustained MDA from the 1-year follow-up to the 2-year follow-up.

The 41 patients who sustained MDA over the follow-up points showed significantly lower odds of progression of atherosclerotic carotid plaques (odds ratio = 0.273; P = .024). They were also significantly less likely to show increases in total carotid plaque area, increased intima-media thickness, or increased measures of arterial stiffness. The researchers also noted a trend toward improvements in pulse wave velocity in this group.

Patients who achieved sustained MDA had lower disease activity at baseline, and a higher proportion of them were already in a state of MDA at baseline, compared with the group of patients who did not achieved sustained MDA.

Sustained MDA appeared to be key to reducing atherosclerosis, as researchers did not see any significant differences in measures of arterial stiffness between those who achieved MDA – sustained or otherwise – at 2 years and those who did not, after adjusting for baseline differences and use of disease-modifying antirheumatic drugs (DMARDs).

“The most important finding in this study is that long-term control of inflammation is important in preventing progression of subclinical atherosclerosis and arterial stiffness, independent of traditional CV risk factors,” wrote Isaac T. Cheng of Prince of Wales Hospital at The Chinese University of Hong Kong, and his coauthors. “These data suggest that low stable disease activity over a prolonged period of time may have a significant protective effect against CVD in PsA compared with those patients with intermittent flare-ups.”

The study also looked at treatment effect. More patients treated with biologic DMARDs achieved MDA, but the researchers saw no association between the use of conventional synthetic DMARDs and the likelihood of achieving MDA.

They noted that the protective effects of achieving sustained MDA seemed to be independent of biologic DMARDs, “suggesting that controlling disease activity using various combinations of conventional and biological DMARD may be useful in improving CV risk in these patients.”

However, the investigators noted that the study was conducted in Hong Kong, where biologics are not reimbursed by the government. Patients in the study had to pay for these medications themselves, and some could not afford them.

They raised the possibility that early initiation with biologic DMARDs might further improve cardiovascular outcomes, but said this needed to be addressed in future studies.

“These data support the EULAR recommendation that disease activity should be controlled optimally in order to lower CVD risk in patients with PsA,” the authors wrote. “Data from the current study confirm that using a treat-to-target strategy, MDA is indeed an achievable target even in a health care system with resource constrain.”

The Health and Medical Research Fund supported the study. No conflicts of interest were declared.

SOURCE: Cheng I et al. Arthritis Rheumatol. 2018 Aug 25. doi: 10.1002/art.40695.

Achieving sustained minimal disease activity in psoriatic arthritis could slow or prevent the progression of carotid atherosclerosis and arterial stiffness, new research suggests.

designer491/iStock/Getty Images

A prospective cohort study, published online Aug. 25 in Arthritis & Rheumatology, involved 90 patients with psoriatic arthritis (PsA) who were followed for at least 24 months. High-resolution carotid ultrasound and arterial stiffness markers were assessed annually.

Overall, 57 patients (63%) achieved minimal disease activity (MDA) – defined as meeting five or more cutoffs for seven domains of disease activity – at 1 year of follow-up, 69% achieved it by 2 years, and 46% sustained MDA from the 1-year follow-up to the 2-year follow-up.

The 41 patients who sustained MDA over the follow-up points showed significantly lower odds of progression of atherosclerotic carotid plaques (odds ratio = 0.273; P = .024). They were also significantly less likely to show increases in total carotid plaque area, increased intima-media thickness, or increased measures of arterial stiffness. The researchers also noted a trend toward improvements in pulse wave velocity in this group.

Patients who achieved sustained MDA had lower disease activity at baseline, and a higher proportion of them were already in a state of MDA at baseline, compared with the group of patients who did not achieved sustained MDA.

Sustained MDA appeared to be key to reducing atherosclerosis, as researchers did not see any significant differences in measures of arterial stiffness between those who achieved MDA – sustained or otherwise – at 2 years and those who did not, after adjusting for baseline differences and use of disease-modifying antirheumatic drugs (DMARDs).

