Adam J. Friedman, MD

Fatigue is defined as “an overwhelming, sustained sense of exhaustion and decreased capacity for physical and mental work,”¹ and it is experienced by most patients with chronic disease. There are 2 types of fatigue: acute and chronic.² Acute fatigue typically is caused by an identified insult (ie, injury), is self-limited, and is relieved by rest. Chronic fatigue, which may have multiple unknown causes, may accompany chronic illness and lasts longer than 6 months.² In chronic disease, fatigue can originate peripherally (neu romuscular dysfunction outside of the central nervous system) or centrally (neurotransmitter activity within the central nervous system). Generally, central fatigue is more relevant in patients with chronic disease; however, both central and peripheral fatigue frequently coexist.

Fatigue, even with its accepted definition, is a nonspecific symptom, making it difficult to measure. Because of its subjective nature and the lack of effective therapies, clinicians often ignore fatigue. Still, patients with chronic disease continue to cite fatigue as one of the most challenging aspects of their disease that frequently decreases their quality of life (QOL).²

Fatigue has been well recognized in a number of chronic inflammatory diseases such as rheumatoid arthritis,^3,4 systemic lupus erythematosus,⁵ fibromyalgia,⁶ and primary Sjögren syndrome.⁷ Similarly, fatigue is a frequent concern among patients with psoriasis and psoriatic arthritis.⁸ Given the prevalence and significance of psoriasis-associated fatigue,⁹ new efforts are needed to understand its pathophysiology, to develop new metrics for its evaluation, and to investigate therapeutic strategies to target it clinically. The following discussion provides an overview of the association between fatigue and psoriatic disease as well as the commonly used metrics for evaluating fatigue. Possible therapeutic agents with which to manage fatigue in this patient population also are provided.

Pathogenesis of Psoriasis-Associated Fatigue

Immunologic/Molecular Basis for Psoriasis-Associated Fatigue

Several theories aim to explain the pathophysiology of fatigue in patients with psoriatic disease. Psoriasis is a chronic inflammatory disease characterized by sharply demarcated erythematous plaques with adherent scale (Figure 1). Many in vitro studies have demonstrated the complex cytokine network that underlies the histopathologic alterations we observe in psoriatic lesions.^10,11 Until recently, psoriasis was considered a type I autoimmune disease with strong T_H1 signaling, influenced by IFN-γ, IL-2, and IL-12.¹² T_H1-producing proinflammatory cytokines, tumor necrosis factor α (TNF-α), and IFN-γ are elevated in psoriatic lesions.¹³ Studies on the efficacy of ustekinumab, a monoclonal antibody targeting IL-12 and IL-23, demonstrate the integral role of the immune system in psoriasis pathogenesis as the production of IL-12 polarizes T cells into T_H1 cells.^14,15 However, in recent years, T_H17 cells have been linked to autoimmune inflammation¹⁶ and have been localized to the dermis in psoriatic lesions.¹⁷

Among a milieu of inflammatory cytokines, IL-1 is crucial for the early differentiation of T_H17 cells.¹⁸ The IL-1 family of cytokines serve as primary mediators of inflammation with members including the IL-1 agonists (IL-1α, IL-1β),¹⁹ IL-1 receptor antagonist (IL-1RA),²⁰ and IL-1 receptor type II (IL-1RII).²⁰ The latter two inhibit IL-1 agonists from binding to their receptor (IL-1RI).^19,20 A study by Yoshinaga et al²¹ investigated the level of inflammatory cytokines within lesional and nonlesional psoriatic skin, finding elevated levels of IL-1β in lesional skin. Another study found that IL-1β expression was increased 357% within biopsied psoriasiform lesions from flaky-skin mice, a useful model to examine the hyperproliferative alterations in the skin. This same study revealed that in vivo IL-1β neutralization alleviated the psoriasiform features in these same mice, suggesting IL-1β is integral to psoriasis pathogenesis.²²

Evidence indicates that the aforementioned inflammatory mediators may contribute to psoriasis-associated fatigue. When the peripheral immune system is continuously activated, such as in psoriasis, the peripherally produced proinflammatory cytokines and subsequent immune signaling are monitored by the brain via afferent nerves, cytokine transporters at the blood-brain barrier, and IL-1 receptors on macrophages and endothelial cells of brain venules.²³ For example, subseptic doses of lipopolysaccharide injected into rats induced messenger RNA expression of IL-1β in the choroid plexus, circumventricular organs, and the meninges,²⁴ sites where cytokines can enter the blood-brain barrier via diffusion or cytokine transporters.²³ These results may suggest a pathway that relays the peripheral immune signals that underlie psoriatic disease to the brain, resulting in activation of brain circuitry that mediates various negative behavioral responses, including fatigue.²³ Following a central IL-1β infusion in mice, investigators found a significant decrease in the running performance (P<.01)²⁵; the same infusion increased lethargy, malaise, and fatigue in rats.²⁶ Interestingly, administration of IL-1RA significantly increased run time to fatigue (P<.05), supporting the hypothesis that IL-1β plays an important role in fatigue.²⁵ Other investigators found that administration of many cytokines (IL-1β, IL-6, TNF-α) into rats induced depressivelike behaviors²⁷ and suppressed locomotor activity.²⁸ Lastly, another investigation found that IL-1RI knockout mice were resistant to symptoms of sickness, such as social exploration, anorexia, immobility, and weight loss, following IL-1β injections.²⁹ Although the translatability of these studies to humans is not entirely clear, one study found that the proinflammatory cytokines IL-1 and TNF-α were elevated in patients with chronic fatigue syndrome.³⁰ Furthermore, a 2013 systematic review found that several serum inflammatory markers including IL-6 and TNF-α were elevated in patients with severe plaque psoriasis compared to healthy controls.³¹ Therefore, these shared inflammatory cytokines may contribute to and explain the pathogenesis of both fatigue and psoriasis.

Confounding Factors

Although fatigue may be partially explained by the joint effect of inflammatory mediators on both the skin and the brain, there is evidence to suggest that other confounding factors may modify this association and affect its clinical presentation. The pathophysiology of fatigue in psoriasis may not be strictly immunologic; the environmental, psychological, and physical effects of psoriasis may all contribute to and perpetuate fatigue.^9,32,33 Interestingly, the pathophysiology of psoriasis involves many cytokines also known to contribute to features of the metabolic syndrome.³⁴ For example, elevated levels of free fatty acids, TNF-α, and IL-6 act in concert to promote inflammation, alter glucose metabolism, and dysregulate endothelial cell function, contributing to dyslipidemia, insulin resistance, and cardiovascular disease.³⁵ A systematic review found a high prevalence of metabolic syndrome in patients with psoriasis and have found that those with more severe disease have an even greater risk for developing metabolic syndrome.³⁴

Numerous studies have documented that upward of 80% of patients consider psoriasis to have a major impact on their QOL.^36-38 The National Psoriasis Foundation assessed patients’ perspectives on the social, physical, and psychological aspects of their disease, finding that health-related QOL is impaired in patients with psoriatic disease.^36,39 Patients reported their disease interfered with overall emotional well-being and life enjoyment and cited feelings of anger, frustration, helplessness, embarrassment, and self-consciousness, all of which can influence fatigue.^36,39 Pain and pruritus (Figure 2) can interrupt sleep and thus may also contribute to symptoms of fatigue.⁴⁰ Patients with psoriatic disease have a higher incidence of both depression and anxiety compared with the general population. Another study found that patient-reported factors of disability, pain, and fatigue were associated with clinical depression and anxiety; however, these factors are commonly observed in this cohort of patients and thus it is unclear whether they are predictors of or the result of depression.³⁸

Furthermore, psoriatic disease leads to considerable economic burdens; one study (N=5604) found that among respondents who were not employed, 92% reported they were unemployed solely due to their psoriatic disease.³⁶ One study explored the relationship between fatigue, work disability, and psoriatic arthritis, finding that the association between fatigue and work productivity loss persisted after controlling for cutaneous/musculoskeletal activity.⁴¹ However, another investigation revealed contradicting results, finding that improvements in fatigue correlated with improvements in joint and skin pain.⁹

Therefore, we can conclude that the pathogenesis of psoriasis-associated fatigue is the result of a multifactorial immunologic, psychologic, and physiologic pathway that triggers symptoms of exhaustion and lethargy. Fatigue is a complex multidimensional symptom activated by psoriatic disease, directly by shared inflammatory cytokines and indirectly by factors of disease activity and psychiatric distress that inherently influence somatic manifestations of fatigue. Regardless of its pathogenesis, these data and observations highlight the importance of fatigue symptoms and the need for new therapeutics to target this debilitating disease.

Measurement of Fatigue in Psoriasis

A patient’s level of fatigue is not objectively quantifiable. For this reason, clinicians and investigators have relied on self-report instruments to gauge fatigue (Table).^{9,38,40,42-53} These survey instruments each have distinct advantages and disadvantages, though all are subject to common difficulties. Many rely on the literacy of patients and their interpretation of each item, which can make completing the survey difficult and yield variability between subjects. Patients are inaccurate in self-reporting even measurable characteristics such as height and weight,⁵⁴ which introduces an element of uncertainty in the reporting of subjective symptoms (ie, fatigue). Lastly, there are several biases implicit in self-reporting including recall bias, selective recall, and digit preference.⁵⁵

When analyzing fatigue due to a chronic disease, several symptoms may be misconstrued or interfere with the interpretation of fatigue. For instance, patients with multiple sclerosis may confuse neuropathy-associated muscle weakness with fatigue. These interactions can be controlled for in self-report instruments and validated through careful study of many patients. Disease-specific questionnaires have been validated for use in several diseases,^56-58 though none have been validated for cutaneous psoriasis in the absence of psoriatic arthritis. The need for validated instruments in psoriasis is great, as symptoms such as sleep disturbance and arthralgia may confound metrics of fatigue.

Thus far, 4 self-report instruments have been used to study fatigue in psoriasis: the medical outcomes 36-item short-form health survey (SF-36), the functional assessment of chronic illness therapy-fatigue, the fatigue severity scale (FSS), and the visual analog scale (VAS) for fatigue.

The SF-36 is a 36-item survey designed to measure 8 dimensions of health status in patients with chronic disease.⁵⁹ Items are answered using a 3- to 6-point Likert scale, or in a yes/no format. Although the SF-36 is typically administered by a trained interviewer, it relies on a patient’s interpretation of language that must be used to describe their level of fatigue, which may not capture the full range of symptoms. Also, the length of the survey makes it impractical for use in clinical practice.

The functional assessment of chronic illness therapy-fatigue survey is validated for use in psoriatic arthritis. It is similar to the SF-36 in its use of a 5-point Likert scale to answer each of 13 items. It improves on the SF-36 model by including questions about associated symptoms (ie, pain, medication side effects) that may interfere with the measurement of fatigue. It also investigates the impact of fatigue on several areas of functioning. However, it is subject to the same pitfalls of interpretation and a rigid scale with which to answer questions.

