The Nuremberg Code in 1947,¹ the Declaration of Helsinki in 1964,² and the Belmont Report in 1979³ were cornerstones in the establishment of ethical principles in the medical field. These documents specifically highlight the concept of informed consent, which maintains that to practice ethical medicine, physicians must fully inform patients of all therapeutic benefits and especially risks as well as treatment alternatives before they consent to therapeutic intervention. Educating patients about risks of treatment is obligatory. Risk communication involves a mutual exchange of information between physicians and patients; the physician presents risk information in an understandable manner that adequately conveys pertinent data that is critical for the patient to make an informed therapeutic decision.⁴

An inherent problem with risk education is that patients may be terrified about risks associated with treatment. Some patients will refuse needed treatment because of fear.⁵ When patients have concerns about the safety profile of a treatment regimen and potential adverse effects, they may be less compliant with treatment.⁶ The intelligent noncompliance phenomenon occurs when a patient knowingly makes the choice to not adhere to treatment, and concern regarding treatment risks relative to benefits is a common reason underlying this phenomenon.^7,8

Behavioral economists have studied how individuals weigh risks. Kahneman and Tversky’s⁹ prospect theory asserts that individuals tend to overweigh unlikely risks and underweigh more certain risks, which they call the certainty effect; it is the basis of the human tendency to avoid risks in situations of likely gain and to pursue risks in situations of likely loss. The tendency to overweigh rare risks is even more pronounced for affect-rich events such as serious side effects.¹⁰ The way data are presented can affect how patients interpret the information. Context and framing of data affect patients’ perceptions.¹¹ We describe several ways to present safety data using graphical presentation of psoriasis treatment safety data as an example and explain how each one can affect patients’ perception of treatment risks.

Approaches to Presenting Safety Data

There are numerous ways to present safety data to patients, including verbal, numeric, and visual strategies.¹² Many methods of presentation are a combination of these strategies. Graphs are visual strategies to further categorize and present numeric data, and physicians may choose to incorporate these aids when presenting safety information to patients. Graphical presentations give the patient a mental picture of the data. Numerous types of graphs can be constructed. Kalb et al¹³ determined the effect of psoriasis treatment on the risk of serious infection from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). We used the results from this study to demonstrate multiple ways of presenting safety data (Figures 1–3).

A graphical presentation with a truncated y-axis is a common approach (Figure 1). Graphs with truncated axes are sometimes used to conserve space or to accentuate certain differences in the graph that would otherwise be less obvious without the zoomed in y-axis.¹⁴ These graphs present quantitatively accurate information that can be visually misleading at the same time. Truncated axes accentuate differences, creating mental impressions that are not reflective of the magnitude of the numeric differences. Alternatively, a graph with a full y-axis includes both the maximum and minimum data values on the y-axis (Figure 2). The y-axis also extends maximally to the total number of patients or patient-years studied. This type of graph presents all of the numeric data without distortion.

Focus on the Patients Who Do Not Have Adverse Effects of Treatments

Fear of adverse effects is one of the most commonly reported causes of poor treatment adherence.¹⁵ New therapies for psoriasis are highly effective and safe, but as with all treatments, they also are associated with some risks. Patients may latch onto those risks too tightly or perhaps, in other circumstances, not tightly enough. The method used by a physician to present safety data to a patient may determine the patient’s perception about treatments.

When trying to give patients an accurate impression of treatment risks, it may be helpful to avoid approaches that focus on presenting the (few) cases of severe adverse drug effects since patients (and physicians) are likely to overweigh the unlikely risk of having an adverse effect if presented with this information. It may be more reassuring to focus on presenting information about the chance of not having an adverse drug effect, assuming the physician’s goal is to be reassuring.

Poor communication with patients when presenting safety data can foster exaggerated fears of an unlikely consequence to the point that patients can be left undertreated and sustaining disease symptoms.¹⁶ Physicians may strive to do no harm to their patients, but without careful presentation of safety data in the process of helping the patient make an informed decision, it is possible to do mental harm to patients in the form of fear or even, in the case of nonadherence or treatment refusal, physical harm in the form of continued disease symptoms.

One limitation of this review is that we only used graphical presentation of data as an example. Similar concerns apply to numerical data presentation. Telling a patient the risk of a severe adverse reaction is doubled by a certain treatment may be terrifying, though if the baseline risk is rare, doubling the baseline risk may represent only a minimal increase in the absolute risk. Telling a patient the risk is only 1 in 1000 may still be alarming because many patients tend to focus on the 1, but telling a patient that 999 of 1000 patients do not have a problem can be much more reassuring.

The physician’s goal—to help patients make informed decisions about their treatment—calls for him/her to assimilate safety data into useful information that the patient can use to make an informed decision.¹⁷ Overly comforting or alarming, confusing, and inaccurate information can misguide the patient, violating the ethical principle of nonmaleficence. Although there is an obligation to educate patients about risks, there may not be a purely objective way to do it. When physicians present objective data to patients, whether in numerical or graphical form, there will be an unavoidable subjective interpretation of the data. The form of presentation will have a critical effect on patients’ subjective perceptions. Physicians can present objective data in such a way as to be reassuring or frightening.

Conclusion

Despite physicians’ best-intentioned efforts, it may be impossible to avoid presenting safety data in a way that will be subjectively interpreted by patients. Physicians have a choice in how they present data to patients; their best judgment should be used in how they present data to inform patients, guide them, and offer them the best treatment outcomes.

Acknowledgment

We thank Scott Jaros, BA (Winston-Salem, North Carolina), for his assistance in the revision of the manuscript.

The Nuremberg Code in 1947,¹ the Declaration of Helsinki in 1964,² and the Belmont Report in 1979³ were cornerstones in the establishment of ethical principles in the medical field. These documents specifically highlight the concept of informed consent, which maintains that to practice ethical medicine, physicians must fully inform patients of all therapeutic benefits and especially risks as well as treatment alternatives before they consent to therapeutic intervention. Educating patients about risks of treatment is obligatory. Risk communication involves a mutual exchange of information between physicians and patients; the physician presents risk information in an understandable manner that adequately conveys pertinent data that is critical for the patient to make an informed therapeutic decision.⁴

An inherent problem with risk education is that patients may be terrified about risks associated with treatment. Some patients will refuse needed treatment because of fear.⁵ When patients have concerns about the safety profile of a treatment regimen and potential adverse effects, they may be less compliant with treatment.⁶ The intelligent noncompliance phenomenon occurs when a patient knowingly makes the choice to not adhere to treatment, and concern regarding treatment risks relative to benefits is a common reason underlying this phenomenon.^7,8

Behavioral economists have studied how individuals weigh risks. Kahneman and Tversky’s⁹ prospect theory asserts that individuals tend to overweigh unlikely risks and underweigh more certain risks, which they call the certainty effect; it is the basis of the human tendency to avoid risks in situations of likely gain and to pursue risks in situations of likely loss. The tendency to overweigh rare risks is even more pronounced for affect-rich events such as serious side effects.¹⁰ The way data are presented can affect how patients interpret the information. Context and framing of data affect patients’ perceptions.¹¹ We describe several ways to present safety data using graphical presentation of psoriasis treatment safety data as an example and explain how each one can affect patients’ perception of treatment risks.

Approaches to Presenting Safety Data

There are numerous ways to present safety data to patients, including verbal, numeric, and visual strategies.¹² Many methods of presentation are a combination of these strategies. Graphs are visual strategies to further categorize and present numeric data, and physicians may choose to incorporate these aids when presenting safety information to patients. Graphical presentations give the patient a mental picture of the data. Numerous types of graphs can be constructed. Kalb et al¹³ determined the effect of psoriasis treatment on the risk of serious infection from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). We used the results from this study to demonstrate multiple ways of presenting safety data (Figures 1–3).

A graphical presentation with a truncated y-axis is a common approach (Figure 1). Graphs with truncated axes are sometimes used to conserve space or to accentuate certain differences in the graph that would otherwise be less obvious without the zoomed in y-axis.¹⁴ These graphs present quantitatively accurate information that can be visually misleading at the same time. Truncated axes accentuate differences, creating mental impressions that are not reflective of the magnitude of the numeric differences. Alternatively, a graph with a full y-axis includes both the maximum and minimum data values on the y-axis (Figure 2). The y-axis also extends maximally to the total number of patients or patient-years studied. This type of graph presents all of the numeric data without distortion.

Focus on the Patients Who Do Not Have Adverse Effects of Treatments

Fear of adverse effects is one of the most commonly reported causes of poor treatment adherence.¹⁵ New therapies for psoriasis are highly effective and safe, but as with all treatments, they also are associated with some risks. Patients may latch onto those risks too tightly or perhaps, in other circumstances, not tightly enough. The method used by a physician to present safety data to a patient may determine the patient’s perception about treatments.

When trying to give patients an accurate impression of treatment risks, it may be helpful to avoid approaches that focus on presenting the (few) cases of severe adverse drug effects since patients (and physicians) are likely to overweigh the unlikely risk of having an adverse effect if presented with this information. It may be more reassuring to focus on presenting information about the chance of not having an adverse drug effect, assuming the physician’s goal is to be reassuring.

Poor communication with patients when presenting safety data can foster exaggerated fears of an unlikely consequence to the point that patients can be left undertreated and sustaining disease symptoms.¹⁶ Physicians may strive to do no harm to their patients, but without careful presentation of safety data in the process of helping the patient make an informed decision, it is possible to do mental harm to patients in the form of fear or even, in the case of nonadherence or treatment refusal, physical harm in the form of continued disease symptoms.

One limitation of this review is that we only used graphical presentation of data as an example. Similar concerns apply to numerical data presentation. Telling a patient the risk of a severe adverse reaction is doubled by a certain treatment may be terrifying, though if the baseline risk is rare, doubling the baseline risk may represent only a minimal increase in the absolute risk. Telling a patient the risk is only 1 in 1000 may still be alarming because many patients tend to focus on the 1, but telling a patient that 999 of 1000 patients do not have a problem can be much more reassuring.

The physician’s goal—to help patients make informed decisions about their treatment—calls for him/her to assimilate safety data into useful information that the patient can use to make an informed decision.¹⁷ Overly comforting or alarming, confusing, and inaccurate information can misguide the patient, violating the ethical principle of nonmaleficence. Although there is an obligation to educate patients about risks, there may not be a purely objective way to do it. When physicians present objective data to patients, whether in numerical or graphical form, there will be an unavoidable subjective interpretation of the data. The form of presentation will have a critical effect on patients’ subjective perceptions. Physicians can present objective data in such a way as to be reassuring or frightening.

Conclusion

Despite physicians’ best-intentioned efforts, it may be impossible to avoid presenting safety data in a way that will be subjectively interpreted by patients. Physicians have a choice in how they present data to patients; their best judgment should be used in how they present data to inform patients, guide them, and offer them the best treatment outcomes.

Acknowledgment

We thank Scott Jaros, BA (Winston-Salem, North Carolina), for his assistance in the revision of the manuscript.

The Nuremberg Code in 1947,¹ the Declaration of Helsinki in 1964,² and the Belmont Report in 1979³ were cornerstones in the establishment of ethical principles in the medical field. These documents specifically highlight the concept of informed consent, which maintains that to practice ethical medicine, physicians must fully inform patients of all therapeutic benefits and especially risks as well as treatment alternatives before they consent to therapeutic intervention. Educating patients about risks of treatment is obligatory. Risk communication involves a mutual exchange of information between physicians and patients; the physician presents risk information in an understandable manner that adequately conveys pertinent data that is critical for the patient to make an informed therapeutic decision.⁴

An inherent problem with risk education is that patients may be terrified about risks associated with treatment. Some patients will refuse needed treatment because of fear.⁵ When patients have concerns about the safety profile of a treatment regimen and potential adverse effects, they may be less compliant with treatment.⁶ The intelligent noncompliance phenomenon occurs when a patient knowingly makes the choice to not adhere to treatment, and concern regarding treatment risks relative to benefits is a common reason underlying this phenomenon.^7,8

Behavioral economists have studied how individuals weigh risks. Kahneman and Tversky’s⁹ prospect theory asserts that individuals tend to overweigh unlikely risks and underweigh more certain risks, which they call the certainty effect; it is the basis of the human tendency to avoid risks in situations of likely gain and to pursue risks in situations of likely loss. The tendency to overweigh rare risks is even more pronounced for affect-rich events such as serious side effects.¹⁰ The way data are presented can affect how patients interpret the information. Context and framing of data affect patients’ perceptions.¹¹ We describe several ways to present safety data using graphical presentation of psoriasis treatment safety data as an example and explain how each one can affect patients’ perception of treatment risks.

Approaches to Presenting Safety Data

There are numerous ways to present safety data to patients, including verbal, numeric, and visual strategies.¹² Many methods of presentation are a combination of these strategies. Graphs are visual strategies to further categorize and present numeric data, and physicians may choose to incorporate these aids when presenting safety information to patients. Graphical presentations give the patient a mental picture of the data. Numerous types of graphs can be constructed. Kalb et al¹³ determined the effect of psoriasis treatment on the risk of serious infection from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). We used the results from this study to demonstrate multiple ways of presenting safety data (Figures 1–3).