“The most important finding in this study is that long-term control of inflammation is important in preventing progression of subclinical atherosclerosis and arterial stiffness, independent of traditional CV risk factors,” wrote Isaac T. Cheng of Prince of Wales Hospital at The Chinese University of Hong Kong, and his coauthors. “These data suggest that low stable disease activity over a prolonged period of time may have a significant protective effect against CVD in PsA compared with those patients with intermittent flare-ups.”

The study also looked at treatment effect. More patients treated with biologic DMARDs achieved MDA, but the researchers saw no association between the use of conventional synthetic DMARDs and the likelihood of achieving MDA.

They noted that the protective effects of achieving sustained MDA seemed to be independent of biologic DMARDs, “suggesting that controlling disease activity using various combinations of conventional and biological DMARD may be useful in improving CV risk in these patients.”

However, the investigators noted that the study was conducted in Hong Kong, where biologics are not reimbursed by the government. Patients in the study had to pay for these medications themselves, and some could not afford them.

They raised the possibility that early initiation with biologic DMARDs might further improve cardiovascular outcomes, but said this needed to be addressed in future studies.

“These data support the EULAR recommendation that disease activity should be controlled optimally in order to lower CVD risk in patients with PsA,” the authors wrote. “Data from the current study confirm that using a treat-to-target strategy, MDA is indeed an achievable target even in a health care system with resource constrain.”

The Health and Medical Research Fund supported the study. No conflicts of interest were declared.

SOURCE: Cheng I et al. Arthritis Rheumatol. 2018 Aug 25. doi: 10.1002/art.40695.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare, often aggressive type of peripheral T-cell lymphoma. It comprises 18% of peripheral T-cell lymphomas and 1% to 2% of all non-Hodgkin lymphomas.¹ The incidence of AITL in the United States is estimated to be 0.05 cases per 100,000 person-years,² and there is a slight male predominance.^1,3,4 It typically presents in the seventh decade of life; however, cases have been reported in adults ranging from 20 to 91 years of age.³

Angioimmunoblastic T-cell lymphoma presents with lymphadenopathy, hepatosplenomegaly, and systemic B symptoms (eg, fever, night sweats, weight loss, generalized pruritus).^4-6 There are cutaneous manifestations in up to 50% of cases^4,5,7 and frequently signs of autoimmune disorder.^4,5 The diagnosis often is made by excisional lymph node biopsy. Lymph node specimens characteristically have a mixed inflammatory infiltrate that includes numerous B cells often infected with Epstein-Barr virus (EBV) and a relatively small population of atypical T lymphocytes.⁸ Identification of this neoplastic population of CD4⁺CD8⁻ T lymphocytes expressing normal follicular helper T-cell markers CD10, chemokine CXCL13, programmed cell death protein 1 (PD-1), and B-cell lymphoma 6 (BCL-6) confirms the diagnosis of AITL.^9,10 These malignant cells can be identified in skin specimens in cases of cutaneous metastatic disease.^11,12 We present a case originally misdiagnosed as diffuse large B-cell lymphoma that was later identified as AITL on skin biopsy.

Case Report

A 72-year-old woman presented with a pruritic erythematous eruption around the neck of 3 weeks’ duration (Figure 1). Her medical history was notable for diffuse large B-cell non-Hodgkin lymphoma diagnosed 3 months prior based on results from a right cervical lymph node biopsy. She was treated with bendamustine and rituximab. On physical examination there were erythematous edematous papules coalescing into indurated plaques around the neck. The differential diagnosis included drug hypersensitivity reaction, herpes zoster, urticaria, and cutaneous metastasis. Two punch biopsies were taken for hematoxylin and eosin and tissue culture.

Tissue cultures and viral polymerase chain reaction were negative. Histopathologic examination revealed a scant atypical lymphoid infiltrate focally involving the deep dermis. The cells were medium to large in size and contained hyperchromatic pleomorphic nuclei (Figure 2). They were positive for CD3 and CD4, which was concerning for T-cell lymphoma. The histologic report of the excisional lymph node biopsy done 3 months prior described an atypical lymphoid neoplasm with extensive necrosis and extranodal spread that stained positively for CD20 (Figure 3).