The FSS is another Likert scale–based instrument that gauges both level of fatigue and its impact using 9 items and a 7-point scale. Investigators used the FSS to uncover an association between increasing fatigue scores and depression in patients with psoriatic disease.³⁸

The VAS overcomes many of the language and interpretation issues inherent in Likert scale–based instruments. Patients are presented with a single item in which they are asked to plot their level of fatigue on a continuous line, with one end representing no fatigue and the other end the worst possible fatigue. Although VAS adds simplicity of response and removes some ambiguity from surveying, it provides no information about the functional impact of fatigue on patients. It also does not provide a method to control for other symptoms.

Treatment of Psoriasis-Associated Fatigue

Much of our understanding of psoriasis-associated fatigue arises from therapeutic clinical trials. Because increased concentrations of proinflammatory cytokines are associated with fatigue, it has been suggested that blocking these cytokines with biologic agents may relieve fatigue symptoms. For example, investigators found that patients treated with etanercept, a soluble TNF-α receptor fusion protein, had clinically meaningful improvement in fatigue compared to those receiving placebo, with sustained improvements at 96 weeks.^9,47 We must note, however, that the decrease in fatigue correlated with improvements in cutaneous/arthritic pain. Nevertheless, another study found that treatment with the same drug decreased fatigue in patients with psoriasis, even after controlling for improvements in the psoriasis area severity index score.⁴⁰ Adalimumab is another monoclonal antibody for TNF-α that has caused a notable decline in fatigue symptoms.⁴⁹

These data suggest that biologic agents are useful in the treatment of fatigue. Biologic agents are frequently administered to patients with moderate to severe psoriasis in whom more conservative treatments previously failed. However, cutaneous/arthritic disease severity is not always correlated with fatigue, so these data may urge clinicians to lower their threshold for treatment with biologics in patients with substantial fatigue symptoms. Although further investigations are necessary, we may even consider using a biologic therapy for severe fatigue in those without severe psoriatic disease.

Conclusion

Fatigue is a multidimensional symptom, impacted both directly and indirectly by psoriasis pathophysiology. The prevalence of fatigue within this patient population suggests that clinicians need to recognize the symptom as a core domain in psoriasis evaluation. Although a host of metrics have been used to quantify/qualify fatigue, there remains a need for a validated instrument for assessing fatigue in patients with psoriatic disease.

Biologic agents have proven useful in the treatment of psoriasis-associated fatigue. The central role of proinflammatory cytokines to both fatigue and psoriasis pathogenesis provide insight into potential treatment targets. Understanding the overlapping pathophysiology of psoriasis and fatigue provides an avenue for developing innovative strategies to target molecules implicated in the activation of the immune system. In the future, it may be possible to predict the severity of fatigue by measuring the levels of serum inflammatory cytokines; in fact, a new study aims to identify a panel of soluble biomarkers that can predict joint damage in psoriatic arthritis.⁶⁰ Taken together, the findings described suggest that further study is needed to characterize, measure, and treat psoriasis-associated fatigue.

Fatigue is defined as “an overwhelming, sustained sense of exhaustion and decreased capacity for physical and mental work,”¹ and it is experienced by most patients with chronic disease. There are 2 types of fatigue: acute and chronic.² Acute fatigue typically is caused by an identified insult (ie, injury), is self-limited, and is relieved by rest. Chronic fatigue, which may have multiple unknown causes, may accompany chronic illness and lasts longer than 6 months.² In chronic disease, fatigue can originate peripherally (neu romuscular dysfunction outside of the central nervous system) or centrally (neurotransmitter activity within the central nervous system). Generally, central fatigue is more relevant in patients with chronic disease; however, both central and peripheral fatigue frequently coexist.

Fatigue, even with its accepted definition, is a nonspecific symptom, making it difficult to measure. Because of its subjective nature and the lack of effective therapies, clinicians often ignore fatigue. Still, patients with chronic disease continue to cite fatigue as one of the most challenging aspects of their disease that frequently decreases their quality of life (QOL).²

Fatigue has been well recognized in a number of chronic inflammatory diseases such as rheumatoid arthritis,^3,4 systemic lupus erythematosus,⁵ fibromyalgia,⁶ and primary Sjögren syndrome.⁷ Similarly, fatigue is a frequent concern among patients with psoriasis and psoriatic arthritis.⁸ Given the prevalence and significance of psoriasis-associated fatigue,⁹ new efforts are needed to understand its pathophysiology, to develop new metrics for its evaluation, and to investigate therapeutic strategies to target it clinically. The following discussion provides an overview of the association between fatigue and psoriatic disease as well as the commonly used metrics for evaluating fatigue. Possible therapeutic agents with which to manage fatigue in this patient population also are provided.

Pathogenesis of Psoriasis-Associated Fatigue

Immunologic/Molecular Basis for Psoriasis-Associated Fatigue

Several theories aim to explain the pathophysiology of fatigue in patients with psoriatic disease. Psoriasis is a chronic inflammatory disease characterized by sharply demarcated erythematous plaques with adherent scale (Figure 1). Many in vitro studies have demonstrated the complex cytokine network that underlies the histopathologic alterations we observe in psoriatic lesions.^10,11 Until recently, psoriasis was considered a type I autoimmune disease with strong T_H1 signaling, influenced by IFN-γ, IL-2, and IL-12.¹² T_H1-producing proinflammatory cytokines, tumor necrosis factor α (TNF-α), and IFN-γ are elevated in psoriatic lesions.¹³ Studies on the efficacy of ustekinumab, a monoclonal antibody targeting IL-12 and IL-23, demonstrate the integral role of the immune system in psoriasis pathogenesis as the production of IL-12 polarizes T cells into T_H1 cells.^14,15 However, in recent years, T_H17 cells have been linked to autoimmune inflammation¹⁶ and have been localized to the dermis in psoriatic lesions.¹⁷

Among a milieu of inflammatory cytokines, IL-1 is crucial for the early differentiation of T_H17 cells.¹⁸ The IL-1 family of cytokines serve as primary mediators of inflammation with members including the IL-1 agonists (IL-1α, IL-1β),¹⁹ IL-1 receptor antagonist (IL-1RA),²⁰ and IL-1 receptor type II (IL-1RII).²⁰ The latter two inhibit IL-1 agonists from binding to their receptor (IL-1RI).^19,20 A study by Yoshinaga et al²¹ investigated the level of inflammatory cytokines within lesional and nonlesional psoriatic skin, finding elevated levels of IL-1β in lesional skin. Another study found that IL-1β expression was increased 357% within biopsied psoriasiform lesions from flaky-skin mice, a useful model to examine the hyperproliferative alterations in the skin. This same study revealed that in vivo IL-1β neutralization alleviated the psoriasiform features in these same mice, suggesting IL-1β is integral to psoriasis pathogenesis.²²

Evidence indicates that the aforementioned inflammatory mediators may contribute to psoriasis-associated fatigue. When the peripheral immune system is continuously activated, such as in psoriasis, the peripherally produced proinflammatory cytokines and subsequent immune signaling are monitored by the brain via afferent nerves, cytokine transporters at the blood-brain barrier, and IL-1 receptors on macrophages and endothelial cells of brain venules.²³ For example, subseptic doses of lipopolysaccharide injected into rats induced messenger RNA expression of IL-1β in the choroid plexus, circumventricular organs, and the meninges,²⁴ sites where cytokines can enter the blood-brain barrier via diffusion or cytokine transporters.²³ These results may suggest a pathway that relays the peripheral immune signals that underlie psoriatic disease to the brain, resulting in activation of brain circuitry that mediates various negative behavioral responses, including fatigue.²³ Following a central IL-1β infusion in mice, investigators found a significant decrease in the running performance (P<.01)²⁵; the same infusion increased lethargy, malaise, and fatigue in rats.²⁶ Interestingly, administration of IL-1RA significantly increased run time to fatigue (P<.05), supporting the hypothesis that IL-1β plays an important role in fatigue.²⁵ Other investigators found that administration of many cytokines (IL-1β, IL-6, TNF-α) into rats induced depressivelike behaviors²⁷ and suppressed locomotor activity.²⁸ Lastly, another investigation found that IL-1RI knockout mice were resistant to symptoms of sickness, such as social exploration, anorexia, immobility, and weight loss, following IL-1β injections.²⁹ Although the translatability of these studies to humans is not entirely clear, one study found that the proinflammatory cytokines IL-1 and TNF-α were elevated in patients with chronic fatigue syndrome.³⁰ Furthermore, a 2013 systematic review found that several serum inflammatory markers including IL-6 and TNF-α were elevated in patients with severe plaque psoriasis compared to healthy controls.³¹ Therefore, these shared inflammatory cytokines may contribute to and explain the pathogenesis of both fatigue and psoriasis.

Confounding Factors

Although fatigue may be partially explained by the joint effect of inflammatory mediators on both the skin and the brain, there is evidence to suggest that other confounding factors may modify this association and affect its clinical presentation. The pathophysiology of fatigue in psoriasis may not be strictly immunologic; the environmental, psychological, and physical effects of psoriasis may all contribute to and perpetuate fatigue.^9,32,33 Interestingly, the pathophysiology of psoriasis involves many cytokines also known to contribute to features of the metabolic syndrome.³⁴ For example, elevated levels of free fatty acids, TNF-α, and IL-6 act in concert to promote inflammation, alter glucose metabolism, and dysregulate endothelial cell function, contributing to dyslipidemia, insulin resistance, and cardiovascular disease.³⁵ A systematic review found a high prevalence of metabolic syndrome in patients with psoriasis and have found that those with more severe disease have an even greater risk for developing metabolic syndrome.³⁴

Numerous studies have documented that upward of 80% of patients consider psoriasis to have a major impact on their QOL.^36-38 The National Psoriasis Foundation assessed patients’ perspectives on the social, physical, and psychological aspects of their disease, finding that health-related QOL is impaired in patients with psoriatic disease.^36,39 Patients reported their disease interfered with overall emotional well-being and life enjoyment and cited feelings of anger, frustration, helplessness, embarrassment, and self-consciousness, all of which can influence fatigue.^36,39 Pain and pruritus (Figure 2) can interrupt sleep and thus may also contribute to symptoms of fatigue.⁴⁰ Patients with psoriatic disease have a higher incidence of both depression and anxiety compared with the general population. Another study found that patient-reported factors of disability, pain, and fatigue were associated with clinical depression and anxiety; however, these factors are commonly observed in this cohort of patients and thus it is unclear whether they are predictors of or the result of depression.³⁸

Furthermore, psoriatic disease leads to considerable economic burdens; one study (N=5604) found that among respondents who were not employed, 92% reported they were unemployed solely due to their psoriatic disease.³⁶ One study explored the relationship between fatigue, work disability, and psoriatic arthritis, finding that the association between fatigue and work productivity loss persisted after controlling for cutaneous/musculoskeletal activity.⁴¹ However, another investigation revealed contradicting results, finding that improvements in fatigue correlated with improvements in joint and skin pain.⁹

Therefore, we can conclude that the pathogenesis of psoriasis-associated fatigue is the result of a multifactorial immunologic, psychologic, and physiologic pathway that triggers symptoms of exhaustion and lethargy. Fatigue is a complex multidimensional symptom activated by psoriatic disease, directly by shared inflammatory cytokines and indirectly by factors of disease activity and psychiatric distress that inherently influence somatic manifestations of fatigue. Regardless of its pathogenesis, these data and observations highlight the importance of fatigue symptoms and the need for new therapeutics to target this debilitating disease.