A graphical presentation with a truncated y-axis is a common approach (Figure 1). Graphs with truncated axes are sometimes used to conserve space or to accentuate certain differences in the graph that would otherwise be less obvious without the zoomed in y-axis.¹⁴ These graphs present quantitatively accurate information that can be visually misleading at the same time. Truncated axes accentuate differences, creating mental impressions that are not reflective of the magnitude of the numeric differences. Alternatively, a graph with a full y-axis includes both the maximum and minimum data values on the y-axis (Figure 2). The y-axis also extends maximally to the total number of patients or patient-years studied. This type of graph presents all of the numeric data without distortion.

Focus on the Patients Who Do Not Have Adverse Effects of Treatments

Fear of adverse effects is one of the most commonly reported causes of poor treatment adherence.¹⁵ New therapies for psoriasis are highly effective and safe, but as with all treatments, they also are associated with some risks. Patients may latch onto those risks too tightly or perhaps, in other circumstances, not tightly enough. The method used by a physician to present safety data to a patient may determine the patient’s perception about treatments.

When trying to give patients an accurate impression of treatment risks, it may be helpful to avoid approaches that focus on presenting the (few) cases of severe adverse drug effects since patients (and physicians) are likely to overweigh the unlikely risk of having an adverse effect if presented with this information. It may be more reassuring to focus on presenting information about the chance of not having an adverse drug effect, assuming the physician’s goal is to be reassuring.

Poor communication with patients when presenting safety data can foster exaggerated fears of an unlikely consequence to the point that patients can be left undertreated and sustaining disease symptoms.¹⁶ Physicians may strive to do no harm to their patients, but without careful presentation of safety data in the process of helping the patient make an informed decision, it is possible to do mental harm to patients in the form of fear or even, in the case of nonadherence or treatment refusal, physical harm in the form of continued disease symptoms.

One limitation of this review is that we only used graphical presentation of data as an example. Similar concerns apply to numerical data presentation. Telling a patient the risk of a severe adverse reaction is doubled by a certain treatment may be terrifying, though if the baseline risk is rare, doubling the baseline risk may represent only a minimal increase in the absolute risk. Telling a patient the risk is only 1 in 1000 may still be alarming because many patients tend to focus on the 1, but telling a patient that 999 of 1000 patients do not have a problem can be much more reassuring.

The physician’s goal—to help patients make informed decisions about their treatment—calls for him/her to assimilate safety data into useful information that the patient can use to make an informed decision.¹⁷ Overly comforting or alarming, confusing, and inaccurate information can misguide the patient, violating the ethical principle of nonmaleficence. Although there is an obligation to educate patients about risks, there may not be a purely objective way to do it. When physicians present objective data to patients, whether in numerical or graphical form, there will be an unavoidable subjective interpretation of the data. The form of presentation will have a critical effect on patients’ subjective perceptions. Physicians can present objective data in such a way as to be reassuring or frightening.

Conclusion

Despite physicians’ best-intentioned efforts, it may be impossible to avoid presenting safety data in a way that will be subjectively interpreted by patients. Physicians have a choice in how they present data to patients; their best judgment should be used in how they present data to inform patients, guide them, and offer them the best treatment outcomes.

Acknowledgment

We thank Scott Jaros, BA (Winston-Salem, North Carolina), for his assistance in the revision of the manuscript.

Psoriasis was not consistently associated with adverse pregnancy outcomes across nine studies in a systematic review of the literature, but four of the studies reported significant increases in at least one adverse outcome among women with psoriasis, according to a report in the British Journal of Dermatology.

Many women with psoriasis develop the disorder during their reproductive years, and more than 100,000 births to such patients are estimated to occur in the United States each year. Other autoimmune diseases are known to adversely affect pregnancy outcomes, but the issue has not been well studied among women with psoriasis, said Robert Bobotsis, a medical student at Western University, London (Ont.), and his associates.

They performed a systematic review of the literature to examine a possible link, but were only able to find nine fair- or good-quality studies involving a total of 4,756 pregnancies from which to extract data concerning a possible association. This small sample size may have been underpowered to detect the uncommon adverse pregnancy outcomes being assessed. Moreover, the investigators were unable to conduct a meta-analysis pooling the data because the effect measures were inconsistent across the nine studies, Mr. Bobotsis and his associates noted.

The review included a retrospective case series, a retrospective case control study, three retrospective cohort studies, two prospective cohort studies, one cross-sectional study, and one study combining prospective and retrospective cohorts. It “did not demonstrate an increased risk of poor outcomes in pregnant women with psoriasis” (Br J Dermatol. 2016 Jul 24;175:464-72).

However, four studies showed that compared with women who didn’t have psoriasis, those who did were at significantly increased risk for spontaneous abortion, cesarean delivery, low birth weight, macrosomia, large for gestational age, and prematurity, with odds ratios as high as 5.6. “Our results should be viewed as an opportunity to further research pregnancy outcomes in psoriasis,” the investigators said.

[email protected]

Psoriasis was not consistently associated with adverse pregnancy outcomes across nine studies in a systematic review of the literature, but four of the studies reported significant increases in at least one adverse outcome among women with psoriasis, according to a report in the British Journal of Dermatology.

Many women with psoriasis develop the disorder during their reproductive years, and more than 100,000 births to such patients are estimated to occur in the United States each year. Other autoimmune diseases are known to adversely affect pregnancy outcomes, but the issue has not been well studied among women with psoriasis, said Robert Bobotsis, a medical student at Western University, London (Ont.), and his associates.

They performed a systematic review of the literature to examine a possible link, but were only able to find nine fair- or good-quality studies involving a total of 4,756 pregnancies from which to extract data concerning a possible association. This small sample size may have been underpowered to detect the uncommon adverse pregnancy outcomes being assessed. Moreover, the investigators were unable to conduct a meta-analysis pooling the data because the effect measures were inconsistent across the nine studies, Mr. Bobotsis and his associates noted.

The review included a retrospective case series, a retrospective case control study, three retrospective cohort studies, two prospective cohort studies, one cross-sectional study, and one study combining prospective and retrospective cohorts. It “did not demonstrate an increased risk of poor outcomes in pregnant women with psoriasis” (Br J Dermatol. 2016 Jul 24;175:464-72).

However, four studies showed that compared with women who didn’t have psoriasis, those who did were at significantly increased risk for spontaneous abortion, cesarean delivery, low birth weight, macrosomia, large for gestational age, and prematurity, with odds ratios as high as 5.6. “Our results should be viewed as an opportunity to further research pregnancy outcomes in psoriasis,” the investigators said.

[email protected]

Psoriasis was not consistently associated with adverse pregnancy outcomes across nine studies in a systematic review of the literature, but four of the studies reported significant increases in at least one adverse outcome among women with psoriasis, according to a report in the British Journal of Dermatology.

Many women with psoriasis develop the disorder during their reproductive years, and more than 100,000 births to such patients are estimated to occur in the United States each year. Other autoimmune diseases are known to adversely affect pregnancy outcomes, but the issue has not been well studied among women with psoriasis, said Robert Bobotsis, a medical student at Western University, London (Ont.), and his associates.

They performed a systematic review of the literature to examine a possible link, but were only able to find nine fair- or good-quality studies involving a total of 4,756 pregnancies from which to extract data concerning a possible association. This small sample size may have been underpowered to detect the uncommon adverse pregnancy outcomes being assessed. Moreover, the investigators were unable to conduct a meta-analysis pooling the data because the effect measures were inconsistent across the nine studies, Mr. Bobotsis and his associates noted.

The review included a retrospective case series, a retrospective case control study, three retrospective cohort studies, two prospective cohort studies, one cross-sectional study, and one study combining prospective and retrospective cohorts. It “did not demonstrate an increased risk of poor outcomes in pregnant women with psoriasis” (Br J Dermatol. 2016 Jul 24;175:464-72).

However, four studies showed that compared with women who didn’t have psoriasis, those who did were at significantly increased risk for spontaneous abortion, cesarean delivery, low birth weight, macrosomia, large for gestational age, and prematurity, with odds ratios as high as 5.6. “Our results should be viewed as an opportunity to further research pregnancy outcomes in psoriasis,” the investigators said.

[email protected]

When Jason Vargas, MD, first moved to the Phoenix area 13 years ago, he found an atmosphere of distant relationships between general pediatricians like him, subspecialists, and hospitals. Getting patients a referral to a subspecialist could take months, and communication among providers was often weak, Dr. Vargas said.

Today, things are vastly different thanks in large part to the clinically integrated network of which Dr. Vargas and 950 area providers are a part.

Courtesy Dr. Vargas

Going from splintered to unified

Like most communities, care delivery in the Phoenix area was relatively fractured prior to 2014. To bring everyone together, Phoenix Children’s started with community outreach and education.

A changing payer relationship

As a network, PCCN works with payers to assume the risk that insurers have historically taken. Payers continue to handle the administrative and billing side of the equation, while the network controls the medical management and care coordination of the patient population, Mr. Johnson said.

“We feel we can do it much more efficiently, much more effectively, and we feel it’s better care for the patient when we’re the one controlling that,” he said. “The insurance companies don’t disagree.”

The network partners with Medicaid and commercial payers and has a direct-to-employer agreement with a major employer in conjunction with an adult partner system/network. Early performance efforts by the PCCN have been rewarded by shared savings disbursements from two payers, according to PCCN officials. The network has also met or exceeded state Medicaid pediatric quality targets and consistently contained medical expenses below expected medical cost trends for its managed pediatric populations.

Building a population health model

For more than 2 decades, PFK in Ohio has taken a novel care delivery approach that has focused on value and community partnerships.

Back in 1994, Nationwide Children’s Hospital partnered with community pediatricians to create PFK, a physician/hospital organization with governance shared equally. Today, PFK has assumed full financial and clinical risk for pediatric managed Medicaid enrollees, and is the largest and oldest known pediatric ACO.

Guidance for other practices

Dr. Gleeson encouraged other pediatricians interested in transitioning to value-based care to start by evaluating their data. Take a hard look at the quality of care you provide and begin to measure it, he said. For smaller practices, consider joining a larger group or network that will allow pediatricians to engage in collaborative work, he added.

Dr. Vargas stressed that change is coming whether pediatricians are prepared or not. Aligning with the right partners will be the difference between sinking or staying afloat in the value-based landscape.

“Payers are moving toward value-based models and it is not practical for the general pediatrician to be able to provide the infrastructure and professional resources necessary,” he said. “To maintain our professional livelihood as independent pediatricians, and to continue to provide the individually crafted, quality care our families are accustomed to, we will have to align ourselves with organizations that value the experience and insight of the independent pediatrician to deliver that care.”

[email protected]

On Twitter @legal_med

When Jason Vargas, MD, first moved to the Phoenix area 13 years ago, he found an atmosphere of distant relationships between general pediatricians like him, subspecialists, and hospitals. Getting patients a referral to a subspecialist could take months, and communication among providers was often weak, Dr. Vargas said.

Today, things are vastly different thanks in large part to the clinically integrated network of which Dr. Vargas and 950 area providers are a part.

Courtesy Dr. Vargas

Going from splintered to unified

Like most communities, care delivery in the Phoenix area was relatively fractured prior to 2014. To bring everyone together, Phoenix Children’s started with community outreach and education.

A changing payer relationship

As a network, PCCN works with payers to assume the risk that insurers have historically taken. Payers continue to handle the administrative and billing side of the equation, while the network controls the medical management and care coordination of the patient population, Mr. Johnson said.

“We feel we can do it much more efficiently, much more effectively, and we feel it’s better care for the patient when we’re the one controlling that,” he said. “The insurance companies don’t disagree.”

The network partners with Medicaid and commercial payers and has a direct-to-employer agreement with a major employer in conjunction with an adult partner system/network. Early performance efforts by the PCCN have been rewarded by shared savings disbursements from two payers, according to PCCN officials. The network has also met or exceeded state Medicaid pediatric quality targets and consistently contained medical expenses below expected medical cost trends for its managed pediatric populations.

Building a population health model

For more than 2 decades, PFK in Ohio has taken a novel care delivery approach that has focused on value and community partnerships.

Back in 1994, Nationwide Children’s Hospital partnered with community pediatricians to create PFK, a physician/hospital organization with governance shared equally. Today, PFK has assumed full financial and clinical risk for pediatric managed Medicaid enrollees, and is the largest and oldest known pediatric ACO.

Guidance for other practices

Dr. Gleeson encouraged other pediatricians interested in transitioning to value-based care to start by evaluating their data. Take a hard look at the quality of care you provide and begin to measure it, he said. For smaller practices, consider joining a larger group or network that will allow pediatricians to engage in collaborative work, he added.

Dr. Vargas stressed that change is coming whether pediatricians are prepared or not. Aligning with the right partners will be the difference between sinking or staying afloat in the value-based landscape.