Comment

Etiology
Angioimmunoblastic T-cell lymphoma was originally named angioimmunoblastic lymphadenopathy with dysproteinemia. It was initially thought to be a benign hyperreactive immune process driven by B cells, and patients often died of infectious complications not long after the diagnosis was made.¹³ As more cases were reported with clonal rearrangements and signs of progressive lymphoma, AITL was recognized as a malignancy.

Presentation
Patients with AITL often present with advanced stage III or IV disease with extranodal and bone marrow involvement.^3-6 Cutaneous disease occurs in up to half of patients and portends a poor prognosis.⁷ The rash often is a nonspecific erythematous macular and papular eruption mimicking a morbilliform viral exanthem or drug reaction. Urticarial, nodular, petechial, purpuric, eczematous, erythrodermic, and vesiculobullous presentations have been described.^4,11,12 In up to one-third of cases, the eruption occurs in association with a new medication, often leading to an initial misdiagnosis of drug hypersensitivity reaction.^4,11 In a review conducted by Balaraman et al,¹⁴ 84% of patients with AITL reported having pruritus.

There is an association of autoimmune phenomena in patients with AITL, which is likely a result of immune dysregulation associated with poorly functioning follicular helper T cells. Patients may present with arthralgia, hemolytic anemia, or thrombocytopenic purpura. Hypergammaglobulinemia has been reported in 30% to 50% of AITL patients.^4,6 Other pertinent immunologic findings include positive Coombs test, cold agglutinins, cryoglobulinemia, hypocomplementemia, and positive antinuclear antibodies.^4-7

Gene Analysis
Affected lymph nodes have a characteristically effaced architecture with proliferative arborizing venules; a hyperplastic population of follicular dendritic cells; and a mixed inflammatory infiltrate that is comprised of atypical lymphocytes and variable numbers of reactive lymphocytes, histiocytes, eosinophils, and plasma cells. The malignant T lymphocytes often account for only a small portion of the infiltrate.⁸ T-cell gene rearrangement studies identify clonal cells with β and γ rearrangements in the majority of cases.⁴ These cells are predominantly CD4⁺CD8⁻ and express normal follicular helper T-cell markers CD10, CXCL13, BCL-6,^5,9 and PD-1.¹⁰ Numerous B cells are seen intermixed with follicular dendritic cells. They are frequently infected with EBV and can have an atypical Reed-Sternberg cell–like appearance.^4,5,15 In the evaluation of AITL, polymerase chain reaction studies with primers for immunoglobulin heavy and light chain should be performed to look for clonal B-cell populations and rule out a possible secondary B-cell lymphoma.

Histology
Five histologic patterns have been described with cutaneous AITL: (1) superficial perivascular infiltrate of eosinophils and lymphocytes that lack atypia, (2) sparse perivascular infiltrate with atypical lymphocytes, (3) dense dermal infiltrate of pleomorphic lymphocytes, (4) leukocytoclastic vasculitis without atypical lymphocytes,¹¹ and (5) necrotizing vasculitis.¹² The finding of vascular hyperplasia, perivascular infiltrate, or vasculitis has been reported in 91% of cases in the literature. Although these findings are nonspecific, an analysis of cutaneous cases reported in the literature found that 87% demonstrated T-cell receptor gene rearrangements.¹⁴ Lymphoid cells are positive for CD10 and PD-1, as was demonstrated in our case, and are CXCL13 positive in the majority of cases.¹² Atypical and EBV-infected B cells also can be found in the skin.^11,12

Differential Diagnosis
Angioimmunoblastic T-cell lymphoma can mimic infectious, autoimmune, or allergic etiologies, and misdiagnosis of another type of lymphoma is not uncommon, as occurred in our case. Patients who have a delay in the correct diagnosis have similar outcomes to those correctly diagnosed at first presentation.⁴

Treatment
There are no effective therapies for AITL. Poor prognostic factors include age (>60 years), stages III to IV disease, male gender, elevated serum lactate dehydrogenase level,^3,5,10 and cutaneous involvement.⁷ Corticosteroids, anthracycline-based chemotherapy, and autologous stem cell transplant are currently the mainstays of therapy. Initial response to chemotherapy is promising, but duration of response is poor overall and there is no increased survival.^5,15 A large population-based study of 1207 cases by Xu and Liu³ showed the overall survival rate at 2 and 10 years was 46.8% and 21.9%, respectively. Ten-year disease-specific survival was 35.9%, and there was no demonstrable improvement in survival over the last 2 decades.³ Case reports have demonstrated that thalidomide,¹⁶ lenalidomide,¹⁷ and cyclosporine plus dexamethasone¹⁸ have been successfully used to achieve remission for up to 3 years.