Measurement of Fatigue in Psoriasis

A patient’s level of fatigue is not objectively quantifiable. For this reason, clinicians and investigators have relied on self-report instruments to gauge fatigue (Table).^{9,38,40,42-53} These survey instruments each have distinct advantages and disadvantages, though all are subject to common difficulties. Many rely on the literacy of patients and their interpretation of each item, which can make completing the survey difficult and yield variability between subjects. Patients are inaccurate in self-reporting even measurable characteristics such as height and weight,⁵⁴ which introduces an element of uncertainty in the reporting of subjective symptoms (ie, fatigue). Lastly, there are several biases implicit in self-reporting including recall bias, selective recall, and digit preference.⁵⁵

When analyzing fatigue due to a chronic disease, several symptoms may be misconstrued or interfere with the interpretation of fatigue. For instance, patients with multiple sclerosis may confuse neuropathy-associated muscle weakness with fatigue. These interactions can be controlled for in self-report instruments and validated through careful study of many patients. Disease-specific questionnaires have been validated for use in several diseases,^56-58 though none have been validated for cutaneous psoriasis in the absence of psoriatic arthritis. The need for validated instruments in psoriasis is great, as symptoms such as sleep disturbance and arthralgia may confound metrics of fatigue.

Thus far, 4 self-report instruments have been used to study fatigue in psoriasis: the medical outcomes 36-item short-form health survey (SF-36), the functional assessment of chronic illness therapy-fatigue, the fatigue severity scale (FSS), and the visual analog scale (VAS) for fatigue.

The SF-36 is a 36-item survey designed to measure 8 dimensions of health status in patients with chronic disease.⁵⁹ Items are answered using a 3- to 6-point Likert scale, or in a yes/no format. Although the SF-36 is typically administered by a trained interviewer, it relies on a patient’s interpretation of language that must be used to describe their level of fatigue, which may not capture the full range of symptoms. Also, the length of the survey makes it impractical for use in clinical practice.

The functional assessment of chronic illness therapy-fatigue survey is validated for use in psoriatic arthritis. It is similar to the SF-36 in its use of a 5-point Likert scale to answer each of 13 items. It improves on the SF-36 model by including questions about associated symptoms (ie, pain, medication side effects) that may interfere with the measurement of fatigue. It also investigates the impact of fatigue on several areas of functioning. However, it is subject to the same pitfalls of interpretation and a rigid scale with which to answer questions.

The FSS is another Likert scale–based instrument that gauges both level of fatigue and its impact using 9 items and a 7-point scale. Investigators used the FSS to uncover an association between increasing fatigue scores and depression in patients with psoriatic disease.³⁸

The VAS overcomes many of the language and interpretation issues inherent in Likert scale–based instruments. Patients are presented with a single item in which they are asked to plot their level of fatigue on a continuous line, with one end representing no fatigue and the other end the worst possible fatigue. Although VAS adds simplicity of response and removes some ambiguity from surveying, it provides no information about the functional impact of fatigue on patients. It also does not provide a method to control for other symptoms.

Treatment of Psoriasis-Associated Fatigue

Much of our understanding of psoriasis-associated fatigue arises from therapeutic clinical trials. Because increased concentrations of proinflammatory cytokines are associated with fatigue, it has been suggested that blocking these cytokines with biologic agents may relieve fatigue symptoms. For example, investigators found that patients treated with etanercept, a soluble TNF-α receptor fusion protein, had clinically meaningful improvement in fatigue compared to those receiving placebo, with sustained improvements at 96 weeks.^9,47 We must note, however, that the decrease in fatigue correlated with improvements in cutaneous/arthritic pain. Nevertheless, another study found that treatment with the same drug decreased fatigue in patients with psoriasis, even after controlling for improvements in the psoriasis area severity index score.⁴⁰ Adalimumab is another monoclonal antibody for TNF-α that has caused a notable decline in fatigue symptoms.⁴⁹

These data suggest that biologic agents are useful in the treatment of fatigue. Biologic agents are frequently administered to patients with moderate to severe psoriasis in whom more conservative treatments previously failed. However, cutaneous/arthritic disease severity is not always correlated with fatigue, so these data may urge clinicians to lower their threshold for treatment with biologics in patients with substantial fatigue symptoms. Although further investigations are necessary, we may even consider using a biologic therapy for severe fatigue in those without severe psoriatic disease.

Conclusion

Fatigue is a multidimensional symptom, impacted both directly and indirectly by psoriasis pathophysiology. The prevalence of fatigue within this patient population suggests that clinicians need to recognize the symptom as a core domain in psoriasis evaluation. Although a host of metrics have been used to quantify/qualify fatigue, there remains a need for a validated instrument for assessing fatigue in patients with psoriatic disease.

Biologic agents have proven useful in the treatment of psoriasis-associated fatigue. The central role of proinflammatory cytokines to both fatigue and psoriasis pathogenesis provide insight into potential treatment targets. Understanding the overlapping pathophysiology of psoriasis and fatigue provides an avenue for developing innovative strategies to target molecules implicated in the activation of the immune system. In the future, it may be possible to predict the severity of fatigue by measuring the levels of serum inflammatory cytokines; in fact, a new study aims to identify a panel of soluble biomarkers that can predict joint damage in psoriatic arthritis.⁶⁰ Taken together, the findings described suggest that further study is needed to characterize, measure, and treat psoriasis-associated fatigue.

Fatigue is defined as “an overwhelming, sustained sense of exhaustion and decreased capacity for physical and mental work,”¹ and it is experienced by most patients with chronic disease. There are 2 types of fatigue: acute and chronic.² Acute fatigue typically is caused by an identified insult (ie, injury), is self-limited, and is relieved by rest. Chronic fatigue, which may have multiple unknown causes, may accompany chronic illness and lasts longer than 6 months.² In chronic disease, fatigue can originate peripherally (neu romuscular dysfunction outside of the central nervous system) or centrally (neurotransmitter activity within the central nervous system). Generally, central fatigue is more relevant in patients with chronic disease; however, both central and peripheral fatigue frequently coexist.

Fatigue, even with its accepted definition, is a nonspecific symptom, making it difficult to measure. Because of its subjective nature and the lack of effective therapies, clinicians often ignore fatigue. Still, patients with chronic disease continue to cite fatigue as one of the most challenging aspects of their disease that frequently decreases their quality of life (QOL).²

Fatigue has been well recognized in a number of chronic inflammatory diseases such as rheumatoid arthritis,^3,4 systemic lupus erythematosus,⁵ fibromyalgia,⁶ and primary Sjögren syndrome.⁷ Similarly, fatigue is a frequent concern among patients with psoriasis and psoriatic arthritis.⁸ Given the prevalence and significance of psoriasis-associated fatigue,⁹ new efforts are needed to understand its pathophysiology, to develop new metrics for its evaluation, and to investigate therapeutic strategies to target it clinically. The following discussion provides an overview of the association between fatigue and psoriatic disease as well as the commonly used metrics for evaluating fatigue. Possible therapeutic agents with which to manage fatigue in this patient population also are provided.

Pathogenesis of Psoriasis-Associated Fatigue

Immunologic/Molecular Basis for Psoriasis-Associated Fatigue

Several theories aim to explain the pathophysiology of fatigue in patients with psoriatic disease. Psoriasis is a chronic inflammatory disease characterized by sharply demarcated erythematous plaques with adherent scale (Figure 1). Many in vitro studies have demonstrated the complex cytokine network that underlies the histopathologic alterations we observe in psoriatic lesions.^10,11 Until recently, psoriasis was considered a type I autoimmune disease with strong T_H1 signaling, influenced by IFN-γ, IL-2, and IL-12.¹² T_H1-producing proinflammatory cytokines, tumor necrosis factor α (TNF-α), and IFN-γ are elevated in psoriatic lesions.¹³ Studies on the efficacy of ustekinumab, a monoclonal antibody targeting IL-12 and IL-23, demonstrate the integral role of the immune system in psoriasis pathogenesis as the production of IL-12 polarizes T cells into T_H1 cells.^14,15 However, in recent years, T_H17 cells have been linked to autoimmune inflammation¹⁶ and have been localized to the dermis in psoriatic lesions.¹⁷

Among a milieu of inflammatory cytokines, IL-1 is crucial for the early differentiation of T_H17 cells.¹⁸ The IL-1 family of cytokines serve as primary mediators of inflammation with members including the IL-1 agonists (IL-1α, IL-1β),¹⁹ IL-1 receptor antagonist (IL-1RA),²⁰ and IL-1 receptor type II (IL-1RII).²⁰ The latter two inhibit IL-1 agonists from binding to their receptor (IL-1RI).^19,20 A study by Yoshinaga et al²¹ investigated the level of inflammatory cytokines within lesional and nonlesional psoriatic skin, finding elevated levels of IL-1β in lesional skin. Another study found that IL-1β expression was increased 357% within biopsied psoriasiform lesions from flaky-skin mice, a useful model to examine the hyperproliferative alterations in the skin. This same study revealed that in vivo IL-1β neutralization alleviated the psoriasiform features in these same mice, suggesting IL-1β is integral to psoriasis pathogenesis.²²

Evidence indicates that the aforementioned inflammatory mediators may contribute to psoriasis-associated fatigue. When the peripheral immune system is continuously activated, such as in psoriasis, the peripherally produced proinflammatory cytokines and subsequent immune signaling are monitored by the brain via afferent nerves, cytokine transporters at the blood-brain barrier, and IL-1 receptors on macrophages and endothelial cells of brain venules.²³ For example, subseptic doses of lipopolysaccharide injected into rats induced messenger RNA expression of IL-1β in the choroid plexus, circumventricular organs, and the meninges,²⁴ sites where cytokines can enter the blood-brain barrier via diffusion or cytokine transporters.²³ These results may suggest a pathway that relays the peripheral immune signals that underlie psoriatic disease to the brain, resulting in activation of brain circuitry that mediates various negative behavioral responses, including fatigue.²³ Following a central IL-1β infusion in mice, investigators found a significant decrease in the running performance (P<.01)²⁵; the same infusion increased lethargy, malaise, and fatigue in rats.²⁶ Interestingly, administration of IL-1RA significantly increased run time to fatigue (P<.05), supporting the hypothesis that IL-1β plays an important role in fatigue.²⁵ Other investigators found that administration of many cytokines (IL-1β, IL-6, TNF-α) into rats induced depressivelike behaviors²⁷ and suppressed locomotor activity.²⁸ Lastly, another investigation found that IL-1RI knockout mice were resistant to symptoms of sickness, such as social exploration, anorexia, immobility, and weight loss, following IL-1β injections.²⁹ Although the translatability of these studies to humans is not entirely clear, one study found that the proinflammatory cytokines IL-1 and TNF-α were elevated in patients with chronic fatigue syndrome.³⁰ Furthermore, a 2013 systematic review found that several serum inflammatory markers including IL-6 and TNF-α were elevated in patients with severe plaque psoriasis compared to healthy controls.³¹ Therefore, these shared inflammatory cytokines may contribute to and explain the pathogenesis of both fatigue and psoriasis.