“Payers are moving toward value-based models and it is not practical for the general pediatrician to be able to provide the infrastructure and professional resources necessary,” he said. “To maintain our professional livelihood as independent pediatricians, and to continue to provide the individually crafted, quality care our families are accustomed to, we will have to align ourselves with organizations that value the experience and insight of the independent pediatrician to deliver that care.”

[email protected]

On Twitter @legal_med

When Jason Vargas, MD, first moved to the Phoenix area 13 years ago, he found an atmosphere of distant relationships between general pediatricians like him, subspecialists, and hospitals. Getting patients a referral to a subspecialist could take months, and communication among providers was often weak, Dr. Vargas said.

Today, things are vastly different thanks in large part to the clinically integrated network of which Dr. Vargas and 950 area providers are a part.

Courtesy Dr. Vargas

Going from splintered to unified

Like most communities, care delivery in the Phoenix area was relatively fractured prior to 2014. To bring everyone together, Phoenix Children’s started with community outreach and education.

A changing payer relationship

As a network, PCCN works with payers to assume the risk that insurers have historically taken. Payers continue to handle the administrative and billing side of the equation, while the network controls the medical management and care coordination of the patient population, Mr. Johnson said.

“We feel we can do it much more efficiently, much more effectively, and we feel it’s better care for the patient when we’re the one controlling that,” he said. “The insurance companies don’t disagree.”

The network partners with Medicaid and commercial payers and has a direct-to-employer agreement with a major employer in conjunction with an adult partner system/network. Early performance efforts by the PCCN have been rewarded by shared savings disbursements from two payers, according to PCCN officials. The network has also met or exceeded state Medicaid pediatric quality targets and consistently contained medical expenses below expected medical cost trends for its managed pediatric populations.

Building a population health model

For more than 2 decades, PFK in Ohio has taken a novel care delivery approach that has focused on value and community partnerships.

Back in 1994, Nationwide Children’s Hospital partnered with community pediatricians to create PFK, a physician/hospital organization with governance shared equally. Today, PFK has assumed full financial and clinical risk for pediatric managed Medicaid enrollees, and is the largest and oldest known pediatric ACO.

Guidance for other practices

Dr. Gleeson encouraged other pediatricians interested in transitioning to value-based care to start by evaluating their data. Take a hard look at the quality of care you provide and begin to measure it, he said. For smaller practices, consider joining a larger group or network that will allow pediatricians to engage in collaborative work, he added.

Dr. Vargas stressed that change is coming whether pediatricians are prepared or not. Aligning with the right partners will be the difference between sinking or staying afloat in the value-based landscape.

“Payers are moving toward value-based models and it is not practical for the general pediatrician to be able to provide the infrastructure and professional resources necessary,” he said. “To maintain our professional livelihood as independent pediatricians, and to continue to provide the individually crafted, quality care our families are accustomed to, we will have to align ourselves with organizations that value the experience and insight of the independent pediatrician to deliver that care.”

[email protected]

On Twitter @legal_med

TORONTO—High levels of occupational complexity, specifically related to work with people, enable individuals to maintain normal cognition despite white matter pathology in the brain, according to research described at the Alzheimer’s Association International Conference. The results “could have potential implications for preventing or maybe delaying Alzheimer’s disease onset in the future,” said Elizabeth Boots, research specialist at Wisconsin Alzheimer’s Disease Research Center in Madison.

According to one estimate, about 30% of cognitively healthy elderly adults may have widespread Alzheimer’s disease pathology. Cognitive reserve may allow these individuals to perform at a normal level of cognition despite this pathology. Because many people spend the majority of their lives at work, Ms. Boots and colleagues chose to examine occupational complexity as a measure of cognitive reserve. The investigators also focused on white matter hyperintensities, which increase the risk for cognitive decline and are common in Alzheimer’s disease. “The objective of our study was to determine whether occupational complexity is associated with more white matter hyperintensities when participants are matched for cognitive function, which would support the cognitive reserve hypothesis,” said Ms. Boots.

Examining Cognitive Testing and Imaging

She and her colleagues, led by senior author Ozioma Okonkwo, PhD, Assistant Professor of Geriatrics at the University of Wisconsin School of Medicine in Madison, selected 284 participants in the Wisconsin Registry for Alzheimer’s Prevention, a group of approximately 1,500 cognitively healthy people with increased risk for Alzheimer’s disease because of parental family history. Participants underwent extensive cognitive testing, and the researchers looked at the average of four cognitive domains—verbal learning and memory, immediate memory, working memory, and speed and flexibility—to match individuals on cognitive function. Participants also underwent a brain scan for white matter hyperintensities.

In addition, study participants described as many as three occupations that they had performed, including the number of years spent on each occupation. Ms. Boots and her colleagues rated each job for three categories of occupational complexity (ie, complexity of work with data, people, and things). In the domain of work with people, for example, the researchers considered taking instructions as the least complex occupation, and mentoring the most complex. They weighted the scores by the number of years on the job and summed the scores to create a total occupational complexity measure.

Social Interaction May Be Crucial

Average age in the study cohort was 60, and 67% of participants were female. Study participants had an average of 16.67 years of education. When the investigators controlled the data for cognitive function, they found that higher levels of occupational complexity were associated with increased white matter hyperintensities in the brain. “Those with higher levels of occupational complexity are able to tolerate more white matter pathology in the brain and still perform at the same cognitive level as their peers,” said Ms. Boots. The association did not change when the researchers controlled for potential confounders such as education, socioeconomic status, and vascular risk. Furthermore, Ms. Boots and colleagues found that complexity of work with people, but not complexity of work with data or things, had the greatest effect on preserving cognitive performance.

The results support the cognitive reserve hypothesis and suggest that social interaction plays a unique role in cognitive reserve, according to Dr. Okonkwo. “These analyses underscore the importance of social engagement in the work setting for building resilience to Alzheimer’s disease,” he added. The Alzheimer’s Association, the NIH, and the Extendicare Foundation funded the study.

Suggested Reading

Boots EA, Schultz SA, Almeida RP, et al. Occupational complexity and cognitive reserve in a middle-aged cohort at risk for Alzheimer’s disease. Arch Clin Neuropsychol. 2015;30(7):634-642.

Lo RY, Jagust WJ; Alzheimer’s Disease Neuroimaging Initiative. Effect of cognitive reserve markers on Alzheimer pathologic progression. Alzheimer Dis Assoc Disord. 2013;27(4):343-350.

Pool LR, Weuve J, Wilson RS, et al. Occupational cognitive requirements and late-life cognitive aging. Neurology. 2016;86(15):1386-1392.

Stern Y. Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol. 2012; 11(11):1006-1012.

TORONTO—High levels of occupational complexity, specifically related to work with people, enable individuals to maintain normal cognition despite white matter pathology in the brain, according to research described at the Alzheimer’s Association International Conference. The results “could have potential implications for preventing or maybe delaying Alzheimer’s disease onset in the future,” said Elizabeth Boots, research specialist at Wisconsin Alzheimer’s Disease Research Center in Madison.

According to one estimate, about 30% of cognitively healthy elderly adults may have widespread Alzheimer’s disease pathology. Cognitive reserve may allow these individuals to perform at a normal level of cognition despite this pathology. Because many people spend the majority of their lives at work, Ms. Boots and colleagues chose to examine occupational complexity as a measure of cognitive reserve. The investigators also focused on white matter hyperintensities, which increase the risk for cognitive decline and are common in Alzheimer’s disease. “The objective of our study was to determine whether occupational complexity is associated with more white matter hyperintensities when participants are matched for cognitive function, which would support the cognitive reserve hypothesis,” said Ms. Boots.

Examining Cognitive Testing and Imaging

She and her colleagues, led by senior author Ozioma Okonkwo, PhD, Assistant Professor of Geriatrics at the University of Wisconsin School of Medicine in Madison, selected 284 participants in the Wisconsin Registry for Alzheimer’s Prevention, a group of approximately 1,500 cognitively healthy people with increased risk for Alzheimer’s disease because of parental family history. Participants underwent extensive cognitive testing, and the researchers looked at the average of four cognitive domains—verbal learning and memory, immediate memory, working memory, and speed and flexibility—to match individuals on cognitive function. Participants also underwent a brain scan for white matter hyperintensities.

In addition, study participants described as many as three occupations that they had performed, including the number of years spent on each occupation. Ms. Boots and her colleagues rated each job for three categories of occupational complexity (ie, complexity of work with data, people, and things). In the domain of work with people, for example, the researchers considered taking instructions as the least complex occupation, and mentoring the most complex. They weighted the scores by the number of years on the job and summed the scores to create a total occupational complexity measure.

Social Interaction May Be Crucial

Average age in the study cohort was 60, and 67% of participants were female. Study participants had an average of 16.67 years of education. When the investigators controlled the data for cognitive function, they found that higher levels of occupational complexity were associated with increased white matter hyperintensities in the brain. “Those with higher levels of occupational complexity are able to tolerate more white matter pathology in the brain and still perform at the same cognitive level as their peers,” said Ms. Boots. The association did not change when the researchers controlled for potential confounders such as education, socioeconomic status, and vascular risk. Furthermore, Ms. Boots and colleagues found that complexity of work with people, but not complexity of work with data or things, had the greatest effect on preserving cognitive performance.

The results support the cognitive reserve hypothesis and suggest that social interaction plays a unique role in cognitive reserve, according to Dr. Okonkwo. “These analyses underscore the importance of social engagement in the work setting for building resilience to Alzheimer’s disease,” he added. The Alzheimer’s Association, the NIH, and the Extendicare Foundation funded the study.

Suggested Reading

Boots EA, Schultz SA, Almeida RP, et al. Occupational complexity and cognitive reserve in a middle-aged cohort at risk for Alzheimer’s disease. Arch Clin Neuropsychol. 2015;30(7):634-642.

Lo RY, Jagust WJ; Alzheimer’s Disease Neuroimaging Initiative. Effect of cognitive reserve markers on Alzheimer pathologic progression. Alzheimer Dis Assoc Disord. 2013;27(4):343-350.

Pool LR, Weuve J, Wilson RS, et al. Occupational cognitive requirements and late-life cognitive aging. Neurology. 2016;86(15):1386-1392.

Stern Y. Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol. 2012; 11(11):1006-1012.

TORONTO—High levels of occupational complexity, specifically related to work with people, enable individuals to maintain normal cognition despite white matter pathology in the brain, according to research described at the Alzheimer’s Association International Conference. The results “could have potential implications for preventing or maybe delaying Alzheimer’s disease onset in the future,” said Elizabeth Boots, research specialist at Wisconsin Alzheimer’s Disease Research Center in Madison.

According to one estimate, about 30% of cognitively healthy elderly adults may have widespread Alzheimer’s disease pathology. Cognitive reserve may allow these individuals to perform at a normal level of cognition despite this pathology. Because many people spend the majority of their lives at work, Ms. Boots and colleagues chose to examine occupational complexity as a measure of cognitive reserve. The investigators also focused on white matter hyperintensities, which increase the risk for cognitive decline and are common in Alzheimer’s disease. “The objective of our study was to determine whether occupational complexity is associated with more white matter hyperintensities when participants are matched for cognitive function, which would support the cognitive reserve hypothesis,” said Ms. Boots.

Examining Cognitive Testing and Imaging

She and her colleagues, led by senior author Ozioma Okonkwo, PhD, Assistant Professor of Geriatrics at the University of Wisconsin School of Medicine in Madison, selected 284 participants in the Wisconsin Registry for Alzheimer’s Prevention, a group of approximately 1,500 cognitively healthy people with increased risk for Alzheimer’s disease because of parental family history. Participants underwent extensive cognitive testing, and the researchers looked at the average of four cognitive domains—verbal learning and memory, immediate memory, working memory, and speed and flexibility—to match individuals on cognitive function. Participants also underwent a brain scan for white matter hyperintensities.

In addition, study participants described as many as three occupations that they had performed, including the number of years spent on each occupation. Ms. Boots and her colleagues rated each job for three categories of occupational complexity (ie, complexity of work with data, people, and things). In the domain of work with people, for example, the researchers considered taking instructions as the least complex occupation, and mentoring the most complex. They weighted the scores by the number of years on the job and summed the scores to create a total occupational complexity measure.

Social Interaction May Be Crucial

Average age in the study cohort was 60, and 67% of participants were female. Study participants had an average of 16.67 years of education. When the investigators controlled the data for cognitive function, they found that higher levels of occupational complexity were associated with increased white matter hyperintensities in the brain. “Those with higher levels of occupational complexity are able to tolerate more white matter pathology in the brain and still perform at the same cognitive level as their peers,” said Ms. Boots. The association did not change when the researchers controlled for potential confounders such as education, socioeconomic status, and vascular risk. Furthermore, Ms. Boots and colleagues found that complexity of work with people, but not complexity of work with data or things, had the greatest effect on preserving cognitive performance.

The results support the cognitive reserve hypothesis and suggest that social interaction plays a unique role in cognitive reserve, according to Dr. Okonkwo. “These analyses underscore the importance of social engagement in the work setting for building resilience to Alzheimer’s disease,” he added. The Alzheimer’s Association, the NIH, and the Extendicare Foundation funded the study.