Conclusion

Angioimmunoblastic T-cell lymphoma is difficult to diagnose due to nonspecific clinical and histologic findings. Cutaneous manifestations are seen in AITL in up to half of cases that may occur early or in advanced disease. Similar to all cutaneous metastases, the appearance of the lesions can greatly vary. Our case demonstrates that dermatologists and dermatopathologists can make this diagnosis in the appropriate clinicopathologic context utilizing appropriate immunohistochemical staining and gene rearrangement studies.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare, often aggressive type of peripheral T-cell lymphoma. It comprises 18% of peripheral T-cell lymphomas and 1% to 2% of all non-Hodgkin lymphomas.¹ The incidence of AITL in the United States is estimated to be 0.05 cases per 100,000 person-years,² and there is a slight male predominance.^1,3,4 It typically presents in the seventh decade of life; however, cases have been reported in adults ranging from 20 to 91 years of age.³

Angioimmunoblastic T-cell lymphoma presents with lymphadenopathy, hepatosplenomegaly, and systemic B symptoms (eg, fever, night sweats, weight loss, generalized pruritus).^4-6 There are cutaneous manifestations in up to 50% of cases^4,5,7 and frequently signs of autoimmune disorder.^4,5 The diagnosis often is made by excisional lymph node biopsy. Lymph node specimens characteristically have a mixed inflammatory infiltrate that includes numerous B cells often infected with Epstein-Barr virus (EBV) and a relatively small population of atypical T lymphocytes.⁸ Identification of this neoplastic population of CD4⁺CD8⁻ T lymphocytes expressing normal follicular helper T-cell markers CD10, chemokine CXCL13, programmed cell death protein 1 (PD-1), and B-cell lymphoma 6 (BCL-6) confirms the diagnosis of AITL.^9,10 These malignant cells can be identified in skin specimens in cases of cutaneous metastatic disease.^11,12 We present a case originally misdiagnosed as diffuse large B-cell lymphoma that was later identified as AITL on skin biopsy.

Case Report

A 72-year-old woman presented with a pruritic erythematous eruption around the neck of 3 weeks’ duration (Figure 1). Her medical history was notable for diffuse large B-cell non-Hodgkin lymphoma diagnosed 3 months prior based on results from a right cervical lymph node biopsy. She was treated with bendamustine and rituximab. On physical examination there were erythematous edematous papules coalescing into indurated plaques around the neck. The differential diagnosis included drug hypersensitivity reaction, herpes zoster, urticaria, and cutaneous metastasis. Two punch biopsies were taken for hematoxylin and eosin and tissue culture.

Tissue cultures and viral polymerase chain reaction were negative. Histopathologic examination revealed a scant atypical lymphoid infiltrate focally involving the deep dermis. The cells were medium to large in size and contained hyperchromatic pleomorphic nuclei (Figure 2). They were positive for CD3 and CD4, which was concerning for T-cell lymphoma. The histologic report of the excisional lymph node biopsy done 3 months prior described an atypical lymphoid neoplasm with extensive necrosis and extranodal spread that stained positively for CD20 (Figure 3).

Comment

Etiology
Angioimmunoblastic T-cell lymphoma was originally named angioimmunoblastic lymphadenopathy with dysproteinemia. It was initially thought to be a benign hyperreactive immune process driven by B cells, and patients often died of infectious complications not long after the diagnosis was made.¹³ As more cases were reported with clonal rearrangements and signs of progressive lymphoma, AITL was recognized as a malignancy.