Confounding Factors

Although fatigue may be partially explained by the joint effect of inflammatory mediators on both the skin and the brain, there is evidence to suggest that other confounding factors may modify this association and affect its clinical presentation. The pathophysiology of fatigue in psoriasis may not be strictly immunologic; the environmental, psychological, and physical effects of psoriasis may all contribute to and perpetuate fatigue.^9,32,33 Interestingly, the pathophysiology of psoriasis involves many cytokines also known to contribute to features of the metabolic syndrome.³⁴ For example, elevated levels of free fatty acids, TNF-α, and IL-6 act in concert to promote inflammation, alter glucose metabolism, and dysregulate endothelial cell function, contributing to dyslipidemia, insulin resistance, and cardiovascular disease.³⁵ A systematic review found a high prevalence of metabolic syndrome in patients with psoriasis and have found that those with more severe disease have an even greater risk for developing metabolic syndrome.³⁴

Numerous studies have documented that upward of 80% of patients consider psoriasis to have a major impact on their QOL.^36-38 The National Psoriasis Foundation assessed patients’ perspectives on the social, physical, and psychological aspects of their disease, finding that health-related QOL is impaired in patients with psoriatic disease.^36,39 Patients reported their disease interfered with overall emotional well-being and life enjoyment and cited feelings of anger, frustration, helplessness, embarrassment, and self-consciousness, all of which can influence fatigue.^36,39 Pain and pruritus (Figure 2) can interrupt sleep and thus may also contribute to symptoms of fatigue.⁴⁰ Patients with psoriatic disease have a higher incidence of both depression and anxiety compared with the general population. Another study found that patient-reported factors of disability, pain, and fatigue were associated with clinical depression and anxiety; however, these factors are commonly observed in this cohort of patients and thus it is unclear whether they are predictors of or the result of depression.³⁸

Furthermore, psoriatic disease leads to considerable economic burdens; one study (N=5604) found that among respondents who were not employed, 92% reported they were unemployed solely due to their psoriatic disease.³⁶ One study explored the relationship between fatigue, work disability, and psoriatic arthritis, finding that the association between fatigue and work productivity loss persisted after controlling for cutaneous/musculoskeletal activity.⁴¹ However, another investigation revealed contradicting results, finding that improvements in fatigue correlated with improvements in joint and skin pain.⁹

Therefore, we can conclude that the pathogenesis of psoriasis-associated fatigue is the result of a multifactorial immunologic, psychologic, and physiologic pathway that triggers symptoms of exhaustion and lethargy. Fatigue is a complex multidimensional symptom activated by psoriatic disease, directly by shared inflammatory cytokines and indirectly by factors of disease activity and psychiatric distress that inherently influence somatic manifestations of fatigue. Regardless of its pathogenesis, these data and observations highlight the importance of fatigue symptoms and the need for new therapeutics to target this debilitating disease.

Measurement of Fatigue in Psoriasis

A patient’s level of fatigue is not objectively quantifiable. For this reason, clinicians and investigators have relied on self-report instruments to gauge fatigue (Table).^{9,38,40,42-53} These survey instruments each have distinct advantages and disadvantages, though all are subject to common difficulties. Many rely on the literacy of patients and their interpretation of each item, which can make completing the survey difficult and yield variability between subjects. Patients are inaccurate in self-reporting even measurable characteristics such as height and weight,⁵⁴ which introduces an element of uncertainty in the reporting of subjective symptoms (ie, fatigue). Lastly, there are several biases implicit in self-reporting including recall bias, selective recall, and digit preference.⁵⁵

When analyzing fatigue due to a chronic disease, several symptoms may be misconstrued or interfere with the interpretation of fatigue. For instance, patients with multiple sclerosis may confuse neuropathy-associated muscle weakness with fatigue. These interactions can be controlled for in self-report instruments and validated through careful study of many patients. Disease-specific questionnaires have been validated for use in several diseases,^56-58 though none have been validated for cutaneous psoriasis in the absence of psoriatic arthritis. The need for validated instruments in psoriasis is great, as symptoms such as sleep disturbance and arthralgia may confound metrics of fatigue.

Thus far, 4 self-report instruments have been used to study fatigue in psoriasis: the medical outcomes 36-item short-form health survey (SF-36), the functional assessment of chronic illness therapy-fatigue, the fatigue severity scale (FSS), and the visual analog scale (VAS) for fatigue.

The SF-36 is a 36-item survey designed to measure 8 dimensions of health status in patients with chronic disease.⁵⁹ Items are answered using a 3- to 6-point Likert scale, or in a yes/no format. Although the SF-36 is typically administered by a trained interviewer, it relies on a patient’s interpretation of language that must be used to describe their level of fatigue, which may not capture the full range of symptoms. Also, the length of the survey makes it impractical for use in clinical practice.

The functional assessment of chronic illness therapy-fatigue survey is validated for use in psoriatic arthritis. It is similar to the SF-36 in its use of a 5-point Likert scale to answer each of 13 items. It improves on the SF-36 model by including questions about associated symptoms (ie, pain, medication side effects) that may interfere with the measurement of fatigue. It also investigates the impact of fatigue on several areas of functioning. However, it is subject to the same pitfalls of interpretation and a rigid scale with which to answer questions.

The FSS is another Likert scale–based instrument that gauges both level of fatigue and its impact using 9 items and a 7-point scale. Investigators used the FSS to uncover an association between increasing fatigue scores and depression in patients with psoriatic disease.³⁸

The VAS overcomes many of the language and interpretation issues inherent in Likert scale–based instruments. Patients are presented with a single item in which they are asked to plot their level of fatigue on a continuous line, with one end representing no fatigue and the other end the worst possible fatigue. Although VAS adds simplicity of response and removes some ambiguity from surveying, it provides no information about the functional impact of fatigue on patients. It also does not provide a method to control for other symptoms.

Treatment of Psoriasis-Associated Fatigue

Much of our understanding of psoriasis-associated fatigue arises from therapeutic clinical trials. Because increased concentrations of proinflammatory cytokines are associated with fatigue, it has been suggested that blocking these cytokines with biologic agents may relieve fatigue symptoms. For example, investigators found that patients treated with etanercept, a soluble TNF-α receptor fusion protein, had clinically meaningful improvement in fatigue compared to those receiving placebo, with sustained improvements at 96 weeks.^9,47 We must note, however, that the decrease in fatigue correlated with improvements in cutaneous/arthritic pain. Nevertheless, another study found that treatment with the same drug decreased fatigue in patients with psoriasis, even after controlling for improvements in the psoriasis area severity index score.⁴⁰ Adalimumab is another monoclonal antibody for TNF-α that has caused a notable decline in fatigue symptoms.⁴⁹

These data suggest that biologic agents are useful in the treatment of fatigue. Biologic agents are frequently administered to patients with moderate to severe psoriasis in whom more conservative treatments previously failed. However, cutaneous/arthritic disease severity is not always correlated with fatigue, so these data may urge clinicians to lower their threshold for treatment with biologics in patients with substantial fatigue symptoms. Although further investigations are necessary, we may even consider using a biologic therapy for severe fatigue in those without severe psoriatic disease.

Conclusion

Fatigue is a multidimensional symptom, impacted both directly and indirectly by psoriasis pathophysiology. The prevalence of fatigue within this patient population suggests that clinicians need to recognize the symptom as a core domain in psoriasis evaluation. Although a host of metrics have been used to quantify/qualify fatigue, there remains a need for a validated instrument for assessing fatigue in patients with psoriatic disease.

Biologic agents have proven useful in the treatment of psoriasis-associated fatigue. The central role of proinflammatory cytokines to both fatigue and psoriasis pathogenesis provide insight into potential treatment targets. Understanding the overlapping pathophysiology of psoriasis and fatigue provides an avenue for developing innovative strategies to target molecules implicated in the activation of the immune system. In the future, it may be possible to predict the severity of fatigue by measuring the levels of serum inflammatory cytokines; in fact, a new study aims to identify a panel of soluble biomarkers that can predict joint damage in psoriatic arthritis.⁶⁰ Taken together, the findings described suggest that further study is needed to characterize, measure, and treat psoriasis-associated fatigue.

At the recent 73rd Annual Meeting of the American Academy of Dermatology (AAD) in San Francisco, California, acne was once again a hot topic. Considerably more attention was paid to the role of androgens and, by default, antihormonal therapy as compared to prior years. Here are some of the highlights.

Spironolactone for Acne

Although not US Food and Drug Administration approved for the treatment of acne, spironolactone can be quite effective in the treatment of adult female acne due to its ability to block androgen receptors, decrease androgen production, inhibit 5α-reductase, and increase sexual hormone–binding protein. The question that often comes up is, how frequently do you need to check serum potassium levels, given that this drug is a potassium-sparing diuretic? According to both a poster at the AAD (P1296) and a study (the largest of its kind) published online on March 22 by Plovanich et al in JAMA Dermatology, the answer is not often or possibly not at all in young, otherwise-healthy women. Who should be checked then? Patients who have known cardiac and renal disease or impaired hepatic functioning as well as patients taking angiotensin-converting enzyme inhibitors, aldosterone blockers, angiotensin II antagonists, nonsteroidal anti-inflammatory drugs, or potassium supplementation. Be cautious with patients on digoxin and lithium, as spironolactone can increase their serum concentration and half-life.