Suggested Reading

Boots EA, Schultz SA, Almeida RP, et al. Occupational complexity and cognitive reserve in a middle-aged cohort at risk for Alzheimer’s disease. Arch Clin Neuropsychol. 2015;30(7):634-642.

Lo RY, Jagust WJ; Alzheimer’s Disease Neuroimaging Initiative. Effect of cognitive reserve markers on Alzheimer pathologic progression. Alzheimer Dis Assoc Disord. 2013;27(4):343-350.

Pool LR, Weuve J, Wilson RS, et al. Occupational cognitive requirements and late-life cognitive aging. Neurology. 2016;86(15):1386-1392.

Stern Y. Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol. 2012; 11(11):1006-1012.

Bullous pemphigoid (BP) is an acquired, autoimmune, subepidermal blistering disease that is more common in elderly patients.¹ An association with internal neoplasms and BP has been established; however, there is debate regarding the precise nature of the relationship.² Several gastrointestinal tract tumors have been associated with BP, including adenocarcinoma of the colon, adenosquamous cell carcinoma and adenocarcinoma of the stomach, adenocarcinoma of the rectum, and liver and bile duct malignancies.^3-5 Association with pancreatic neoplasms (eg, carcinoma of the pancreas) rarely has been reported.^5-7 We present an unusual case of a lymphoepithelial cyst of the pancreas in a patient with BP.

Case Report

A 67-year-old man presented with erythematous crusted plaques and pink scars over the chest, back, arms, and legs (Figure 1). A 1.5-cm tense bullous lesion was observed on the right knee. The patient’s medical history was notable for biopsy-proven BP of 8 months’ duration as well as diabetes mellitus and hypothyroidism. The patient was being followed by his surgeon for a 1.9-cm soft-tissue lesion in the pancreatic tail and was awaiting surgical excision at the time of the current presentation. The pancreatic lesion was discovered incidentally on magnetic resonance imaging performed following urologic concerns. At the current presentation, the patient’s medications included nifedipine, hydralazine, metoprolol, torsemide, aspirin, levothyroxine, atorvastatin, insulin lispro, and insulin glargine. He had previously been treated for BP with prednisone at a maximum dosage of 60 mg daily, clobetasol propionate cream 0.05%, and mupirocin ointment 2% without improvement. Because of substantial weight gain and poorly controlled diabetes, prednisone was discontinued.

Bullous pemphigoid had been diagnosed histopathologically by a prior dermatologist. Hematoxylin and eosin staining demonstrated a subepidermal separation with eosinophils within the perivascular infiltrate (Figure 2). Direct immunofluorescence was noted in a linear pattern at the dermoepidermal junction with IgG and C3. Bullous pemphigoid antigen antibodies 1 and 2 were obtained via enzyme-linked immunosorbent assay with a positive BP-1 antigen antibody of 19 U/mL (positive, >15 U/mL) and a normal BP-2 antigen antibody of less than 9 U/mL (reference range, <9 U/mL). The glucagon level was elevated at 245 pg/mL (reference range, ≤134 pg/mL).

The patient was prescribed minocycline 100 mg twice daily and niacinamide 500 mg 3 times daily. Topical treatment with clobetasol and mupirocin was continued. One month later, the patient returned with an increase in disease activity. Changes to his therapeutic regimen were deferred until after excision of the pancreatic lesion based on the decision not to start immunosuppressive therapy until the precise nature of the pancreatic lesion was determined.

The patient underwent excision of the pancreatic lesion approximately 3 months later, which proved to be a benign lymphoepithelial cyst of the pancreas. Histology of the cyst consisted of dense fibrous tissue with a squamous epithelial lining focally infiltrated by lymphocytes (Figure 3A). Immunoperoxidase staining of the cyst revealed focal linear areas of C3d staining along the basement membrane of the stratified squamous epithelium (Figure 3B).

The patient stated that his skin started to improve virtually immediately following the excision without systemic treatment for BP. On follow-up examination 3 weeks postoperatively, no bullae were observed and there was a notable decrease in erythematous crusted plaques (Figure 4).

Comment

Paraneoplastic BP has been documented; however, lymphoepithelial cysts of the pancreas in association with BP are rare. We propose that the lymphoepithelial cyst of the pancreas provided the immunologic stimulus for the development of cutaneous BP based on the observation that our patient’s condition remarkably improved with resection of the tumor.

There are fewer than 100 cases of lymphoepithelial cysts of the pancreas reported in the literature.⁸ The histologic appearance is consistent with a true cyst exhibiting a well-differentiated stratified squamous epithelium, often with keratinization, surrounded by lymphoid tissue. These tumors are most commonly seen in middle-aged men and are frequently found incidentally,^8-10 as was the case with our patient. Although histologically similar, lymphoepithelial cysts of the pancreas are considered distinct from lymphoepithelial cysts of the parotid gland or head and neck region.¹⁰ Lymphoepithelial cysts of the pancreas are unrelated to elevated glucagon levels; it is likely that our patient’s glucagon levels were associated with his history of diabetes.¹¹

In theory, any process that involves deposition of C3 should be positive for C3d on immunoperoxidase staining. Other dermatologic inflammatory conditions stain positively with C3d, such as systemic lupus erythematosus, discoid lupus erythematosus, subacute cutaneous lupus erythematosus, and dermatomysositis.¹³ The staining for these diseases correlates with the site of the associated inflammatory component seen on hematoxylin and eosin staining. The staining of C3d along the basement membrane of stratified squamous epithelium in the lymphoepithelial cyst of the pancreas seen in our patient closely resembles the staining seen in cutaneous BP.

A proposed mechanism for BP in our patient would be exposure of BP-1 antigen in the pancreatic cyst leading to antibody recognition and C3 deposition along the basement membrane in the cyst, as evidenced by C3d immunoperoxidase staining. The IgG and C3 deposition along the cutaneous basement membrane would then represent a systemic response to the antigen exposure in the cyst. Thus, the lymphoepithelial cyst provided the immunologic stimulus for the development of the cutaneous BP. This theory is based on the observation of our patient’s rapid improvement without a change in his treatment regimen immediately after surgical excision of the cyst.

Despite the plausibility of our hypothesis, several questions remain regarding the validity of our assumptions. Although sensitive for C3 deposition, C3d immunoperoxidase staining is not specific for BP. If the proposed mechanism for causation is true, one might have expected that a subepithelial cleft along the basement membrane of the pancreatic cyst would be observed, which was not seen. A repeat BP antigen antibody was not obtained, which would have been helpful in determining if there was clearance of the antibody that would have correlated with the clinical resolution of the BP lesions.

Conclusion

Our case suggests that paraneoplastic BP is a genuine entity. Indeed, the primary tumor itself may be the immunologic stimulus in the development of BP. Recalcitrant BP should raise the question of a neoplastic process that is exposing the BP antigen. If a thorough review of systems accompanied by corroborating laboratory studies suggests a neoplastic process, the suspect lesion should be further evaluated and surgically excised if clinically indicated. Further evaluation of neoplasms with advanced staining methods may aid in establishing the causative nature of tumors in the development of BP.

Acknowledgments

We are grateful to John Stanley, MD, and Aimee Payne, MD (both from Philadelphia, Pennsylvania), for theirinsights into this case.

Bullous pemphigoid (BP) is an acquired, autoimmune, subepidermal blistering disease that is more common in elderly patients.¹ An association with internal neoplasms and BP has been established; however, there is debate regarding the precise nature of the relationship.² Several gastrointestinal tract tumors have been associated with BP, including adenocarcinoma of the colon, adenosquamous cell carcinoma and adenocarcinoma of the stomach, adenocarcinoma of the rectum, and liver and bile duct malignancies.^3-5 Association with pancreatic neoplasms (eg, carcinoma of the pancreas) rarely has been reported.^5-7 We present an unusual case of a lymphoepithelial cyst of the pancreas in a patient with BP.

Case Report

A 67-year-old man presented with erythematous crusted plaques and pink scars over the chest, back, arms, and legs (Figure 1). A 1.5-cm tense bullous lesion was observed on the right knee. The patient’s medical history was notable for biopsy-proven BP of 8 months’ duration as well as diabetes mellitus and hypothyroidism. The patient was being followed by his surgeon for a 1.9-cm soft-tissue lesion in the pancreatic tail and was awaiting surgical excision at the time of the current presentation. The pancreatic lesion was discovered incidentally on magnetic resonance imaging performed following urologic concerns. At the current presentation, the patient’s medications included nifedipine, hydralazine, metoprolol, torsemide, aspirin, levothyroxine, atorvastatin, insulin lispro, and insulin glargine. He had previously been treated for BP with prednisone at a maximum dosage of 60 mg daily, clobetasol propionate cream 0.05%, and mupirocin ointment 2% without improvement. Because of substantial weight gain and poorly controlled diabetes, prednisone was discontinued.

Bullous pemphigoid had been diagnosed histopathologically by a prior dermatologist. Hematoxylin and eosin staining demonstrated a subepidermal separation with eosinophils within the perivascular infiltrate (Figure 2). Direct immunofluorescence was noted in a linear pattern at the dermoepidermal junction with IgG and C3. Bullous pemphigoid antigen antibodies 1 and 2 were obtained via enzyme-linked immunosorbent assay with a positive BP-1 antigen antibody of 19 U/mL (positive, >15 U/mL) and a normal BP-2 antigen antibody of less than 9 U/mL (reference range, <9 U/mL). The glucagon level was elevated at 245 pg/mL (reference range, ≤134 pg/mL).

The patient was prescribed minocycline 100 mg twice daily and niacinamide 500 mg 3 times daily. Topical treatment with clobetasol and mupirocin was continued. One month later, the patient returned with an increase in disease activity. Changes to his therapeutic regimen were deferred until after excision of the pancreatic lesion based on the decision not to start immunosuppressive therapy until the precise nature of the pancreatic lesion was determined.

The patient underwent excision of the pancreatic lesion approximately 3 months later, which proved to be a benign lymphoepithelial cyst of the pancreas. Histology of the cyst consisted of dense fibrous tissue with a squamous epithelial lining focally infiltrated by lymphocytes (Figure 3A). Immunoperoxidase staining of the cyst revealed focal linear areas of C3d staining along the basement membrane of the stratified squamous epithelium (Figure 3B).

The patient stated that his skin started to improve virtually immediately following the excision without systemic treatment for BP. On follow-up examination 3 weeks postoperatively, no bullae were observed and there was a notable decrease in erythematous crusted plaques (Figure 4).

Comment

Paraneoplastic BP has been documented; however, lymphoepithelial cysts of the pancreas in association with BP are rare. We propose that the lymphoepithelial cyst of the pancreas provided the immunologic stimulus for the development of cutaneous BP based on the observation that our patient’s condition remarkably improved with resection of the tumor.

There are fewer than 100 cases of lymphoepithelial cysts of the pancreas reported in the literature.⁸ The histologic appearance is consistent with a true cyst exhibiting a well-differentiated stratified squamous epithelium, often with keratinization, surrounded by lymphoid tissue. These tumors are most commonly seen in middle-aged men and are frequently found incidentally,^8-10 as was the case with our patient. Although histologically similar, lymphoepithelial cysts of the pancreas are considered distinct from lymphoepithelial cysts of the parotid gland or head and neck region.¹⁰ Lymphoepithelial cysts of the pancreas are unrelated to elevated glucagon levels; it is likely that our patient’s glucagon levels were associated with his history of diabetes.¹¹

In theory, any process that involves deposition of C3 should be positive for C3d on immunoperoxidase staining. Other dermatologic inflammatory conditions stain positively with C3d, such as systemic lupus erythematosus, discoid lupus erythematosus, subacute cutaneous lupus erythematosus, and dermatomysositis.¹³ The staining for these diseases correlates with the site of the associated inflammatory component seen on hematoxylin and eosin staining. The staining of C3d along the basement membrane of stratified squamous epithelium in the lymphoepithelial cyst of the pancreas seen in our patient closely resembles the staining seen in cutaneous BP.

A proposed mechanism for BP in our patient would be exposure of BP-1 antigen in the pancreatic cyst leading to antibody recognition and C3 deposition along the basement membrane in the cyst, as evidenced by C3d immunoperoxidase staining. The IgG and C3 deposition along the cutaneous basement membrane would then represent a systemic response to the antigen exposure in the cyst. Thus, the lymphoepithelial cyst provided the immunologic stimulus for the development of the cutaneous BP. This theory is based on the observation of our patient’s rapid improvement without a change in his treatment regimen immediately after surgical excision of the cyst.

Despite the plausibility of our hypothesis, several questions remain regarding the validity of our assumptions. Although sensitive for C3 deposition, C3d immunoperoxidase staining is not specific for BP. If the proposed mechanism for causation is true, one might have expected that a subepithelial cleft along the basement membrane of the pancreatic cyst would be observed, which was not seen. A repeat BP antigen antibody was not obtained, which would have been helpful in determining if there was clearance of the antibody that would have correlated with the clinical resolution of the BP lesions.