Presentation
Patients with AITL often present with advanced stage III or IV disease with extranodal and bone marrow involvement.^3-6 Cutaneous disease occurs in up to half of patients and portends a poor prognosis.⁷ The rash often is a nonspecific erythematous macular and papular eruption mimicking a morbilliform viral exanthem or drug reaction. Urticarial, nodular, petechial, purpuric, eczematous, erythrodermic, and vesiculobullous presentations have been described.^4,11,12 In up to one-third of cases, the eruption occurs in association with a new medication, often leading to an initial misdiagnosis of drug hypersensitivity reaction.^4,11 In a review conducted by Balaraman et al,¹⁴ 84% of patients with AITL reported having pruritus.

There is an association of autoimmune phenomena in patients with AITL, which is likely a result of immune dysregulation associated with poorly functioning follicular helper T cells. Patients may present with arthralgia, hemolytic anemia, or thrombocytopenic purpura. Hypergammaglobulinemia has been reported in 30% to 50% of AITL patients.^4,6 Other pertinent immunologic findings include positive Coombs test, cold agglutinins, cryoglobulinemia, hypocomplementemia, and positive antinuclear antibodies.^4-7

Gene Analysis
Affected lymph nodes have a characteristically effaced architecture with proliferative arborizing venules; a hyperplastic population of follicular dendritic cells; and a mixed inflammatory infiltrate that is comprised of atypical lymphocytes and variable numbers of reactive lymphocytes, histiocytes, eosinophils, and plasma cells. The malignant T lymphocytes often account for only a small portion of the infiltrate.⁸ T-cell gene rearrangement studies identify clonal cells with β and γ rearrangements in the majority of cases.⁴ These cells are predominantly CD4⁺CD8⁻ and express normal follicular helper T-cell markers CD10, CXCL13, BCL-6,^5,9 and PD-1.¹⁰ Numerous B cells are seen intermixed with follicular dendritic cells. They are frequently infected with EBV and can have an atypical Reed-Sternberg cell–like appearance.^4,5,15 In the evaluation of AITL, polymerase chain reaction studies with primers for immunoglobulin heavy and light chain should be performed to look for clonal B-cell populations and rule out a possible secondary B-cell lymphoma.

Histology
Five histologic patterns have been described with cutaneous AITL: (1) superficial perivascular infiltrate of eosinophils and lymphocytes that lack atypia, (2) sparse perivascular infiltrate with atypical lymphocytes, (3) dense dermal infiltrate of pleomorphic lymphocytes, (4) leukocytoclastic vasculitis without atypical lymphocytes,¹¹ and (5) necrotizing vasculitis.¹² The finding of vascular hyperplasia, perivascular infiltrate, or vasculitis has been reported in 91% of cases in the literature. Although these findings are nonspecific, an analysis of cutaneous cases reported in the literature found that 87% demonstrated T-cell receptor gene rearrangements.¹⁴ Lymphoid cells are positive for CD10 and PD-1, as was demonstrated in our case, and are CXCL13 positive in the majority of cases.¹² Atypical and EBV-infected B cells also can be found in the skin.^11,12

Differential Diagnosis
Angioimmunoblastic T-cell lymphoma can mimic infectious, autoimmune, or allergic etiologies, and misdiagnosis of another type of lymphoma is not uncommon, as occurred in our case. Patients who have a delay in the correct diagnosis have similar outcomes to those correctly diagnosed at first presentation.⁴

Treatment
There are no effective therapies for AITL. Poor prognostic factors include age (>60 years), stages III to IV disease, male gender, elevated serum lactate dehydrogenase level,^3,5,10 and cutaneous involvement.⁷ Corticosteroids, anthracycline-based chemotherapy, and autologous stem cell transplant are currently the mainstays of therapy. Initial response to chemotherapy is promising, but duration of response is poor overall and there is no increased survival.^5,15 A large population-based study of 1207 cases by Xu and Liu³ showed the overall survival rate at 2 and 10 years was 46.8% and 21.9%, respectively. Ten-year disease-specific survival was 35.9%, and there was no demonstrable improvement in survival over the last 2 decades.³ Case reports have demonstrated that thalidomide,¹⁶ lenalidomide,¹⁷ and cyclosporine plus dexamethasone¹⁸ have been successfully used to achieve remission for up to 3 years.