Isotretinoin Risk

During a symposium (Acne Treatment Controversies), Dr. Diane M. Thiboutot discussed what’s new in the world of isotretinoin safety myths as well as useful tips to improve outcomes. The most recent data do not support a link between isotretinoin and inflammatory bowel disease. Prednisone and lower doses of isotretinoin can be used when initiating in a patient with severe inflammatory acne. Isotretinoin use also can be considered in patients with prior history of pseudotumor from tetracycline antibiotics with appropriate consultation. No significant issues regarding wound healing have been demonstrated or reported with isotretinoin, so the need to stop before cutaneous surgery is unlikely. Additionally, there are limited reports of complications with rhinoplasty, a possible slight increased risk for dry socket, and few cases of keloidal scarring with dermabrasion.

Updates in Pathophysiology

New immunologic targets for therapy and a better understanding of the role of the sebocyte in acne pathogenesis dominated the discussions at the AAD. In a workshop (Translating Evidence Into Practice: Acne Guidelines), Dr. Rachel V. Reynolds discussed the many hats worn by the sebocyte from an endocrine organ responsive to melanocortins, vitamin D, and corticotropin-releasing hormone to an immune cell responsible for secreting antimicrobial peptides and a broad array of inflammatory mediators implicated in the pathogenesis of acne. Fitting in with the recent excitement surrounding the identification of a key inflammasome (NLRP3 [NOD-like receptor family, pyrin domain containing 3]) in the IL-1β-induced subclinical inflammation in acne (Qin et al. J Invest Dermatol. 2014;134:381-388), it also was found that the sebocyte can participate in the same pathway. Propionibacterium acnes–induced NLRP3-derived IL-1β activation in sebocytes also has a role in acne pathogenesis (Li et al. J Invest Dermatol. 2014;134:2747-2756).

With respect to targeting elements of the inflammasome, during a forum (Treating Tumors and Inflammatory Skin Diseases With Immunomodulators and Biologics) I had the opportunity to discuss my collaboration with Dr. Jenny Kim of the University of California, Los Angeles, using nitric oxide–releasing nanoparticles (P1691). We found that not only do nitric oxide–releasing nanoparticles prevent the release of inflammatory cytokines from P acnes–stimulated human keratinocytes and monocytes, but even more importantly, this nanotechnology can inhibit multiple elements of the inflammasome cascade at the gene level. For example, caspase-1 and IL-1β suggests a mechanism(s) by which this technology could serve as not only a treatment of acne but of other inflammatory dermatoses.

That’s all for now! Stay tuned for more updates and hot topics in the world of acne.

We want to know your views! Tell us what you think.

At the recent 73rd Annual Meeting of the American Academy of Dermatology (AAD) in San Francisco, California, acne was once again a hot topic. Considerably more attention was paid to the role of androgens and, by default, antihormonal therapy as compared to prior years. Here are some of the highlights.

Spironolactone for Acne

Although not US Food and Drug Administration approved for the treatment of acne, spironolactone can be quite effective in the treatment of adult female acne due to its ability to block androgen receptors, decrease androgen production, inhibit 5α-reductase, and increase sexual hormone–binding protein. The question that often comes up is, how frequently do you need to check serum potassium levels, given that this drug is a potassium-sparing diuretic? According to both a poster at the AAD (P1296) and a study (the largest of its kind) published online on March 22 by Plovanich et al in JAMA Dermatology, the answer is not often or possibly not at all in young, otherwise-healthy women. Who should be checked then? Patients who have known cardiac and renal disease or impaired hepatic functioning as well as patients taking angiotensin-converting enzyme inhibitors, aldosterone blockers, angiotensin II antagonists, nonsteroidal anti-inflammatory drugs, or potassium supplementation. Be cautious with patients on digoxin and lithium, as spironolactone can increase their serum concentration and half-life.

Isotretinoin Risk

During a symposium (Acne Treatment Controversies), Dr. Diane M. Thiboutot discussed what’s new in the world of isotretinoin safety myths as well as useful tips to improve outcomes. The most recent data do not support a link between isotretinoin and inflammatory bowel disease. Prednisone and lower doses of isotretinoin can be used when initiating in a patient with severe inflammatory acne. Isotretinoin use also can be considered in patients with prior history of pseudotumor from tetracycline antibiotics with appropriate consultation. No significant issues regarding wound healing have been demonstrated or reported with isotretinoin, so the need to stop before cutaneous surgery is unlikely. Additionally, there are limited reports of complications with rhinoplasty, a possible slight increased risk for dry socket, and few cases of keloidal scarring with dermabrasion.

Updates in Pathophysiology

New immunologic targets for therapy and a better understanding of the role of the sebocyte in acne pathogenesis dominated the discussions at the AAD. In a workshop (Translating Evidence Into Practice: Acne Guidelines), Dr. Rachel V. Reynolds discussed the many hats worn by the sebocyte from an endocrine organ responsive to melanocortins, vitamin D, and corticotropin-releasing hormone to an immune cell responsible for secreting antimicrobial peptides and a broad array of inflammatory mediators implicated in the pathogenesis of acne. Fitting in with the recent excitement surrounding the identification of a key inflammasome (NLRP3 [NOD-like receptor family, pyrin domain containing 3]) in the IL-1β-induced subclinical inflammation in acne (Qin et al. J Invest Dermatol. 2014;134:381-388), it also was found that the sebocyte can participate in the same pathway. Propionibacterium acnes–induced NLRP3-derived IL-1β activation in sebocytes also has a role in acne pathogenesis (Li et al. J Invest Dermatol. 2014;134:2747-2756).

With respect to targeting elements of the inflammasome, during a forum (Treating Tumors and Inflammatory Skin Diseases With Immunomodulators and Biologics) I had the opportunity to discuss my collaboration with Dr. Jenny Kim of the University of California, Los Angeles, using nitric oxide–releasing nanoparticles (P1691). We found that not only do nitric oxide–releasing nanoparticles prevent the release of inflammatory cytokines from P acnes–stimulated human keratinocytes and monocytes, but even more importantly, this nanotechnology can inhibit multiple elements of the inflammasome cascade at the gene level. For example, caspase-1 and IL-1β suggests a mechanism(s) by which this technology could serve as not only a treatment of acne but of other inflammatory dermatoses.

That’s all for now! Stay tuned for more updates and hot topics in the world of acne.

We want to know your views! Tell us what you think.

At the recent 73rd Annual Meeting of the American Academy of Dermatology (AAD) in San Francisco, California, acne was once again a hot topic. Considerably more attention was paid to the role of androgens and, by default, antihormonal therapy as compared to prior years. Here are some of the highlights.

Spironolactone for Acne

Although not US Food and Drug Administration approved for the treatment of acne, spironolactone can be quite effective in the treatment of adult female acne due to its ability to block androgen receptors, decrease androgen production, inhibit 5α-reductase, and increase sexual hormone–binding protein. The question that often comes up is, how frequently do you need to check serum potassium levels, given that this drug is a potassium-sparing diuretic? According to both a poster at the AAD (P1296) and a study (the largest of its kind) published online on March 22 by Plovanich et al in JAMA Dermatology, the answer is not often or possibly not at all in young, otherwise-healthy women. Who should be checked then? Patients who have known cardiac and renal disease or impaired hepatic functioning as well as patients taking angiotensin-converting enzyme inhibitors, aldosterone blockers, angiotensin II antagonists, nonsteroidal anti-inflammatory drugs, or potassium supplementation. Be cautious with patients on digoxin and lithium, as spironolactone can increase their serum concentration and half-life.

Isotretinoin Risk

During a symposium (Acne Treatment Controversies), Dr. Diane M. Thiboutot discussed what’s new in the world of isotretinoin safety myths as well as useful tips to improve outcomes. The most recent data do not support a link between isotretinoin and inflammatory bowel disease. Prednisone and lower doses of isotretinoin can be used when initiating in a patient with severe inflammatory acne. Isotretinoin use also can be considered in patients with prior history of pseudotumor from tetracycline antibiotics with appropriate consultation. No significant issues regarding wound healing have been demonstrated or reported with isotretinoin, so the need to stop before cutaneous surgery is unlikely. Additionally, there are limited reports of complications with rhinoplasty, a possible slight increased risk for dry socket, and few cases of keloidal scarring with dermabrasion.

Updates in Pathophysiology

New immunologic targets for therapy and a better understanding of the role of the sebocyte in acne pathogenesis dominated the discussions at the AAD. In a workshop (Translating Evidence Into Practice: Acne Guidelines), Dr. Rachel V. Reynolds discussed the many hats worn by the sebocyte from an endocrine organ responsive to melanocortins, vitamin D, and corticotropin-releasing hormone to an immune cell responsible for secreting antimicrobial peptides and a broad array of inflammatory mediators implicated in the pathogenesis of acne. Fitting in with the recent excitement surrounding the identification of a key inflammasome (NLRP3 [NOD-like receptor family, pyrin domain containing 3]) in the IL-1β-induced subclinical inflammation in acne (Qin et al. J Invest Dermatol. 2014;134:381-388), it also was found that the sebocyte can participate in the same pathway. Propionibacterium acnes–induced NLRP3-derived IL-1β activation in sebocytes also has a role in acne pathogenesis (Li et al. J Invest Dermatol. 2014;134:2747-2756).

With respect to targeting elements of the inflammasome, during a forum (Treating Tumors and Inflammatory Skin Diseases With Immunomodulators and Biologics) I had the opportunity to discuss my collaboration with Dr. Jenny Kim of the University of California, Los Angeles, using nitric oxide–releasing nanoparticles (P1691). We found that not only do nitric oxide–releasing nanoparticles prevent the release of inflammatory cytokines from P acnes–stimulated human keratinocytes and monocytes, but even more importantly, this nanotechnology can inhibit multiple elements of the inflammasome cascade at the gene level. For example, caspase-1 and IL-1β suggests a mechanism(s) by which this technology could serve as not only a treatment of acne but of other inflammatory dermatoses.

That’s all for now! Stay tuned for more updates and hot topics in the world of acne.

We want to know your views! Tell us what you think.

The role of diet in acne, both as a causative agent and therapeutic intervention, has been the topic of discussion in both the dermatology community as well as the laypress for decades. There is ample evidence highlighting the association of acne and high glycemic loads, certain dairy products, and refined sugar product ingestion. In the most recent edition to the repository, Grossi et al (J Eur Acad Dermatol Venereol. doi:10.1111/jdv.12878) reanalyzed data from their case-control study among young patients (age range, 10–24 years; N=563) with a diagnosis of moderate to severe acne versus control (participants with no or mild acne) between March 2009 and February 2010 that was originally published in 2012 (J Am Acad Dermatol. 2012;67:1129-1135). The unique element was how they evaluated the data. The investigators utilized a semantic connectivity map approach derived from artificial neural network computational models, which allowed for a better understanding of the complex connections between all of the studied variables. (The assumption of a given relation between any variables would not influence the results.) The data were presented on an Auto Semantic Connectivity Map that resembled a 4-leaf clover, representing “explanatory” information pertaining to the cases and controls and “residual” information of less importance. It is worth seeing in the manuscript to better appreciate the data.