Conclusion

Our case suggests that paraneoplastic BP is a genuine entity. Indeed, the primary tumor itself may be the immunologic stimulus in the development of BP. Recalcitrant BP should raise the question of a neoplastic process that is exposing the BP antigen. If a thorough review of systems accompanied by corroborating laboratory studies suggests a neoplastic process, the suspect lesion should be further evaluated and surgically excised if clinically indicated. Further evaluation of neoplasms with advanced staining methods may aid in establishing the causative nature of tumors in the development of BP.

Acknowledgments

We are grateful to John Stanley, MD, and Aimee Payne, MD (both from Philadelphia, Pennsylvania), for theirinsights into this case.

Bullous pemphigoid (BP) is an acquired, autoimmune, subepidermal blistering disease that is more common in elderly patients.¹ An association with internal neoplasms and BP has been established; however, there is debate regarding the precise nature of the relationship.² Several gastrointestinal tract tumors have been associated with BP, including adenocarcinoma of the colon, adenosquamous cell carcinoma and adenocarcinoma of the stomach, adenocarcinoma of the rectum, and liver and bile duct malignancies.^3-5 Association with pancreatic neoplasms (eg, carcinoma of the pancreas) rarely has been reported.^5-7 We present an unusual case of a lymphoepithelial cyst of the pancreas in a patient with BP.

Case Report

A 67-year-old man presented with erythematous crusted plaques and pink scars over the chest, back, arms, and legs (Figure 1). A 1.5-cm tense bullous lesion was observed on the right knee. The patient’s medical history was notable for biopsy-proven BP of 8 months’ duration as well as diabetes mellitus and hypothyroidism. The patient was being followed by his surgeon for a 1.9-cm soft-tissue lesion in the pancreatic tail and was awaiting surgical excision at the time of the current presentation. The pancreatic lesion was discovered incidentally on magnetic resonance imaging performed following urologic concerns. At the current presentation, the patient’s medications included nifedipine, hydralazine, metoprolol, torsemide, aspirin, levothyroxine, atorvastatin, insulin lispro, and insulin glargine. He had previously been treated for BP with prednisone at a maximum dosage of 60 mg daily, clobetasol propionate cream 0.05%, and mupirocin ointment 2% without improvement. Because of substantial weight gain and poorly controlled diabetes, prednisone was discontinued.

Bullous pemphigoid had been diagnosed histopathologically by a prior dermatologist. Hematoxylin and eosin staining demonstrated a subepidermal separation with eosinophils within the perivascular infiltrate (Figure 2). Direct immunofluorescence was noted in a linear pattern at the dermoepidermal junction with IgG and C3. Bullous pemphigoid antigen antibodies 1 and 2 were obtained via enzyme-linked immunosorbent assay with a positive BP-1 antigen antibody of 19 U/mL (positive, >15 U/mL) and a normal BP-2 antigen antibody of less than 9 U/mL (reference range, <9 U/mL). The glucagon level was elevated at 245 pg/mL (reference range, ≤134 pg/mL).

The patient was prescribed minocycline 100 mg twice daily and niacinamide 500 mg 3 times daily. Topical treatment with clobetasol and mupirocin was continued. One month later, the patient returned with an increase in disease activity. Changes to his therapeutic regimen were deferred until after excision of the pancreatic lesion based on the decision not to start immunosuppressive therapy until the precise nature of the pancreatic lesion was determined.

The patient underwent excision of the pancreatic lesion approximately 3 months later, which proved to be a benign lymphoepithelial cyst of the pancreas. Histology of the cyst consisted of dense fibrous tissue with a squamous epithelial lining focally infiltrated by lymphocytes (Figure 3A). Immunoperoxidase staining of the cyst revealed focal linear areas of C3d staining along the basement membrane of the stratified squamous epithelium (Figure 3B).

The patient stated that his skin started to improve virtually immediately following the excision without systemic treatment for BP. On follow-up examination 3 weeks postoperatively, no bullae were observed and there was a notable decrease in erythematous crusted plaques (Figure 4).

Comment

Paraneoplastic BP has been documented; however, lymphoepithelial cysts of the pancreas in association with BP are rare. We propose that the lymphoepithelial cyst of the pancreas provided the immunologic stimulus for the development of cutaneous BP based on the observation that our patient’s condition remarkably improved with resection of the tumor.

There are fewer than 100 cases of lymphoepithelial cysts of the pancreas reported in the literature.⁸ The histologic appearance is consistent with a true cyst exhibiting a well-differentiated stratified squamous epithelium, often with keratinization, surrounded by lymphoid tissue. These tumors are most commonly seen in middle-aged men and are frequently found incidentally,^8-10 as was the case with our patient. Although histologically similar, lymphoepithelial cysts of the pancreas are considered distinct from lymphoepithelial cysts of the parotid gland or head and neck region.¹⁰ Lymphoepithelial cysts of the pancreas are unrelated to elevated glucagon levels; it is likely that our patient’s glucagon levels were associated with his history of diabetes.¹¹

In theory, any process that involves deposition of C3 should be positive for C3d on immunoperoxidase staining. Other dermatologic inflammatory conditions stain positively with C3d, such as systemic lupus erythematosus, discoid lupus erythematosus, subacute cutaneous lupus erythematosus, and dermatomysositis.¹³ The staining for these diseases correlates with the site of the associated inflammatory component seen on hematoxylin and eosin staining. The staining of C3d along the basement membrane of stratified squamous epithelium in the lymphoepithelial cyst of the pancreas seen in our patient closely resembles the staining seen in cutaneous BP.

A proposed mechanism for BP in our patient would be exposure of BP-1 antigen in the pancreatic cyst leading to antibody recognition and C3 deposition along the basement membrane in the cyst, as evidenced by C3d immunoperoxidase staining. The IgG and C3 deposition along the cutaneous basement membrane would then represent a systemic response to the antigen exposure in the cyst. Thus, the lymphoepithelial cyst provided the immunologic stimulus for the development of the cutaneous BP. This theory is based on the observation of our patient’s rapid improvement without a change in his treatment regimen immediately after surgical excision of the cyst.

Despite the plausibility of our hypothesis, several questions remain regarding the validity of our assumptions. Although sensitive for C3 deposition, C3d immunoperoxidase staining is not specific for BP. If the proposed mechanism for causation is true, one might have expected that a subepithelial cleft along the basement membrane of the pancreatic cyst would be observed, which was not seen. A repeat BP antigen antibody was not obtained, which would have been helpful in determining if there was clearance of the antibody that would have correlated with the clinical resolution of the BP lesions.

Conclusion

Our case suggests that paraneoplastic BP is a genuine entity. Indeed, the primary tumor itself may be the immunologic stimulus in the development of BP. Recalcitrant BP should raise the question of a neoplastic process that is exposing the BP antigen. If a thorough review of systems accompanied by corroborating laboratory studies suggests a neoplastic process, the suspect lesion should be further evaluated and surgically excised if clinically indicated. Further evaluation of neoplasms with advanced staining methods may aid in establishing the causative nature of tumors in the development of BP.

Acknowledgments

We are grateful to John Stanley, MD, and Aimee Payne, MD (both from Philadelphia, Pennsylvania), for theirinsights into this case.

We live inundated with promises that technology will solve our most challenging problems, yet we are regularly disappointed when it does not. New technological solutions seem to appear daily, and we feel like we are falling behind if we do not jump to join the people who are implementing, selling, or imposing new solutions. Often these solutions are offered before the problem is even fully understood, and no assessment has been made to determine if the solution actually helps to solve the challenge identified. With 80% of us now having transitioned to EHRs, we know full well their benefits as well as their pitfalls. While we have mostly accommodated to electronic documentation, we are now at the point where we are beginning to explore some of the most exciting potential benefits of our EHRs – population health, enhanced data on medication adherence, and improved patient communication. As we look at this next stage of growth, we are reminded of a lesson from an old joke:

A rabbi dies and goes to heaven. When he gets there he is given an old robe and a wooden walking stick and is told to get in line to the entrance to heaven. While the rabbi waits in the long line, a taxi driver walks up and is greeted by a group of angels blowing their horns announcing his arrival. One of the angels walks over to the driver and gives him a flowing white satin robe and a golden walking stick. Another angel then escorts him to the front of the line.

Reference

Jakicic JM, et al. Effect of Wearable Technology Combined With a Lifestyle Intervention on Long-term Weight Loss The IDEA Randomized Clinical Trial. JAMA. 2016;316[11]:1161-71. doi: 10.1001/jama.2016.12858

Dr. Skolnik is associate director of the family medicine residency program at Abington Memorial Hospital and professor of family and community medicine at Temple University in Philadelphia. Dr. Notte is a family physician and clinical informaticist for Abington (Pa.) Memorial Hospital. He is a partner in EHR Practice Consultants, a firm that aids physicians in adopting electronic health records.

We live inundated with promises that technology will solve our most challenging problems, yet we are regularly disappointed when it does not. New technological solutions seem to appear daily, and we feel like we are falling behind if we do not jump to join the people who are implementing, selling, or imposing new solutions. Often these solutions are offered before the problem is even fully understood, and no assessment has been made to determine if the solution actually helps to solve the challenge identified. With 80% of us now having transitioned to EHRs, we know full well their benefits as well as their pitfalls. While we have mostly accommodated to electronic documentation, we are now at the point where we are beginning to explore some of the most exciting potential benefits of our EHRs – population health, enhanced data on medication adherence, and improved patient communication. As we look at this next stage of growth, we are reminded of a lesson from an old joke:

A rabbi dies and goes to heaven. When he gets there he is given an old robe and a wooden walking stick and is told to get in line to the entrance to heaven. While the rabbi waits in the long line, a taxi driver walks up and is greeted by a group of angels blowing their horns announcing his arrival. One of the angels walks over to the driver and gives him a flowing white satin robe and a golden walking stick. Another angel then escorts him to the front of the line.

Reference

Jakicic JM, et al. Effect of Wearable Technology Combined With a Lifestyle Intervention on Long-term Weight Loss The IDEA Randomized Clinical Trial. JAMA. 2016;316[11]:1161-71. doi: 10.1001/jama.2016.12858

Dr. Skolnik is associate director of the family medicine residency program at Abington Memorial Hospital and professor of family and community medicine at Temple University in Philadelphia. Dr. Notte is a family physician and clinical informaticist for Abington (Pa.) Memorial Hospital. He is a partner in EHR Practice Consultants, a firm that aids physicians in adopting electronic health records.

We live inundated with promises that technology will solve our most challenging problems, yet we are regularly disappointed when it does not. New technological solutions seem to appear daily, and we feel like we are falling behind if we do not jump to join the people who are implementing, selling, or imposing new solutions. Often these solutions are offered before the problem is even fully understood, and no assessment has been made to determine if the solution actually helps to solve the challenge identified. With 80% of us now having transitioned to EHRs, we know full well their benefits as well as their pitfalls. While we have mostly accommodated to electronic documentation, we are now at the point where we are beginning to explore some of the most exciting potential benefits of our EHRs – population health, enhanced data on medication adherence, and improved patient communication. As we look at this next stage of growth, we are reminded of a lesson from an old joke:

A rabbi dies and goes to heaven. When he gets there he is given an old robe and a wooden walking stick and is told to get in line to the entrance to heaven. While the rabbi waits in the long line, a taxi driver walks up and is greeted by a group of angels blowing their horns announcing his arrival. One of the angels walks over to the driver and gives him a flowing white satin robe and a golden walking stick. Another angel then escorts him to the front of the line.

Reference

Jakicic JM, et al. Effect of Wearable Technology Combined With a Lifestyle Intervention on Long-term Weight Loss The IDEA Randomized Clinical Trial. JAMA. 2016;316[11]:1161-71. doi: 10.1001/jama.2016.12858

Dr. Skolnik is associate director of the family medicine residency program at Abington Memorial Hospital and professor of family and community medicine at Temple University in Philadelphia. Dr. Notte is a family physician and clinical informaticist for Abington (Pa.) Memorial Hospital. He is a partner in EHR Practice Consultants, a firm that aids physicians in adopting electronic health records.

Researchers have proposed the term “congenital Zika syndrome” to cover the range of severe damage and developmental abnormalities – including microcephaly – caused by Zika virus infection.

In the Oct. 3 online edition of JAMA Neurology, Adriana Suely de Oliveira Melo, MD, PhD, of the Instituto de Pesquisa Professor Amorim Neto in Campina Grande, Brazil, and her coauthors report on 11 babies with congenital Zika virus infection who were followed from gestation to 6 months of age.

©Devonyu/Thinkstock

Researchers have proposed the term “congenital Zika syndrome” to cover the range of severe damage and developmental abnormalities – including microcephaly – caused by Zika virus infection.

In the Oct. 3 online edition of JAMA Neurology, Adriana Suely de Oliveira Melo, MD, PhD, of the Instituto de Pesquisa Professor Amorim Neto in Campina Grande, Brazil, and her coauthors report on 11 babies with congenital Zika virus infection who were followed from gestation to 6 months of age.