Conclusion

Angioimmunoblastic T-cell lymphoma is difficult to diagnose due to nonspecific clinical and histologic findings. Cutaneous manifestations are seen in AITL in up to half of cases that may occur early or in advanced disease. Similar to all cutaneous metastases, the appearance of the lesions can greatly vary. Our case demonstrates that dermatologists and dermatopathologists can make this diagnosis in the appropriate clinicopathologic context utilizing appropriate immunohistochemical staining and gene rearrangement studies.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare, often aggressive type of peripheral T-cell lymphoma. It comprises 18% of peripheral T-cell lymphomas and 1% to 2% of all non-Hodgkin lymphomas.¹ The incidence of AITL in the United States is estimated to be 0.05 cases per 100,000 person-years,² and there is a slight male predominance.^1,3,4 It typically presents in the seventh decade of life; however, cases have been reported in adults ranging from 20 to 91 years of age.³

Angioimmunoblastic T-cell lymphoma presents with lymphadenopathy, hepatosplenomegaly, and systemic B symptoms (eg, fever, night sweats, weight loss, generalized pruritus).^4-6 There are cutaneous manifestations in up to 50% of cases^4,5,7 and frequently signs of autoimmune disorder.^4,5 The diagnosis often is made by excisional lymph node biopsy. Lymph node specimens characteristically have a mixed inflammatory infiltrate that includes numerous B cells often infected with Epstein-Barr virus (EBV) and a relatively small population of atypical T lymphocytes.⁸ Identification of this neoplastic population of CD4⁺CD8⁻ T lymphocytes expressing normal follicular helper T-cell markers CD10, chemokine CXCL13, programmed cell death protein 1 (PD-1), and B-cell lymphoma 6 (BCL-6) confirms the diagnosis of AITL.^9,10 These malignant cells can be identified in skin specimens in cases of cutaneous metastatic disease.^11,12 We present a case originally misdiagnosed as diffuse large B-cell lymphoma that was later identified as AITL on skin biopsy.

Case Report

A 72-year-old woman presented with a pruritic erythematous eruption around the neck of 3 weeks’ duration (Figure 1). Her medical history was notable for diffuse large B-cell non-Hodgkin lymphoma diagnosed 3 months prior based on results from a right cervical lymph node biopsy. She was treated with bendamustine and rituximab. On physical examination there were erythematous edematous papules coalescing into indurated plaques around the neck. The differential diagnosis included drug hypersensitivity reaction, herpes zoster, urticaria, and cutaneous metastasis. Two punch biopsies were taken for hematoxylin and eosin and tissue culture.

Tissue cultures and viral polymerase chain reaction were negative. Histopathologic examination revealed a scant atypical lymphoid infiltrate focally involving the deep dermis. The cells were medium to large in size and contained hyperchromatic pleomorphic nuclei (Figure 2). They were positive for CD3 and CD4, which was concerning for T-cell lymphoma. The histologic report of the excisional lymph node biopsy done 3 months prior described an atypical lymphoid neoplasm with extensive necrosis and extranodal spread that stained positively for CD20 (Figure 3).

Comment

Etiology
Angioimmunoblastic T-cell lymphoma was originally named angioimmunoblastic lymphadenopathy with dysproteinemia. It was initially thought to be a benign hyperreactive immune process driven by B cells, and patients often died of infectious complications not long after the diagnosis was made.¹³ As more cases were reported with clonal rearrangements and signs of progressive lymphoma, AITL was recognized as a malignancy.

Presentation
Patients with AITL often present with advanced stage III or IV disease with extranodal and bone marrow involvement.^3-6 Cutaneous disease occurs in up to half of patients and portends a poor prognosis.⁷ The rash often is a nonspecific erythematous macular and papular eruption mimicking a morbilliform viral exanthem or drug reaction. Urticarial, nodular, petechial, purpuric, eczematous, erythrodermic, and vesiculobullous presentations have been described.^4,11,12 In up to one-third of cases, the eruption occurs in association with a new medication, often leading to an initial misdiagnosis of drug hypersensitivity reaction.^4,11 In a review conducted by Balaraman et al,¹⁴ 84% of patients with AITL reported having pruritus.