What did they find? There is a close association between moderate to severe acne and a high intake of milk, other dairy products, sweets, and chocolate. Obesity and the low consumption of fish were linked to the presence of moderate to severe acne, while high consumption of fish (1 d/wk or more), high intake of fruits and vegetables, and body mass index lower than 18.5 were all associated with limited or no acne.

What’s the issue?

By adopting a different analytic approach, it was shown once again that diet plays a substantial role in acne, indicating that some food items may stimulate selected acne-promoting pathways. But what now? Here is the evidence yet again, but where is the medicine of “evidence-based medicine”? It is time to recommend guidelines for screening and counseling. In a recent article, Bronsnick et al (J Am Acad Dermatol. 2014;71:1039.e1-1039.e12) found that the level of evidence supporting the benefit of a low-glycemic, low-carbohydrate diet was sufficient to recommend to acne patients. How many dermatologists feel comfortable providing dietary guidance to their acne patients? A consensus statement from relevant organizations such as the American Academy of Dermatology, the Society for Investigative Dermatology, and the American Acne & Rosacea Society that provides tangible and realistic screening tools to identify those who would benefit from dietary intervention and implementation and practice guidelines for Dr. Derm seeing 40 to 50 patients a day in Springfield, USA (homage to The Simpsons) based on the level of evidence available would be useful. What are your thoughts?

We want to know your views! Tell us what you think.

Suggested Readings

• Bowe WP, Joshi SS, Shalita AR. Diet and acne. J Am Acad Dermatol. 2010;63:124-141.
• Ferdowsian HR, Levin S. Does diet really affect acne? Skin Therapy Lett. 2010;15:1-2, 5.
• Melnik B. Dietary intervention in acne: attenuation of increased mTORC1 signaling promoted by Western diet. Dermatoendocrinol. 2012;4:20-32.
• Veith WB, Silverberg NB. The association of acne vulgaris with diet. Cutis. 2011;88:84-91.

The role of diet in acne, both as a causative agent and therapeutic intervention, has been the topic of discussion in both the dermatology community as well as the laypress for decades. There is ample evidence highlighting the association of acne and high glycemic loads, certain dairy products, and refined sugar product ingestion. In the most recent edition to the repository, Grossi et al (J Eur Acad Dermatol Venereol. doi:10.1111/jdv.12878) reanalyzed data from their case-control study among young patients (age range, 10–24 years; N=563) with a diagnosis of moderate to severe acne versus control (participants with no or mild acne) between March 2009 and February 2010 that was originally published in 2012 (J Am Acad Dermatol. 2012;67:1129-1135). The unique element was how they evaluated the data. The investigators utilized a semantic connectivity map approach derived from artificial neural network computational models, which allowed for a better understanding of the complex connections between all of the studied variables. (The assumption of a given relation between any variables would not influence the results.) The data were presented on an Auto Semantic Connectivity Map that resembled a 4-leaf clover, representing “explanatory” information pertaining to the cases and controls and “residual” information of less importance. It is worth seeing in the manuscript to better appreciate the data.

What did they find? There is a close association between moderate to severe acne and a high intake of milk, other dairy products, sweets, and chocolate. Obesity and the low consumption of fish were linked to the presence of moderate to severe acne, while high consumption of fish (1 d/wk or more), high intake of fruits and vegetables, and body mass index lower than 18.5 were all associated with limited or no acne.

What’s the issue?

By adopting a different analytic approach, it was shown once again that diet plays a substantial role in acne, indicating that some food items may stimulate selected acne-promoting pathways. But what now? Here is the evidence yet again, but where is the medicine of “evidence-based medicine”? It is time to recommend guidelines for screening and counseling. In a recent article, Bronsnick et al (J Am Acad Dermatol. 2014;71:1039.e1-1039.e12) found that the level of evidence supporting the benefit of a low-glycemic, low-carbohydrate diet was sufficient to recommend to acne patients. How many dermatologists feel comfortable providing dietary guidance to their acne patients? A consensus statement from relevant organizations such as the American Academy of Dermatology, the Society for Investigative Dermatology, and the American Acne & Rosacea Society that provides tangible and realistic screening tools to identify those who would benefit from dietary intervention and implementation and practice guidelines for Dr. Derm seeing 40 to 50 patients a day in Springfield, USA (homage to The Simpsons) based on the level of evidence available would be useful. What are your thoughts?

We want to know your views! Tell us what you think.

Suggested Readings

• Bowe WP, Joshi SS, Shalita AR. Diet and acne. J Am Acad Dermatol. 2010;63:124-141.
• Ferdowsian HR, Levin S. Does diet really affect acne? Skin Therapy Lett. 2010;15:1-2, 5.
• Melnik B. Dietary intervention in acne: attenuation of increased mTORC1 signaling promoted by Western diet. Dermatoendocrinol. 2012;4:20-32.
• Veith WB, Silverberg NB. The association of acne vulgaris with diet. Cutis. 2011;88:84-91.

The role of diet in acne, both as a causative agent and therapeutic intervention, has been the topic of discussion in both the dermatology community as well as the laypress for decades. There is ample evidence highlighting the association of acne and high glycemic loads, certain dairy products, and refined sugar product ingestion. In the most recent edition to the repository, Grossi et al (J Eur Acad Dermatol Venereol. doi:10.1111/jdv.12878) reanalyzed data from their case-control study among young patients (age range, 10–24 years; N=563) with a diagnosis of moderate to severe acne versus control (participants with no or mild acne) between March 2009 and February 2010 that was originally published in 2012 (J Am Acad Dermatol. 2012;67:1129-1135). The unique element was how they evaluated the data. The investigators utilized a semantic connectivity map approach derived from artificial neural network computational models, which allowed for a better understanding of the complex connections between all of the studied variables. (The assumption of a given relation between any variables would not influence the results.) The data were presented on an Auto Semantic Connectivity Map that resembled a 4-leaf clover, representing “explanatory” information pertaining to the cases and controls and “residual” information of less importance. It is worth seeing in the manuscript to better appreciate the data.

What did they find? There is a close association between moderate to severe acne and a high intake of milk, other dairy products, sweets, and chocolate. Obesity and the low consumption of fish were linked to the presence of moderate to severe acne, while high consumption of fish (1 d/wk or more), high intake of fruits and vegetables, and body mass index lower than 18.5 were all associated with limited or no acne.

What’s the issue?

By adopting a different analytic approach, it was shown once again that diet plays a substantial role in acne, indicating that some food items may stimulate selected acne-promoting pathways. But what now? Here is the evidence yet again, but where is the medicine of “evidence-based medicine”? It is time to recommend guidelines for screening and counseling. In a recent article, Bronsnick et al (J Am Acad Dermatol. 2014;71:1039.e1-1039.e12) found that the level of evidence supporting the benefit of a low-glycemic, low-carbohydrate diet was sufficient to recommend to acne patients. How many dermatologists feel comfortable providing dietary guidance to their acne patients? A consensus statement from relevant organizations such as the American Academy of Dermatology, the Society for Investigative Dermatology, and the American Acne & Rosacea Society that provides tangible and realistic screening tools to identify those who would benefit from dietary intervention and implementation and practice guidelines for Dr. Derm seeing 40 to 50 patients a day in Springfield, USA (homage to The Simpsons) based on the level of evidence available would be useful. What are your thoughts?

We want to know your views! Tell us what you think.

Suggested Readings

• Bowe WP, Joshi SS, Shalita AR. Diet and acne. J Am Acad Dermatol. 2010;63:124-141.
• Ferdowsian HR, Levin S. Does diet really affect acne? Skin Therapy Lett. 2010;15:1-2, 5.
• Melnik B. Dietary intervention in acne: attenuation of increased mTORC1 signaling promoted by Western diet. Dermatoendocrinol. 2012;4:20-32.
• Veith WB, Silverberg NB. The association of acne vulgaris with diet. Cutis. 2011;88:84-91.

Acne vulgaris is a chronic inflammatory disease that affects the majority of the population at some point in their lifetime. It is characterized by comedones, pustules, and papules. Acne pathogenesis is multifactorial with 4 primary factors that play a pivotal role in the formation of acne lesions: excess sebum production, abnormal keratinization, inflammation, and bacterial colonization of Propionibacterium acnes in the pilosebaceous unit.¹ Although there is a general consensus on the pathogenic factors, the sequence of events in acne development is controversial. Traditionally it was believed that abnormal keratinization resulted in the creation of the microcomedone, the earliest subclinical acne lesion.² Activation of sebaceous glands by androgens, excess sebum production, and keratin plug formation then were followed by P acnes colonization, with induction of the innate immune system culminating in inflammation.² Androgen-induced sebum production and follicular hyperkeratinization and plugging have been cited as initial events that alter the pilosebaceous milieu, favoring the proliferation of P acnes^1,3; however, evidence suggests inflammation as the inciting factor, with proof of significant inflammatory factors surrounding the pilosebaceous unit even in clinically uninvolved skin units in acne patients.⁴ Herein we will briefly review the most recent data and translational applications pertaining to the P acnes–triggered innate immune response via activation of toll-like receptor 2 (TLR2)⁵ and importantly the inflammasome.^6,7

A new understanding of how P acnes induces the inflammatory cascade may represent a paradigm shift in the management of acne. Recognition of microbes, namely P acnes, by the innate immune system is the body’s first line of defense against pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).⁶ Although these pathways combat infection and prevent foreign invasion, they also result in inflammation and tissue injury. The inflammatory response to PAMPs and DAMPs is mediated by the inflammasome, a caspase 1–activating cytoplasmic complex that induces the secretion of crucial proinflammatory cytokines.⁷ The exact mechanism by which P acnes exerts its proinflammatory activity has been somewhat unclear, though P acnes–induced inflammation has been shown to be mediated by proinflammatory cytokines tumor necrosis factor α, IL-1, IL-6, IL-8, and IL-12.^5,8 However, remarkable evidence recently was presented regarding triggers of inflammation and the precise mechanism involved. Qin et al⁹ showed that P acnes is a potent trigger of IL-1β generation via activation of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome. Specifically, the study showed that human monocytes respond to P acnes by upregulating caspase 1, an inflammatory caspase required for proteolytic cleavage of IL-1β. The authors correlated their in vitro findings with clinical evidence of caspase 1 and NLRP3 expression in the dermis surrounding the pilosebaceous units of biopsied lesions.⁹ Kistowska et al⁶ confirmed and expanded on these data by showing the inability of NLRP3-deficient myeloid cells to secrete IL-1β and induce an inflammatory response in vivo. A recent investigation demonstrated that human sebocytes can function as constituents of the innate immune response, with P acnes triggering sebocyte NLRP3-inflammasome activation and subsequent IL-1β secretion. These observations were further confirmed in vivo with NLRP3-deficient mice displaying an impaired inflammatory response to P acnes.¹⁰

Our understanding of TLR2 signaling in the pathogenesis of acne also has expanded. It is well established that recognition of extracellular PAMPs and DAMPs is mediated by the expression of toll-like receptors on the surface of a variety of cells within the skin.¹¹ Prior research demonstrated how P acnes increases TLR2 expression in keratinocytes, even in vivo.¹² Stimulation by P acnes was shown to induce secretion of IL-8 (promoting a T_H1 response) and IL-12 (promoting neutrophil chemotaxis) via TLR2 activation.⁵ Selway et al¹¹ validated this finding by demonstrating that infundibular keratinocytes secrete IL-1α in response to the peptidoglycan cell wall of P acnes. Interestingly, Qin et al⁹ determined TLR2 inhibition resulted in partial suppression of IL-1β, possibly providing new evidence of TLR2-mediated activation of the NLRP3 inflammasome. Therefore, P acnes activates both extracellular and intracellular triggers of the innate immune response: TLR2 activation (requiring extracellular recognition of pathogens) and inflammasome-mediated activation (requiring internalization and access of the bacterium to the interior compartments of the cells).