©Devonyu/Thinkstock

Researchers have proposed the term “congenital Zika syndrome” to cover the range of severe damage and developmental abnormalities – including microcephaly – caused by Zika virus infection.

In the Oct. 3 online edition of JAMA Neurology, Adriana Suely de Oliveira Melo, MD, PhD, of the Instituto de Pesquisa Professor Amorim Neto in Campina Grande, Brazil, and her coauthors report on 11 babies with congenital Zika virus infection who were followed from gestation to 6 months of age.

©Devonyu/Thinkstock

Rosacea is a chronic inflammatory disorder that may negatively impact patients’ quality of life (QOL).^1,2 Papulopustular rosacea (PPR) is characterized by centrofacial inflammatory lesions and erythema as well as burning and stinging secondary to skin barrier dysfunction.^3-5 Increasing rosacea severity is associated with greater rates of anxiety and depression and lower QOL⁶ as well as low self-esteem and feelings of embarrassment.^7,8 Accordingly, assessing patient perceptions of rosacea treatments is necessary for understanding its impact on patient health.^6,9

The Rosacea International Expert Group has emphasized the need to incorporate patient assessments of disease severity and QOL when developing therapeutic strategies for rosacea.⁷ Ease of use, sensory experience, and patient preference also are important dimensions in the evaluation of topical medications, as attributes of specific formulations may affect usability, adherence, and efficacy.^10,11

An azelaic acid (AzA) 15% foam formulation, which was approved by the US Food and Drug Administration in 2015, was developed to deliver AzA in a vehicle designed to improve treatment experience in patients with mild to moderate PPR.¹² Results from a clinical trial demonstrated superiority of AzA foam to vehicle foam for primary end points that included therapeutic success rate and change in inflammatory lesion count.^13,14 Secondary end points assessed in the current analysis included patient perception of product usability, efficacy, and effect on QOL. These patient-reported outcome (PRO) results are reported here.

Methods

Study Design

The design of this phase 3 multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical trial was described in more detail in an earlier report.¹³ This study was approved by all appropriate institutional review boards. Eligible participants were 18 years and older with moderate or severe PPR, 12 to 50 inflammatory lesions, and persistent erythema with or without telangiectasia. Exclusion criteria included known nonresponse to AzA, current or prior use (within 6 weeks of randomization) of noninvestigational products to treat rosacea, and presence of other dermatoses that could interfere with rosacea evaluation.

Participants were randomized into the AzA foam or vehicle group (1:1 ratio). The study medication (0.5 g) or vehicle foam was applied twice daily to the entire face until the end of treatment (EoT) at 12 weeks. Efficacy and safety parameters were evaluated at baseline and at 4, 8, and 12 weeks of treatment, and at a follow-up visit 4 weeks after EoT (week 16).

Results for the coprimary efficacy end points—therapeutic success rate according to investigator global assessment and nominal change in inflammatory lesion count—were previously reported,¹³ as well as secondary efficacy outcomes including change in inflammatory lesion count, therapeutic response rate, and change in erythema rating.¹⁴

Patient-Reported Secondary Efficacy Outcomes

The secondary PRO end points were patient-reported global assessment of treatment response (rated as excellent, good, fair, none, or worse), global assessment of tolerability (rated as excellent, good, acceptable despite minor irritation, less acceptable due to continuous irritation, not acceptable, or no opinion), and opinion on cosmetic acceptability and practicability of product use in areas adjacent to the hairline (rated as very good, good, satisfactory, poor, or no opinion).

Additionally, QOL was measured by 3 validated standardized PRO tools, including the Rosacea Quality of Life Index (RosaQOL),¹⁵ the EuroQOL 5-dimension 5-level questionnaire (EQ-5D-5L),¹⁶ and the Dermatology Life Quality Index (DLQI). The RosaQOL is a rosacea-specific instrument assessing 3 constructs: (1) symptom, (2) emotion, and (3) function. The EQ-5D-5L questionnaire measures overall health status and comprises 5 constructs: (1) mobility, (2) self-care, (3) usual activities, (4) pain/discomfort, and (5) anxiety/depression. The DLQI is a general, dermatology-oriented instrument categorized into 6 constructs: (1) symptoms and feelings, (2) daily activities, (3) leisure, (4) work and school, (5) personal relationships, and (6) treatment.

Statistical Analyses

Patient-reported outcomes were analyzed in an exploratory manner and evaluated at EoT relative to baseline. Self-reported global assessment of treatment response and change in RosaQOL, EQ-5D-5L, and DLQI scores between AzA foam and vehicle foam groups were evaluated using the Wilcoxon rank sum test. Categorical change in the number of participants achieving an increase of 5 or more points in overall DLQI score was evaluated using a χ² test.

Safety

Safety was analyzed for all randomized patients who were dispensed any study medication. All analyses were performed using SAS version 9.2.

Results

Of the 961 participants included in the study, 483 were randomized to receive AzA foam and 478 were randomized to receive vehicle foam. The mean age was 51.5 years, and the majority of participants were female (73.0%) and white (95.5%)(Table). At baseline, 834 (86.8%) participants had moderate PPR and 127 (13.2%) had severe PPR. The mean inflammatory lesion count (SD) was 21.4 (8.9). No significant differences in baseline characteristics were observed between treatment groups.

Patient-reported global assessment of treatment response differed between treatment groups at EoT (P<.001)(Figure 1). Higher ratings of treatment response were reported among the AzA foam group (excellent, 17.2%; good, 40.0%) versus vehicle foam (excellent, 9.7%; good, 35.0%). The number of participants reporting no treatment response was 13.1% in the AzA foam group, with 1.8% reporting worsening of their condition, while 19.4% of participants in the vehicle foam group reported no response, with 6.3% reporting worsening of their condition (Figure 1).

The incidence of drug-related adverse events (AEs) was greater in the AzA foam group versus the vehicle foam group (7.7% vs 4.8%). Drug-related AEs occurring in 1% of the AzA foam group were application-site pain including tenderness, stinging, and burning (3.5% for AzA foam vs 1.3% for vehicle foam); application-site pruritus (1.4% vs 0.4%); and application-site dryness (1.0% vs 0.6%). One drug-related AE of severe intensity—application-site dermatitis—occurred in the vehicle foam group; all other drug-related AEs were mild or moderate.¹⁴ More detailed safety results are described in a previous report.¹³

Comment

The PRO outcome data reported here are consistent with previously reported statistically significant improvements in investigator-assessed primary end points for the treatment of PPR with AzA foam.^13,14 The data demonstrate that AzA foam benefits both clinical and patient-oriented dimensions of rosacea disease burden and suggest an association between positive treatment response and improved QOL.

Specifically, patient evaluation of treatment response to AzA foam was highly favorable, with 57.2% reporting excellent or good response and 85.1% reporting positive response overall. Recognizing the relapsing-remitting course of PPR, only 1.8% of the AzA foam group experienced worsening of disease at EoT.

The DLQI and RosaQOL instruments revealed notable improvements in QOL from baseline for both treatment groups. Although no significant differences in RosaQOL scores were observed between groups at EoT, significant differences in DLQI scores were detected. Almost one-quarter of participants in the AzA foam group achieved at least a 5-point improvement in DLQI score, exceeding the 4-point threshold for clinically meaningful change.¹⁷ Although little change in EQ-5D-5L scores was observed at EoT for both groups with no between-group differences, this finding is not unexpected, as this instrument assesses QOL dimensions such as loss of function, mobility, and ability to wash or dress, which are unlikely to be compromised in most rosacea patients.

Our results also underscore the importance of vehicle in the treatment of compromised skin. Studies of topical treatments for other dermatoses suggest that vehicle properties may reduce disease severity and improve QOL independent of active ingredients.^10,18 For example, ease of application, minimal residue, and less time spent in application may explain the superiority of foam to other vehicles in the treatment of psoriasis.¹⁸ Our data demonstrating high cosmetic favorability of AzA foam are consistent with these prior observations. Increased tolerability of foam formulations also may affect response to treatment, in part by supporting adherence.¹⁸ Most participants receiving AzA foam described tolerability as excellent or good, and the discontinuation rate was low (1.2% of participants in the AzA foam group left the study due to AEs) in the setting of near-complete dosage administration (97% of expected doses applied).¹³

Conclusion

These results indicate that use of AzA foam as well as its novel vehicle results in high patient satisfaction and improved QOL. Although additional research is necessary to further delineate the relationship between PROs and other measures of clinical efficacy, our data demonstrate a positive treatment experience as perceived by patients that parallels the clinical efficacy of AzA foam for the treatment of PPR.^13,14

Acknowledgment

Editorial support through inVentiv Medical Communications (New York, New York) was provided by Bayer Pharmaceuticals.

Rosacea is a chronic inflammatory disorder that may negatively impact patients’ quality of life (QOL).^1,2 Papulopustular rosacea (PPR) is characterized by centrofacial inflammatory lesions and erythema as well as burning and stinging secondary to skin barrier dysfunction.^3-5 Increasing rosacea severity is associated with greater rates of anxiety and depression and lower QOL⁶ as well as low self-esteem and feelings of embarrassment.^7,8 Accordingly, assessing patient perceptions of rosacea treatments is necessary for understanding its impact on patient health.^6,9

The Rosacea International Expert Group has emphasized the need to incorporate patient assessments of disease severity and QOL when developing therapeutic strategies for rosacea.⁷ Ease of use, sensory experience, and patient preference also are important dimensions in the evaluation of topical medications, as attributes of specific formulations may affect usability, adherence, and efficacy.^10,11

An azelaic acid (AzA) 15% foam formulation, which was approved by the US Food and Drug Administration in 2015, was developed to deliver AzA in a vehicle designed to improve treatment experience in patients with mild to moderate PPR.¹² Results from a clinical trial demonstrated superiority of AzA foam to vehicle foam for primary end points that included therapeutic success rate and change in inflammatory lesion count.^13,14 Secondary end points assessed in the current analysis included patient perception of product usability, efficacy, and effect on QOL. These patient-reported outcome (PRO) results are reported here.

Methods

Study Design

The design of this phase 3 multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical trial was described in more detail in an earlier report.¹³ This study was approved by all appropriate institutional review boards. Eligible participants were 18 years and older with moderate or severe PPR, 12 to 50 inflammatory lesions, and persistent erythema with or without telangiectasia. Exclusion criteria included known nonresponse to AzA, current or prior use (within 6 weeks of randomization) of noninvestigational products to treat rosacea, and presence of other dermatoses that could interfere with rosacea evaluation.

Participants were randomized into the AzA foam or vehicle group (1:1 ratio). The study medication (0.5 g) or vehicle foam was applied twice daily to the entire face until the end of treatment (EoT) at 12 weeks. Efficacy and safety parameters were evaluated at baseline and at 4, 8, and 12 weeks of treatment, and at a follow-up visit 4 weeks after EoT (week 16).

Results for the coprimary efficacy end points—therapeutic success rate according to investigator global assessment and nominal change in inflammatory lesion count—were previously reported,¹³ as well as secondary efficacy outcomes including change in inflammatory lesion count, therapeutic response rate, and change in erythema rating.¹⁴

Patient-Reported Secondary Efficacy Outcomes

The secondary PRO end points were patient-reported global assessment of treatment response (rated as excellent, good, fair, none, or worse), global assessment of tolerability (rated as excellent, good, acceptable despite minor irritation, less acceptable due to continuous irritation, not acceptable, or no opinion), and opinion on cosmetic acceptability and practicability of product use in areas adjacent to the hairline (rated as very good, good, satisfactory, poor, or no opinion).

Additionally, QOL was measured by 3 validated standardized PRO tools, including the Rosacea Quality of Life Index (RosaQOL),¹⁵ the EuroQOL 5-dimension 5-level questionnaire (EQ-5D-5L),¹⁶ and the Dermatology Life Quality Index (DLQI). The RosaQOL is a rosacea-specific instrument assessing 3 constructs: (1) symptom, (2) emotion, and (3) function. The EQ-5D-5L questionnaire measures overall health status and comprises 5 constructs: (1) mobility, (2) self-care, (3) usual activities, (4) pain/discomfort, and (5) anxiety/depression. The DLQI is a general, dermatology-oriented instrument categorized into 6 constructs: (1) symptoms and feelings, (2) daily activities, (3) leisure, (4) work and school, (5) personal relationships, and (6) treatment.

Statistical Analyses

Patient-reported outcomes were analyzed in an exploratory manner and evaluated at EoT relative to baseline. Self-reported global assessment of treatment response and change in RosaQOL, EQ-5D-5L, and DLQI scores between AzA foam and vehicle foam groups were evaluated using the Wilcoxon rank sum test. Categorical change in the number of participants achieving an increase of 5 or more points in overall DLQI score was evaluated using a χ² test.

Safety

Safety was analyzed for all randomized patients who were dispensed any study medication. All analyses were performed using SAS version 9.2.

Results

Of the 961 participants included in the study, 483 were randomized to receive AzA foam and 478 were randomized to receive vehicle foam. The mean age was 51.5 years, and the majority of participants were female (73.0%) and white (95.5%)(Table). At baseline, 834 (86.8%) participants had moderate PPR and 127 (13.2%) had severe PPR. The mean inflammatory lesion count (SD) was 21.4 (8.9). No significant differences in baseline characteristics were observed between treatment groups.