There is an association of autoimmune phenomena in patients with AITL, which is likely a result of immune dysregulation associated with poorly functioning follicular helper T cells. Patients may present with arthralgia, hemolytic anemia, or thrombocytopenic purpura. Hypergammaglobulinemia has been reported in 30% to 50% of AITL patients.^4,6 Other pertinent immunologic findings include positive Coombs test, cold agglutinins, cryoglobulinemia, hypocomplementemia, and positive antinuclear antibodies.^4-7

Gene Analysis
Affected lymph nodes have a characteristically effaced architecture with proliferative arborizing venules; a hyperplastic population of follicular dendritic cells; and a mixed inflammatory infiltrate that is comprised of atypical lymphocytes and variable numbers of reactive lymphocytes, histiocytes, eosinophils, and plasma cells. The malignant T lymphocytes often account for only a small portion of the infiltrate.⁸ T-cell gene rearrangement studies identify clonal cells with β and γ rearrangements in the majority of cases.⁴ These cells are predominantly CD4⁺CD8⁻ and express normal follicular helper T-cell markers CD10, CXCL13, BCL-6,^5,9 and PD-1.¹⁰ Numerous B cells are seen intermixed with follicular dendritic cells. They are frequently infected with EBV and can have an atypical Reed-Sternberg cell–like appearance.^4,5,15 In the evaluation of AITL, polymerase chain reaction studies with primers for immunoglobulin heavy and light chain should be performed to look for clonal B-cell populations and rule out a possible secondary B-cell lymphoma.

Histology
Five histologic patterns have been described with cutaneous AITL: (1) superficial perivascular infiltrate of eosinophils and lymphocytes that lack atypia, (2) sparse perivascular infiltrate with atypical lymphocytes, (3) dense dermal infiltrate of pleomorphic lymphocytes, (4) leukocytoclastic vasculitis without atypical lymphocytes,¹¹ and (5) necrotizing vasculitis.¹² The finding of vascular hyperplasia, perivascular infiltrate, or vasculitis has been reported in 91% of cases in the literature. Although these findings are nonspecific, an analysis of cutaneous cases reported in the literature found that 87% demonstrated T-cell receptor gene rearrangements.¹⁴ Lymphoid cells are positive for CD10 and PD-1, as was demonstrated in our case, and are CXCL13 positive in the majority of cases.¹² Atypical and EBV-infected B cells also can be found in the skin.^11,12

Differential Diagnosis
Angioimmunoblastic T-cell lymphoma can mimic infectious, autoimmune, or allergic etiologies, and misdiagnosis of another type of lymphoma is not uncommon, as occurred in our case. Patients who have a delay in the correct diagnosis have similar outcomes to those correctly diagnosed at first presentation.⁴

Treatment
There are no effective therapies for AITL. Poor prognostic factors include age (>60 years), stages III to IV disease, male gender, elevated serum lactate dehydrogenase level,^3,5,10 and cutaneous involvement.⁷ Corticosteroids, anthracycline-based chemotherapy, and autologous stem cell transplant are currently the mainstays of therapy. Initial response to chemotherapy is promising, but duration of response is poor overall and there is no increased survival.^5,15 A large population-based study of 1207 cases by Xu and Liu³ showed the overall survival rate at 2 and 10 years was 46.8% and 21.9%, respectively. Ten-year disease-specific survival was 35.9%, and there was no demonstrable improvement in survival over the last 2 decades.³ Case reports have demonstrated that thalidomide,¹⁶ lenalidomide,¹⁷ and cyclosporine plus dexamethasone¹⁸ have been successfully used to achieve remission for up to 3 years.