Overall, these findings suggest that P acnes–induced inflammation can be selectively targeted by agents directed at inflammasome components, IL-1β, or toll-like receptors. A phase 2 double-blind, placebo-controlled trial assessing the efficacy of the anti–IL-1β monoclonal antibody gevokizumab found that 0.6 mg/kg administered subcutaneously resulted in a significant reduction in mean inflammatory lesion count compared to placebo (P=.077).¹³ The success of the IL-1 receptor antagonist anakinra against rare genetic autoinflammatory syndromes such as PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome, an NLRP3 inflammasomopathy, sheds light onto new therapeutics that may be used to target acne vulgaris.¹⁴ Current topical therapies such as retinoids, which have already proven efficacious in the treatment of inflammatory acne, target these pathways. In vivo data revealed that treatment with isotretinoin significantly decreased TLR2 expression in monocytes (P<.001) and suppressed inflammatory cytokine responses to P acnes (P<.001).¹⁵ Adapalene, with or without benzoyl peroxide, also was shown to exert anti-inflammatory effects via TLR2 downregulation.¹⁶

These data and observations highlight a paradigm shift in our perception of acne. All acne is truly inflammatory, and by identifying aberrations in the immune response, we can develop targeted treatments for this chronic debilitating disease.

Acne vulgaris is a chronic inflammatory disease that affects the majority of the population at some point in their lifetime. It is characterized by comedones, pustules, and papules. Acne pathogenesis is multifactorial with 4 primary factors that play a pivotal role in the formation of acne lesions: excess sebum production, abnormal keratinization, inflammation, and bacterial colonization of Propionibacterium acnes in the pilosebaceous unit.¹ Although there is a general consensus on the pathogenic factors, the sequence of events in acne development is controversial. Traditionally it was believed that abnormal keratinization resulted in the creation of the microcomedone, the earliest subclinical acne lesion.² Activation of sebaceous glands by androgens, excess sebum production, and keratin plug formation then were followed by P acnes colonization, with induction of the innate immune system culminating in inflammation.² Androgen-induced sebum production and follicular hyperkeratinization and plugging have been cited as initial events that alter the pilosebaceous milieu, favoring the proliferation of P acnes^1,3; however, evidence suggests inflammation as the inciting factor, with proof of significant inflammatory factors surrounding the pilosebaceous unit even in clinically uninvolved skin units in acne patients.⁴ Herein we will briefly review the most recent data and translational applications pertaining to the P acnes–triggered innate immune response via activation of toll-like receptor 2 (TLR2)⁵ and importantly the inflammasome.^6,7

A new understanding of how P acnes induces the inflammatory cascade may represent a paradigm shift in the management of acne. Recognition of microbes, namely P acnes, by the innate immune system is the body’s first line of defense against pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).⁶ Although these pathways combat infection and prevent foreign invasion, they also result in inflammation and tissue injury. The inflammatory response to PAMPs and DAMPs is mediated by the inflammasome, a caspase 1–activating cytoplasmic complex that induces the secretion of crucial proinflammatory cytokines.⁷ The exact mechanism by which P acnes exerts its proinflammatory activity has been somewhat unclear, though P acnes–induced inflammation has been shown to be mediated by proinflammatory cytokines tumor necrosis factor α, IL-1, IL-6, IL-8, and IL-12.^5,8 However, remarkable evidence recently was presented regarding triggers of inflammation and the precise mechanism involved. Qin et al⁹ showed that P acnes is a potent trigger of IL-1β generation via activation of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome. Specifically, the study showed that human monocytes respond to P acnes by upregulating caspase 1, an inflammatory caspase required for proteolytic cleavage of IL-1β. The authors correlated their in vitro findings with clinical evidence of caspase 1 and NLRP3 expression in the dermis surrounding the pilosebaceous units of biopsied lesions.⁹ Kistowska et al⁶ confirmed and expanded on these data by showing the inability of NLRP3-deficient myeloid cells to secrete IL-1β and induce an inflammatory response in vivo. A recent investigation demonstrated that human sebocytes can function as constituents of the innate immune response, with P acnes triggering sebocyte NLRP3-inflammasome activation and subsequent IL-1β secretion. These observations were further confirmed in vivo with NLRP3-deficient mice displaying an impaired inflammatory response to P acnes.¹⁰

Our understanding of TLR2 signaling in the pathogenesis of acne also has expanded. It is well established that recognition of extracellular PAMPs and DAMPs is mediated by the expression of toll-like receptors on the surface of a variety of cells within the skin.¹¹ Prior research demonstrated how P acnes increases TLR2 expression in keratinocytes, even in vivo.¹² Stimulation by P acnes was shown to induce secretion of IL-8 (promoting a T_H1 response) and IL-12 (promoting neutrophil chemotaxis) via TLR2 activation.⁵ Selway et al¹¹ validated this finding by demonstrating that infundibular keratinocytes secrete IL-1α in response to the peptidoglycan cell wall of P acnes. Interestingly, Qin et al⁹ determined TLR2 inhibition resulted in partial suppression of IL-1β, possibly providing new evidence of TLR2-mediated activation of the NLRP3 inflammasome. Therefore, P acnes activates both extracellular and intracellular triggers of the innate immune response: TLR2 activation (requiring extracellular recognition of pathogens) and inflammasome-mediated activation (requiring internalization and access of the bacterium to the interior compartments of the cells).

Overall, these findings suggest that P acnes–induced inflammation can be selectively targeted by agents directed at inflammasome components, IL-1β, or toll-like receptors. A phase 2 double-blind, placebo-controlled trial assessing the efficacy of the anti–IL-1β monoclonal antibody gevokizumab found that 0.6 mg/kg administered subcutaneously resulted in a significant reduction in mean inflammatory lesion count compared to placebo (P=.077).¹³ The success of the IL-1 receptor antagonist anakinra against rare genetic autoinflammatory syndromes such as PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome, an NLRP3 inflammasomopathy, sheds light onto new therapeutics that may be used to target acne vulgaris.¹⁴ Current topical therapies such as retinoids, which have already proven efficacious in the treatment of inflammatory acne, target these pathways. In vivo data revealed that treatment with isotretinoin significantly decreased TLR2 expression in monocytes (P<.001) and suppressed inflammatory cytokine responses to P acnes (P<.001).¹⁵ Adapalene, with or without benzoyl peroxide, also was shown to exert anti-inflammatory effects via TLR2 downregulation.¹⁶

These data and observations highlight a paradigm shift in our perception of acne. All acne is truly inflammatory, and by identifying aberrations in the immune response, we can develop targeted treatments for this chronic debilitating disease.

Acne vulgaris is a chronic inflammatory disease that affects the majority of the population at some point in their lifetime. It is characterized by comedones, pustules, and papules. Acne pathogenesis is multifactorial with 4 primary factors that play a pivotal role in the formation of acne lesions: excess sebum production, abnormal keratinization, inflammation, and bacterial colonization of Propionibacterium acnes in the pilosebaceous unit.¹ Although there is a general consensus on the pathogenic factors, the sequence of events in acne development is controversial. Traditionally it was believed that abnormal keratinization resulted in the creation of the microcomedone, the earliest subclinical acne lesion.² Activation of sebaceous glands by androgens, excess sebum production, and keratin plug formation then were followed by P acnes colonization, with induction of the innate immune system culminating in inflammation.² Androgen-induced sebum production and follicular hyperkeratinization and plugging have been cited as initial events that alter the pilosebaceous milieu, favoring the proliferation of P acnes^1,3; however, evidence suggests inflammation as the inciting factor, with proof of significant inflammatory factors surrounding the pilosebaceous unit even in clinically uninvolved skin units in acne patients.⁴ Herein we will briefly review the most recent data and translational applications pertaining to the P acnes–triggered innate immune response via activation of toll-like receptor 2 (TLR2)⁵ and importantly the inflammasome.^6,7

A new understanding of how P acnes induces the inflammatory cascade may represent a paradigm shift in the management of acne. Recognition of microbes, namely P acnes, by the innate immune system is the body’s first line of defense against pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).⁶ Although these pathways combat infection and prevent foreign invasion, they also result in inflammation and tissue injury. The inflammatory response to PAMPs and DAMPs is mediated by the inflammasome, a caspase 1–activating cytoplasmic complex that induces the secretion of crucial proinflammatory cytokines.⁷ The exact mechanism by which P acnes exerts its proinflammatory activity has been somewhat unclear, though P acnes–induced inflammation has been shown to be mediated by proinflammatory cytokines tumor necrosis factor α, IL-1, IL-6, IL-8, and IL-12.^5,8 However, remarkable evidence recently was presented regarding triggers of inflammation and the precise mechanism involved. Qin et al⁹ showed that P acnes is a potent trigger of IL-1β generation via activation of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome. Specifically, the study showed that human monocytes respond to P acnes by upregulating caspase 1, an inflammatory caspase required for proteolytic cleavage of IL-1β. The authors correlated their in vitro findings with clinical evidence of caspase 1 and NLRP3 expression in the dermis surrounding the pilosebaceous units of biopsied lesions.⁹ Kistowska et al⁶ confirmed and expanded on these data by showing the inability of NLRP3-deficient myeloid cells to secrete IL-1β and induce an inflammatory response in vivo. A recent investigation demonstrated that human sebocytes can function as constituents of the innate immune response, with P acnes triggering sebocyte NLRP3-inflammasome activation and subsequent IL-1β secretion. These observations were further confirmed in vivo with NLRP3-deficient mice displaying an impaired inflammatory response to P acnes.¹⁰

Our understanding of TLR2 signaling in the pathogenesis of acne also has expanded. It is well established that recognition of extracellular PAMPs and DAMPs is mediated by the expression of toll-like receptors on the surface of a variety of cells within the skin.¹¹ Prior research demonstrated how P acnes increases TLR2 expression in keratinocytes, even in vivo.¹² Stimulation by P acnes was shown to induce secretion of IL-8 (promoting a T_H1 response) and IL-12 (promoting neutrophil chemotaxis) via TLR2 activation.⁵ Selway et al¹¹ validated this finding by demonstrating that infundibular keratinocytes secrete IL-1α in response to the peptidoglycan cell wall of P acnes. Interestingly, Qin et al⁹ determined TLR2 inhibition resulted in partial suppression of IL-1β, possibly providing new evidence of TLR2-mediated activation of the NLRP3 inflammasome. Therefore, P acnes activates both extracellular and intracellular triggers of the innate immune response: TLR2 activation (requiring extracellular recognition of pathogens) and inflammasome-mediated activation (requiring internalization and access of the bacterium to the interior compartments of the cells).