Patient-reported global assessment of treatment response differed between treatment groups at EoT (P<.001)(Figure 1). Higher ratings of treatment response were reported among the AzA foam group (excellent, 17.2%; good, 40.0%) versus vehicle foam (excellent, 9.7%; good, 35.0%). The number of participants reporting no treatment response was 13.1% in the AzA foam group, with 1.8% reporting worsening of their condition, while 19.4% of participants in the vehicle foam group reported no response, with 6.3% reporting worsening of their condition (Figure 1).

The incidence of drug-related adverse events (AEs) was greater in the AzA foam group versus the vehicle foam group (7.7% vs 4.8%). Drug-related AEs occurring in 1% of the AzA foam group were application-site pain including tenderness, stinging, and burning (3.5% for AzA foam vs 1.3% for vehicle foam); application-site pruritus (1.4% vs 0.4%); and application-site dryness (1.0% vs 0.6%). One drug-related AE of severe intensity—application-site dermatitis—occurred in the vehicle foam group; all other drug-related AEs were mild or moderate.¹⁴ More detailed safety results are described in a previous report.¹³

Comment

The PRO outcome data reported here are consistent with previously reported statistically significant improvements in investigator-assessed primary end points for the treatment of PPR with AzA foam.^13,14 The data demonstrate that AzA foam benefits both clinical and patient-oriented dimensions of rosacea disease burden and suggest an association between positive treatment response and improved QOL.

Specifically, patient evaluation of treatment response to AzA foam was highly favorable, with 57.2% reporting excellent or good response and 85.1% reporting positive response overall. Recognizing the relapsing-remitting course of PPR, only 1.8% of the AzA foam group experienced worsening of disease at EoT.

The DLQI and RosaQOL instruments revealed notable improvements in QOL from baseline for both treatment groups. Although no significant differences in RosaQOL scores were observed between groups at EoT, significant differences in DLQI scores were detected. Almost one-quarter of participants in the AzA foam group achieved at least a 5-point improvement in DLQI score, exceeding the 4-point threshold for clinically meaningful change.¹⁷ Although little change in EQ-5D-5L scores was observed at EoT for both groups with no between-group differences, this finding is not unexpected, as this instrument assesses QOL dimensions such as loss of function, mobility, and ability to wash or dress, which are unlikely to be compromised in most rosacea patients.

Our results also underscore the importance of vehicle in the treatment of compromised skin. Studies of topical treatments for other dermatoses suggest that vehicle properties may reduce disease severity and improve QOL independent of active ingredients.^10,18 For example, ease of application, minimal residue, and less time spent in application may explain the superiority of foam to other vehicles in the treatment of psoriasis.¹⁸ Our data demonstrating high cosmetic favorability of AzA foam are consistent with these prior observations. Increased tolerability of foam formulations also may affect response to treatment, in part by supporting adherence.¹⁸ Most participants receiving AzA foam described tolerability as excellent or good, and the discontinuation rate was low (1.2% of participants in the AzA foam group left the study due to AEs) in the setting of near-complete dosage administration (97% of expected doses applied).¹³

Conclusion

These results indicate that use of AzA foam as well as its novel vehicle results in high patient satisfaction and improved QOL. Although additional research is necessary to further delineate the relationship between PROs and other measures of clinical efficacy, our data demonstrate a positive treatment experience as perceived by patients that parallels the clinical efficacy of AzA foam for the treatment of PPR.^13,14

Acknowledgment

Editorial support through inVentiv Medical Communications (New York, New York) was provided by Bayer Pharmaceuticals.

Rosacea is a chronic inflammatory disorder that may negatively impact patients’ quality of life (QOL).^1,2 Papulopustular rosacea (PPR) is characterized by centrofacial inflammatory lesions and erythema as well as burning and stinging secondary to skin barrier dysfunction.^3-5 Increasing rosacea severity is associated with greater rates of anxiety and depression and lower QOL⁶ as well as low self-esteem and feelings of embarrassment.^7,8 Accordingly, assessing patient perceptions of rosacea treatments is necessary for understanding its impact on patient health.^6,9

The Rosacea International Expert Group has emphasized the need to incorporate patient assessments of disease severity and QOL when developing therapeutic strategies for rosacea.⁷ Ease of use, sensory experience, and patient preference also are important dimensions in the evaluation of topical medications, as attributes of specific formulations may affect usability, adherence, and efficacy.^10,11

An azelaic acid (AzA) 15% foam formulation, which was approved by the US Food and Drug Administration in 2015, was developed to deliver AzA in a vehicle designed to improve treatment experience in patients with mild to moderate PPR.¹² Results from a clinical trial demonstrated superiority of AzA foam to vehicle foam for primary end points that included therapeutic success rate and change in inflammatory lesion count.^13,14 Secondary end points assessed in the current analysis included patient perception of product usability, efficacy, and effect on QOL. These patient-reported outcome (PRO) results are reported here.

Methods

Study Design

The design of this phase 3 multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical trial was described in more detail in an earlier report.¹³ This study was approved by all appropriate institutional review boards. Eligible participants were 18 years and older with moderate or severe PPR, 12 to 50 inflammatory lesions, and persistent erythema with or without telangiectasia. Exclusion criteria included known nonresponse to AzA, current or prior use (within 6 weeks of randomization) of noninvestigational products to treat rosacea, and presence of other dermatoses that could interfere with rosacea evaluation.

Participants were randomized into the AzA foam or vehicle group (1:1 ratio). The study medication (0.5 g) or vehicle foam was applied twice daily to the entire face until the end of treatment (EoT) at 12 weeks. Efficacy and safety parameters were evaluated at baseline and at 4, 8, and 12 weeks of treatment, and at a follow-up visit 4 weeks after EoT (week 16).

Results for the coprimary efficacy end points—therapeutic success rate according to investigator global assessment and nominal change in inflammatory lesion count—were previously reported,¹³ as well as secondary efficacy outcomes including change in inflammatory lesion count, therapeutic response rate, and change in erythema rating.¹⁴

Patient-Reported Secondary Efficacy Outcomes

The secondary PRO end points were patient-reported global assessment of treatment response (rated as excellent, good, fair, none, or worse), global assessment of tolerability (rated as excellent, good, acceptable despite minor irritation, less acceptable due to continuous irritation, not acceptable, or no opinion), and opinion on cosmetic acceptability and practicability of product use in areas adjacent to the hairline (rated as very good, good, satisfactory, poor, or no opinion).

Additionally, QOL was measured by 3 validated standardized PRO tools, including the Rosacea Quality of Life Index (RosaQOL),¹⁵ the EuroQOL 5-dimension 5-level questionnaire (EQ-5D-5L),¹⁶ and the Dermatology Life Quality Index (DLQI). The RosaQOL is a rosacea-specific instrument assessing 3 constructs: (1) symptom, (2) emotion, and (3) function. The EQ-5D-5L questionnaire measures overall health status and comprises 5 constructs: (1) mobility, (2) self-care, (3) usual activities, (4) pain/discomfort, and (5) anxiety/depression. The DLQI is a general, dermatology-oriented instrument categorized into 6 constructs: (1) symptoms and feelings, (2) daily activities, (3) leisure, (4) work and school, (5) personal relationships, and (6) treatment.

Statistical Analyses

Patient-reported outcomes were analyzed in an exploratory manner and evaluated at EoT relative to baseline. Self-reported global assessment of treatment response and change in RosaQOL, EQ-5D-5L, and DLQI scores between AzA foam and vehicle foam groups were evaluated using the Wilcoxon rank sum test. Categorical change in the number of participants achieving an increase of 5 or more points in overall DLQI score was evaluated using a χ² test.

Safety

Safety was analyzed for all randomized patients who were dispensed any study medication. All analyses were performed using SAS version 9.2.

Results

Of the 961 participants included in the study, 483 were randomized to receive AzA foam and 478 were randomized to receive vehicle foam. The mean age was 51.5 years, and the majority of participants were female (73.0%) and white (95.5%)(Table). At baseline, 834 (86.8%) participants had moderate PPR and 127 (13.2%) had severe PPR. The mean inflammatory lesion count (SD) was 21.4 (8.9). No significant differences in baseline characteristics were observed between treatment groups.

Patient-reported global assessment of treatment response differed between treatment groups at EoT (P<.001)(Figure 1). Higher ratings of treatment response were reported among the AzA foam group (excellent, 17.2%; good, 40.0%) versus vehicle foam (excellent, 9.7%; good, 35.0%). The number of participants reporting no treatment response was 13.1% in the AzA foam group, with 1.8% reporting worsening of their condition, while 19.4% of participants in the vehicle foam group reported no response, with 6.3% reporting worsening of their condition (Figure 1).

The incidence of drug-related adverse events (AEs) was greater in the AzA foam group versus the vehicle foam group (7.7% vs 4.8%). Drug-related AEs occurring in 1% of the AzA foam group were application-site pain including tenderness, stinging, and burning (3.5% for AzA foam vs 1.3% for vehicle foam); application-site pruritus (1.4% vs 0.4%); and application-site dryness (1.0% vs 0.6%). One drug-related AE of severe intensity—application-site dermatitis—occurred in the vehicle foam group; all other drug-related AEs were mild or moderate.¹⁴ More detailed safety results are described in a previous report.¹³

Comment

The PRO outcome data reported here are consistent with previously reported statistically significant improvements in investigator-assessed primary end points for the treatment of PPR with AzA foam.^13,14 The data demonstrate that AzA foam benefits both clinical and patient-oriented dimensions of rosacea disease burden and suggest an association between positive treatment response and improved QOL.

Specifically, patient evaluation of treatment response to AzA foam was highly favorable, with 57.2% reporting excellent or good response and 85.1% reporting positive response overall. Recognizing the relapsing-remitting course of PPR, only 1.8% of the AzA foam group experienced worsening of disease at EoT.

The DLQI and RosaQOL instruments revealed notable improvements in QOL from baseline for both treatment groups. Although no significant differences in RosaQOL scores were observed between groups at EoT, significant differences in DLQI scores were detected. Almost one-quarter of participants in the AzA foam group achieved at least a 5-point improvement in DLQI score, exceeding the 4-point threshold for clinically meaningful change.¹⁷ Although little change in EQ-5D-5L scores was observed at EoT for both groups with no between-group differences, this finding is not unexpected, as this instrument assesses QOL dimensions such as loss of function, mobility, and ability to wash or dress, which are unlikely to be compromised in most rosacea patients.

Our results also underscore the importance of vehicle in the treatment of compromised skin. Studies of topical treatments for other dermatoses suggest that vehicle properties may reduce disease severity and improve QOL independent of active ingredients.^10,18 For example, ease of application, minimal residue, and less time spent in application may explain the superiority of foam to other vehicles in the treatment of psoriasis.¹⁸ Our data demonstrating high cosmetic favorability of AzA foam are consistent with these prior observations. Increased tolerability of foam formulations also may affect response to treatment, in part by supporting adherence.¹⁸ Most participants receiving AzA foam described tolerability as excellent or good, and the discontinuation rate was low (1.2% of participants in the AzA foam group left the study due to AEs) in the setting of near-complete dosage administration (97% of expected doses applied).¹³

Conclusion

These results indicate that use of AzA foam as well as its novel vehicle results in high patient satisfaction and improved QOL. Although additional research is necessary to further delineate the relationship between PROs and other measures of clinical efficacy, our data demonstrate a positive treatment experience as perceived by patients that parallels the clinical efficacy of AzA foam for the treatment of PPR.^13,14

Acknowledgment

Editorial support through inVentiv Medical Communications (New York, New York) was provided by Bayer Pharmaceuticals.

BOSTON – Shortening the radiation dosing schedule by 3 weeks in men with early-stage, low-risk prostate cancer does not appear to result in worse outcomes or diminished quality of life, according to investigators in the NRG Oncology/RTOG 0415 trial.

Efficacy results from the trial, reported at the annual meeting of the American Society for Radiation Oncology, showed that a radiation schedule of 70 Gy in 28 fractions delivered over 5.6 weeks was not inferior to 73.8 Gy delivered in 41 fractions over 8.2 weeks in terms of disease-free, progression-free, or overall survival.

Courtesy ASTRO

BOSTON – Shortening the radiation dosing schedule by 3 weeks in men with early-stage, low-risk prostate cancer does not appear to result in worse outcomes or diminished quality of life, according to investigators in the NRG Oncology/RTOG 0415 trial.

Efficacy results from the trial, reported at the annual meeting of the American Society for Radiation Oncology, showed that a radiation schedule of 70 Gy in 28 fractions delivered over 5.6 weeks was not inferior to 73.8 Gy delivered in 41 fractions over 8.2 weeks in terms of disease-free, progression-free, or overall survival.

Courtesy ASTRO

BOSTON – Shortening the radiation dosing schedule by 3 weeks in men with early-stage, low-risk prostate cancer does not appear to result in worse outcomes or diminished quality of life, according to investigators in the NRG Oncology/RTOG 0415 trial.