Conclusion

Angioimmunoblastic T-cell lymphoma is difficult to diagnose due to nonspecific clinical and histologic findings. Cutaneous manifestations are seen in AITL in up to half of cases that may occur early or in advanced disease. Similar to all cutaneous metastases, the appearance of the lesions can greatly vary. Our case demonstrates that dermatologists and dermatopathologists can make this diagnosis in the appropriate clinicopathologic context utilizing appropriate immunohistochemical staining and gene rearrangement studies.

Based on the clinical findings, the patient was diagnosed with flagellate shiitake mushroom dermatitis.  (Subsequent treponemal and nontreponemal tests were negative for syphilis.)

Shiitake dermatitis is a rare disease that appears in susceptible patients after the consumption of large amounts of raw or undercooked shiitake mushrooms. The eruption is believed to be attributable to either a toxic or hypersensitivity reaction to lentinan, a polysaccharide component found within the mushroom cell wall.¹ Shiitake dermatitis is self-limiting and treatment focuses on symptomatic management.

Early recognition and proper counseling should ensure symptomatic relief and prevent future episodes. In addition, anyone preparing shiitake mushrooms should make sure that they are fully cooked before serving or eating them.²

In the case described here, the patient was advised to avoid eating undercooked shiitake mushrooms in the future and he was prescribed topical steroids (mometasone furoate 0.1% cream). The eruption resolved 2 weeks later.

References

1. Nguyen AH, Gonzaga MI, Lim VM, et al. Clinical features of shiitake dermatitis: a systematic review. Int J Dermatol. 2017;56:610-616.

2. Stephany MP, Chung S, Handler MZ, et al. Shiitake mushroom dermatitis: a review. Am J Clin Dermatol. 2016;17:485-489.

Based on the clinical findings, the patient was diagnosed with flagellate shiitake mushroom dermatitis.  (Subsequent treponemal and nontreponemal tests were negative for syphilis.)

Shiitake dermatitis is a rare disease that appears in susceptible patients after the consumption of large amounts of raw or undercooked shiitake mushrooms. The eruption is believed to be attributable to either a toxic or hypersensitivity reaction to lentinan, a polysaccharide component found within the mushroom cell wall.¹ Shiitake dermatitis is self-limiting and treatment focuses on symptomatic management.

Early recognition and proper counseling should ensure symptomatic relief and prevent future episodes. In addition, anyone preparing shiitake mushrooms should make sure that they are fully cooked before serving or eating them.²

In the case described here, the patient was advised to avoid eating undercooked shiitake mushrooms in the future and he was prescribed topical steroids (mometasone furoate 0.1% cream). The eruption resolved 2 weeks later.

References

1. Nguyen AH, Gonzaga MI, Lim VM, et al. Clinical features of shiitake dermatitis: a systematic review. Int J Dermatol. 2017;56:610-616.

2. Stephany MP, Chung S, Handler MZ, et al. Shiitake mushroom dermatitis: a review. Am J Clin Dermatol. 2016;17:485-489.

Based on the clinical findings, the patient was diagnosed with flagellate shiitake mushroom dermatitis.  (Subsequent treponemal and nontreponemal tests were negative for syphilis.)

Shiitake dermatitis is a rare disease that appears in susceptible patients after the consumption of large amounts of raw or undercooked shiitake mushrooms. The eruption is believed to be attributable to either a toxic or hypersensitivity reaction to lentinan, a polysaccharide component found within the mushroom cell wall.¹ Shiitake dermatitis is self-limiting and treatment focuses on symptomatic management.

Early recognition and proper counseling should ensure symptomatic relief and prevent future episodes. In addition, anyone preparing shiitake mushrooms should make sure that they are fully cooked before serving or eating them.²

In the case described here, the patient was advised to avoid eating undercooked shiitake mushrooms in the future and he was prescribed topical steroids (mometasone furoate 0.1% cream). The eruption resolved 2 weeks later.

References

1. Nguyen AH, Gonzaga MI, Lim VM, et al. Clinical features of shiitake dermatitis: a systematic review. Int J Dermatol. 2017;56:610-616.

2. Stephany MP, Chung S, Handler MZ, et al. Shiitake mushroom dermatitis: a review. Am J Clin Dermatol. 2016;17:485-489.