Overall, these findings suggest that P acnes–induced inflammation can be selectively targeted by agents directed at inflammasome components, IL-1β, or toll-like receptors. A phase 2 double-blind, placebo-controlled trial assessing the efficacy of the anti–IL-1β monoclonal antibody gevokizumab found that 0.6 mg/kg administered subcutaneously resulted in a significant reduction in mean inflammatory lesion count compared to placebo (P=.077).¹³ The success of the IL-1 receptor antagonist anakinra against rare genetic autoinflammatory syndromes such as PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome, an NLRP3 inflammasomopathy, sheds light onto new therapeutics that may be used to target acne vulgaris.¹⁴ Current topical therapies such as retinoids, which have already proven efficacious in the treatment of inflammatory acne, target these pathways. In vivo data revealed that treatment with isotretinoin significantly decreased TLR2 expression in monocytes (P<.001) and suppressed inflammatory cytokine responses to P acnes (P<.001).¹⁵ Adapalene, with or without benzoyl peroxide, also was shown to exert anti-inflammatory effects via TLR2 downregulation.¹⁶

These data and observations highlight a paradigm shift in our perception of acne. All acne is truly inflammatory, and by identifying aberrations in the immune response, we can develop targeted treatments for this chronic debilitating disease.

As one of the most common skin diseases, acne research, clinical guidelines, and therapeutic innovation are always a hot topic at the Annual Meeting of the American Academy of Dermatology (March 21-25, 2014). A new dimension in the chicken and egg, or rather microcomedone and inflammation, story of acne pathogenesis emerged in a recent Journal of Investigative Dermatology (2014;134:381-388) article, which demonstrated that Propionibacterium acnes triggers a key inflammatory mediator, IL-1β, via the inflammasome (a compilation of inflammatory proteins such as caspases and NOD-like receptors) activation, suggesting a role for inflammasome-mediated inflammation in acne pathogenesis in addition to and independent of toll-like receptor activation. A potential therapeutic target, perhaps?

Drs. Ted Rosen and Joshua Zeichner in 2 independent sessions (Treating Tumors and Inflammatory Skin Diseases With Immunomodulators and Biologics [Rosen] and Acne Treatment Controversies [Zeichner]) discussed the importance of purposeful utilization of oral antibiotics—less is more—to prevent the continued emergence of antimicrobial resistance. Dr. Rosen commented that doxycycline at doses ≥50 mg daily provides serum levels that have an impact on commensal or colonized organisms, while lower doses provide only the anti-inflammatory effects without any bacteriostatic impact. This finding highlights the importance of low-dose controlled-release formulations. Dr. Zeichner also stressed the importance of knowing when to quit; if a patient does not improve in 6 to 8 weeks of therapy, move on. He also commented on the importance of multimechanistic therapy (solo is a no-go), utilizing benzoyl peroxide–containing products and most importantly retinoids from day 1. Dr. Zeichner also stressed the importance of recognizing acne mimics, such as gram-negative folliculitis, and made it clear that hormonally driven acne must not be missed, especially in the adult female population.

Lastly, new directions in acne are emerging, utilizing the science of nanotechnology (nano is equivalent to 1 billionth of a part). Drug delivery with nanomaterials is being fervently pursued across the globe in the field of acne. Nanoparticles can allow for sustained and controlled release of established products, increasing efficacy and stability, compliance due to decreased dosing, and safety by limiting associated irritation and dryness. In a session on nanotechnology, Dr. Rox Anderson presented his work utilizing gold nanoparticles to selectively destroy sebaceous glands via selective photothermolysis. He commented, “Do we really need our sebaceous glands,” citing that babies and infants do just fine without their activity. This work is currently in clinical trials in Europe. Nanotechnology also can be used to deliver previously undeliverable actives, such as the gaseous molecule nitric oxide. It was shown that a nitric oxide–releasing nanoparticle technology effectively penetrated the pilosebaceous unit, killed P acnes in culture, and inhibited inflammatory cytokine production by keratinocytes exposed to P acnes.

Stay tuned for more innovation coming soon!

We want to know your views! Tell us what you think.

As one of the most common skin diseases, acne research, clinical guidelines, and therapeutic innovation are always a hot topic at the Annual Meeting of the American Academy of Dermatology (March 21-25, 2014). A new dimension in the chicken and egg, or rather microcomedone and inflammation, story of acne pathogenesis emerged in a recent Journal of Investigative Dermatology (2014;134:381-388) article, which demonstrated that Propionibacterium acnes triggers a key inflammatory mediator, IL-1β, via the inflammasome (a compilation of inflammatory proteins such as caspases and NOD-like receptors) activation, suggesting a role for inflammasome-mediated inflammation in acne pathogenesis in addition to and independent of toll-like receptor activation. A potential therapeutic target, perhaps?

Drs. Ted Rosen and Joshua Zeichner in 2 independent sessions (Treating Tumors and Inflammatory Skin Diseases With Immunomodulators and Biologics [Rosen] and Acne Treatment Controversies [Zeichner]) discussed the importance of purposeful utilization of oral antibiotics—less is more—to prevent the continued emergence of antimicrobial resistance. Dr. Rosen commented that doxycycline at doses ≥50 mg daily provides serum levels that have an impact on commensal or colonized organisms, while lower doses provide only the anti-inflammatory effects without any bacteriostatic impact. This finding highlights the importance of low-dose controlled-release formulations. Dr. Zeichner also stressed the importance of knowing when to quit; if a patient does not improve in 6 to 8 weeks of therapy, move on. He also commented on the importance of multimechanistic therapy (solo is a no-go), utilizing benzoyl peroxide–containing products and most importantly retinoids from day 1. Dr. Zeichner also stressed the importance of recognizing acne mimics, such as gram-negative folliculitis, and made it clear that hormonally driven acne must not be missed, especially in the adult female population.

Lastly, new directions in acne are emerging, utilizing the science of nanotechnology (nano is equivalent to 1 billionth of a part). Drug delivery with nanomaterials is being fervently pursued across the globe in the field of acne. Nanoparticles can allow for sustained and controlled release of established products, increasing efficacy and stability, compliance due to decreased dosing, and safety by limiting associated irritation and dryness. In a session on nanotechnology, Dr. Rox Anderson presented his work utilizing gold nanoparticles to selectively destroy sebaceous glands via selective photothermolysis. He commented, “Do we really need our sebaceous glands,” citing that babies and infants do just fine without their activity. This work is currently in clinical trials in Europe. Nanotechnology also can be used to deliver previously undeliverable actives, such as the gaseous molecule nitric oxide. It was shown that a nitric oxide–releasing nanoparticle technology effectively penetrated the pilosebaceous unit, killed P acnes in culture, and inhibited inflammatory cytokine production by keratinocytes exposed to P acnes.

Stay tuned for more innovation coming soon!

We want to know your views! Tell us what you think.

As one of the most common skin diseases, acne research, clinical guidelines, and therapeutic innovation are always a hot topic at the Annual Meeting of the American Academy of Dermatology (March 21-25, 2014). A new dimension in the chicken and egg, or rather microcomedone and inflammation, story of acne pathogenesis emerged in a recent Journal of Investigative Dermatology (2014;134:381-388) article, which demonstrated that Propionibacterium acnes triggers a key inflammatory mediator, IL-1β, via the inflammasome (a compilation of inflammatory proteins such as caspases and NOD-like receptors) activation, suggesting a role for inflammasome-mediated inflammation in acne pathogenesis in addition to and independent of toll-like receptor activation. A potential therapeutic target, perhaps?

Drs. Ted Rosen and Joshua Zeichner in 2 independent sessions (Treating Tumors and Inflammatory Skin Diseases With Immunomodulators and Biologics [Rosen] and Acne Treatment Controversies [Zeichner]) discussed the importance of purposeful utilization of oral antibiotics—less is more—to prevent the continued emergence of antimicrobial resistance. Dr. Rosen commented that doxycycline at doses ≥50 mg daily provides serum levels that have an impact on commensal or colonized organisms, while lower doses provide only the anti-inflammatory effects without any bacteriostatic impact. This finding highlights the importance of low-dose controlled-release formulations. Dr. Zeichner also stressed the importance of knowing when to quit; if a patient does not improve in 6 to 8 weeks of therapy, move on. He also commented on the importance of multimechanistic therapy (solo is a no-go), utilizing benzoyl peroxide–containing products and most importantly retinoids from day 1. Dr. Zeichner also stressed the importance of recognizing acne mimics, such as gram-negative folliculitis, and made it clear that hormonally driven acne must not be missed, especially in the adult female population.

Lastly, new directions in acne are emerging, utilizing the science of nanotechnology (nano is equivalent to 1 billionth of a part). Drug delivery with nanomaterials is being fervently pursued across the globe in the field of acne. Nanoparticles can allow for sustained and controlled release of established products, increasing efficacy and stability, compliance due to decreased dosing, and safety by limiting associated irritation and dryness. In a session on nanotechnology, Dr. Rox Anderson presented his work utilizing gold nanoparticles to selectively destroy sebaceous glands via selective photothermolysis. He commented, “Do we really need our sebaceous glands,” citing that babies and infants do just fine without their activity. This work is currently in clinical trials in Europe. Nanotechnology also can be used to deliver previously undeliverable actives, such as the gaseous molecule nitric oxide. It was shown that a nitric oxide–releasing nanoparticle technology effectively penetrated the pilosebaceous unit, killed P acnes in culture, and inhibited inflammatory cytokine production by keratinocytes exposed to P acnes.

Stay tuned for more innovation coming soon!

We want to know your views! Tell us what you think.