Efficacy results from the trial, reported at the annual meeting of the American Society for Radiation Oncology, showed that a radiation schedule of 70 Gy in 28 fractions delivered over 5.6 weeks was not inferior to 73.8 Gy delivered in 41 fractions over 8.2 weeks in terms of disease-free, progression-free, or overall survival.

Courtesy ASTRO

Folliculotropic Mycosis Fungoides

Folliculotropic mycosis fungoides (FMF) is a variant of mycosis fungoides (MF) that occurs mostly in adults with a male predilection. The disease clinically favors the head and neck. Patients commonly present with pruritic papules that often are grouped, alopecia, and frequent secondary bacterial infections. Less commonly patients present with acneiform lesions and mucinorrhea. Patients often experience more pruritus in FMF than in classic MF, which can provide a good means of assessing disease activity. Disease-specific 5-year survival is approximately 70% to 80%, which is worse than classic plaque-stage MF and similar to tumor-stage MF.¹

Treatment of FMF differs from classic MF in that the lesions are less responsive to skin-targeted therapies due to the perifollicular nature of dermal infiltrates. Superficial skin lesions can be treated with psoralen plus UVA (PUVA) therapy. Other options include PUVA in combination with interferon alfa or retinoids and local radiotherapy for solitary thick tumors; however, in patients who have more infiltrative skin lesions or had PUVA therapy that failed, total skin electron beam therapy may be required.²

On histologic examination, there typically is perivascular and periadnexal localization of dermal infiltrates with varied involvement of the follicular epithelium and damage to hair follicles by atypical small, medium, and large hyperchromatic lymphocytes with cerebriform nuclei. Mucinous degeneration of the follicular epithelium can be seen, as highlighted on Alcian blue staining, and a mixed infiltrate of eosinophils and plasma cells often is present (quiz image and Figure 1). Frequent sparing of the epidermis is noteworthy.^2-4 In most cases, the neoplastic T lymphocytes are characterized by a CD3⁺CD4⁺CD8^-immunophenotype as is seen in classic MF. Sometimes an admixture of CD30⁺ blast cells is seen.¹

Histologic differential considerations for FMF include eosinophilic pustular folliculitis (EPF), primary follicular mucinosis, lupus erythematosus, and pityrosporum folliculitis.

Eosinophilic pustular folliculitis has several clinical subtypes, such as classic Ofuji disease and immunosuppression-associated EPF secondary to human immunodeficiency virus. Histologically, EPF is characterized by spongiosis of the hair follicle epithelium with exocytosis of a mixed infiltrate of lymphocytes and eosinophils extending from the sebaceous gland and its duct to the infundibulum with formation of hallmark eosinophilic pustules (Figure 2). Infiltration of neutrophils in inflamed lesions generally is seen. Eosinophilic pustular folliculitis is an important differential for FMF, as follicular mucinosis has been observed in lesions of EPF.⁵ Both EPF and FMF can exhibit eosinophils and lymphocytes in the upper dermis, spongiosis of the hair follicle epithelium, and mucinous degeneration of follicles,⁶ though lymphocytic atypia and relatively fewer eosinophils are suggestive of the latter.

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Primary follicular mucinosis (PFM) tends to occur as a solitary lesion in younger female patients in contrast to the multiple lesions that typically appear in older male patients with FMF. Histologically, PFM usually manifests as large, cystic, mucin-filled spaces and polyclonal perivascular and periadnexal lymphocytic infiltrate without notable cellular atypia or epidermotropism (Figure 3). Because follicular mucinosis is a common feature of FMF, its distinction from PFM can be challenging and often is aided by the absence of cellular atypia and relatively mild lymphocytic infiltrate in the latter.⁷

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Cutaneous lupus erythematosus with its characteristic folliculocentric lymphocytic infiltration and associated dermal mucin also qualifies as a potential differential possibility for FMF; however, the perivascular and periadnexal pattern of lymphocytic infiltration as well as the localization of mucin to the reticular dermal interstitium^8,9 are key histopathologic distinctions (Figure 4). Furthermore, although the histologic presentation of lupus erythematosus can be variable, it also classically shows interface dermatitis, basement membrane thickening, and follicular plugging.

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Pityrosporum folliculitis is the most common cause of fungal folliculitis and is caused by the Malassezia species. On histology, there typically is an unremarkable epithelium with plugged follicles and suppurative folliculitis. Serial sections of the biopsy specimen often are required to identify dilated, follicle-containing, budding yeast cells (Figure 5). Organisms are located predominantly within the infundibulum and orifice of follicular lumen, are positive for periodic acid-Schiff, and are diastase resistant.¹⁰

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Folliculotropic Mycosis Fungoides

Folliculotropic mycosis fungoides (FMF) is a variant of mycosis fungoides (MF) that occurs mostly in adults with a male predilection. The disease clinically favors the head and neck. Patients commonly present with pruritic papules that often are grouped, alopecia, and frequent secondary bacterial infections. Less commonly patients present with acneiform lesions and mucinorrhea. Patients often experience more pruritus in FMF than in classic MF, which can provide a good means of assessing disease activity. Disease-specific 5-year survival is approximately 70% to 80%, which is worse than classic plaque-stage MF and similar to tumor-stage MF.¹

Treatment of FMF differs from classic MF in that the lesions are less responsive to skin-targeted therapies due to the perifollicular nature of dermal infiltrates. Superficial skin lesions can be treated with psoralen plus UVA (PUVA) therapy. Other options include PUVA in combination with interferon alfa or retinoids and local radiotherapy for solitary thick tumors; however, in patients who have more infiltrative skin lesions or had PUVA therapy that failed, total skin electron beam therapy may be required.²

On histologic examination, there typically is perivascular and periadnexal localization of dermal infiltrates with varied involvement of the follicular epithelium and damage to hair follicles by atypical small, medium, and large hyperchromatic lymphocytes with cerebriform nuclei. Mucinous degeneration of the follicular epithelium can be seen, as highlighted on Alcian blue staining, and a mixed infiltrate of eosinophils and plasma cells often is present (quiz image and Figure 1). Frequent sparing of the epidermis is noteworthy.^2-4 In most cases, the neoplastic T lymphocytes are characterized by a CD3⁺CD4⁺CD8^-immunophenotype as is seen in classic MF. Sometimes an admixture of CD30⁺ blast cells is seen.¹

Histologic differential considerations for FMF include eosinophilic pustular folliculitis (EPF), primary follicular mucinosis, lupus erythematosus, and pityrosporum folliculitis.

Eosinophilic pustular folliculitis has several clinical subtypes, such as classic Ofuji disease and immunosuppression-associated EPF secondary to human immunodeficiency virus. Histologically, EPF is characterized by spongiosis of the hair follicle epithelium with exocytosis of a mixed infiltrate of lymphocytes and eosinophils extending from the sebaceous gland and its duct to the infundibulum with formation of hallmark eosinophilic pustules (Figure 2). Infiltration of neutrophils in inflamed lesions generally is seen. Eosinophilic pustular folliculitis is an important differential for FMF, as follicular mucinosis has been observed in lesions of EPF.⁵ Both EPF and FMF can exhibit eosinophils and lymphocytes in the upper dermis, spongiosis of the hair follicle epithelium, and mucinous degeneration of follicles,⁶ though lymphocytic atypia and relatively fewer eosinophils are suggestive of the latter.

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Primary follicular mucinosis (PFM) tends to occur as a solitary lesion in younger female patients in contrast to the multiple lesions that typically appear in older male patients with FMF. Histologically, PFM usually manifests as large, cystic, mucin-filled spaces and polyclonal perivascular and periadnexal lymphocytic infiltrate without notable cellular atypia or epidermotropism (Figure 3). Because follicular mucinosis is a common feature of FMF, its distinction from PFM can be challenging and often is aided by the absence of cellular atypia and relatively mild lymphocytic infiltrate in the latter.⁷

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Cutaneous lupus erythematosus with its characteristic folliculocentric lymphocytic infiltration and associated dermal mucin also qualifies as a potential differential possibility for FMF; however, the perivascular and periadnexal pattern of lymphocytic infiltration as well as the localization of mucin to the reticular dermal interstitium^8,9 are key histopathologic distinctions (Figure 4). Furthermore, although the histologic presentation of lupus erythematosus can be variable, it also classically shows interface dermatitis, basement membrane thickening, and follicular plugging.

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Pityrosporum folliculitis is the most common cause of fungal folliculitis and is caused by the Malassezia species. On histology, there typically is an unremarkable epithelium with plugged follicles and suppurative folliculitis. Serial sections of the biopsy specimen often are required to identify dilated, follicle-containing, budding yeast cells (Figure 5). Organisms are located predominantly within the infundibulum and orifice of follicular lumen, are positive for periodic acid-Schiff, and are diastase resistant.¹⁰

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Folliculotropic Mycosis Fungoides

Folliculotropic mycosis fungoides (FMF) is a variant of mycosis fungoides (MF) that occurs mostly in adults with a male predilection. The disease clinically favors the head and neck. Patients commonly present with pruritic papules that often are grouped, alopecia, and frequent secondary bacterial infections. Less commonly patients present with acneiform lesions and mucinorrhea. Patients often experience more pruritus in FMF than in classic MF, which can provide a good means of assessing disease activity. Disease-specific 5-year survival is approximately 70% to 80%, which is worse than classic plaque-stage MF and similar to tumor-stage MF.¹

Treatment of FMF differs from classic MF in that the lesions are less responsive to skin-targeted therapies due to the perifollicular nature of dermal infiltrates. Superficial skin lesions can be treated with psoralen plus UVA (PUVA) therapy. Other options include PUVA in combination with interferon alfa or retinoids and local radiotherapy for solitary thick tumors; however, in patients who have more infiltrative skin lesions or had PUVA therapy that failed, total skin electron beam therapy may be required.²

On histologic examination, there typically is perivascular and periadnexal localization of dermal infiltrates with varied involvement of the follicular epithelium and damage to hair follicles by atypical small, medium, and large hyperchromatic lymphocytes with cerebriform nuclei. Mucinous degeneration of the follicular epithelium can be seen, as highlighted on Alcian blue staining, and a mixed infiltrate of eosinophils and plasma cells often is present (quiz image and Figure 1). Frequent sparing of the epidermis is noteworthy.^2-4 In most cases, the neoplastic T lymphocytes are characterized by a CD3⁺CD4⁺CD8^-immunophenotype as is seen in classic MF. Sometimes an admixture of CD30⁺ blast cells is seen.¹

Histologic differential considerations for FMF include eosinophilic pustular folliculitis (EPF), primary follicular mucinosis, lupus erythematosus, and pityrosporum folliculitis.

Eosinophilic pustular folliculitis has several clinical subtypes, such as classic Ofuji disease and immunosuppression-associated EPF secondary to human immunodeficiency virus. Histologically, EPF is characterized by spongiosis of the hair follicle epithelium with exocytosis of a mixed infiltrate of lymphocytes and eosinophils extending from the sebaceous gland and its duct to the infundibulum with formation of hallmark eosinophilic pustules (Figure 2). Infiltration of neutrophils in inflamed lesions generally is seen. Eosinophilic pustular folliculitis is an important differential for FMF, as follicular mucinosis has been observed in lesions of EPF.⁵ Both EPF and FMF can exhibit eosinophils and lymphocytes in the upper dermis, spongiosis of the hair follicle epithelium, and mucinous degeneration of follicles,⁶ though lymphocytic atypia and relatively fewer eosinophils are suggestive of the latter.

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Primary follicular mucinosis (PFM) tends to occur as a solitary lesion in younger female patients in contrast to the multiple lesions that typically appear in older male patients with FMF. Histologically, PFM usually manifests as large, cystic, mucin-filled spaces and polyclonal perivascular and periadnexal lymphocytic infiltrate without notable cellular atypia or epidermotropism (Figure 3). Because follicular mucinosis is a common feature of FMF, its distinction from PFM can be challenging and often is aided by the absence of cellular atypia and relatively mild lymphocytic infiltrate in the latter.⁷

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Cutaneous lupus erythematosus with its characteristic folliculocentric lymphocytic infiltration and associated dermal mucin also qualifies as a potential differential possibility for FMF; however, the perivascular and periadnexal pattern of lymphocytic infiltration as well as the localization of mucin to the reticular dermal interstitium^8,9 are key histopathologic distinctions (Figure 4). Furthermore, although the histologic presentation of lupus erythematosus can be variable, it also classically shows interface dermatitis, basement membrane thickening, and follicular plugging.

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Pityrosporum folliculitis is the most common cause of fungal folliculitis and is caused by the Malassezia species. On histology, there typically is an unremarkable epithelium with plugged follicles and suppurative folliculitis. Serial sections of the biopsy specimen often are required to identify dilated, follicle-containing, budding yeast cells (Figure 5). Organisms are located predominantly within the infundibulum and orifice of follicular lumen, are positive for periodic acid-Schiff, and are diastase resistant.¹⁰

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).