Inflammatory skin conditions often have a relapsing and remitting course and represent a large proportion of chronic skin diseases. Common inflammatory skin disorders include acne, psoriasis, hidradenitis suppurativa (HS), atopic dermatitis (AD), and seborrheic dermatitis (SD).¹ Although each of these conditions has a unique pathogenesis, they all are driven by a background of chronic inflammation. It has been reported that diets with high levels of refined carbohydrates and saturated or trans-fatty acids may exacerbate existing inflammation.² Consequently, dietary interventions, such as the ketogenic and low-glycemic diets, have potential anti-inflammatory and metabolic effects that are being assessed as stand-alone or adjunctive therapies for dermatologic diseases.

Diet may partially influence systemic inflammation through its effect on weight. Higher body mass index and obesity are linked to a low-grade inflammatory state and higher levels of circulating inflammatory markers. Therefore, weight loss leads to decreases in inflammatory cytokines, including C-reactive protein, tumor necrosis factor α, and IL-6.³ These cytokines and metabolic effects overlap with inflammatory skin condition pathways. It also is posited that decreased insulin release associated with weight loss results in decreased sebaceous lipogenesis and androgens, which drive keratinocyte proliferation and acne development.^4,5 For instance, in a 2015 meta-analysis of 5 randomized controlled trials on psoriasis, patients in the weight loss intervention group had more substantial reductions in psoriasis area and severity index (PASI) scores compared with controls receiving usual care (P=.004).⁶ However, in a systematic review of 35 studies on acne vulgaris, overweight and obese patients (defined by a body mass index of ≥23 kg/m²) had similar odds of having acne compared with normal-weight individuals (P=.671).⁷

Similar to weight loss, ketogenesis acts as a negative feedback mechanism to reduce insulin release, leading to decreased inflammation and androgens that often exacerbate inflammatory skin diseases.⁸ Ketogenesis ensues when daily carbohydrate intake is limited to less than 50 g, and long-term adherence to a ketogenic diet results in metabolic reliance on ketone bodies such as acetoacetate, β-hydroxybutyrate, and acetone.⁹ These metabolites may decrease free radical damage and consequently improve signs and symptoms of acne, psoriasis, and other inflammatory skin diseases.^10-12 Similarly, increased ketones also may decrease activation of the NLRP3 (NOD-, LRR-, and Pyrin domain-containing protein 3) inflammasome and therefore reduce inflammatory markers such as IL-1β and IL-1.^4,13 Several proposed mechanisms are outlined in the Table.

Collectively, low-glycemic and ketogenic diets have been proposed as potential interventions for reducing inflammatory skin conditions. These dietary approaches are hypothesized to exert their effects by facilitating weight loss, elevating ketone levels, and reducing systemic inflammation. The current review summarizes the existing evidence on ketogenic and low-glycemic diets as treatments for inflammatory skin conditions and evaluates the potential benefits of these dietary interventions in managing and improving outcomes for individuals with inflammatory skin conditions.

Methods

Using PubMed for articles indexed for MEDLINE and Google Scholar, a review of the literature was conducted with a combination of the following search terms: low-glycemic diet, inflammatory, dermatologic, ketogenic diet, inflammation, dermatology, acne, psoriasis, eczema, seborrheic dermatitis, and hidradenitis suppurativa. Reference citations in identified works also were reviewed. Interventional (experimental studies or clinical trials), survey-based, and observational studies that investigated the effects of low-glycemic or ketogenic diets for the treatment of inflammatory skin conditions were included. Inclusion criteria were studies assessing acne, psoriasis, SD, AD, and HS. Exclusion criteria were studies published before 1965; those written in languages other than English; and those analyzing other diets, such as the Mediterranean or low-fat diets. The search yielded a total of 11 observational studies and 4 controlled studies published between 1966 and January 2023. Because this analysis utilized publicly available data and did not qualify as human subject research, institutional review board approval was not required.

Results

Acne Vulgaris—Acne vulgaris is a disease of chronic pilosebaceous inflammation and follicular epithelial proliferation associated with Propionibacterium acnes. The association between acne and low-glycemic diets has been examined in several studies. Diet quality is measured and assessed using the glycemic index (GI), which is the effect of a single food on postprandial blood glucose, and the glycemic load, which is the GI adjusted for carbohydrates per serving.¹⁴ High levels of GI and glycemic load are associated with hyperinsulinemia and an increase in insulinlike growth factor 1 concentration that promotes mechanistic target of rapamycin (mTOR) complex 1–mediated follicular lipogenesis, sebum fatty acid production, and androgen synthesis.¹⁵Propionibacterium acnes directly activates toll-like receptor 2 on monocytes through damage-associated molecular patterns and indirectly through products of triglyceride catalysis, causing release of IL-12, IL-6, tumor necrosis factor α, and other proinflammatory cytokines.¹⁶ Therefore, lifestyle modifications focused on strict glucose control have been postulated to reduce acne severity via modulation of lipogenesis, androgen concentration, and inflammation.

Six survey-based studies evaluated sugar intake in patients with acne compared to healthy matched controls (eTable). Among these studies, 5 reported higher glycemic loads or daily sugar intake in acne patients compared to individuals without acne.^{12,19,20,26,28} The remaining study was conducted in 1967 and enrolled 16 acne patients and 32 matched controls. It reported no significant difference in sugar intake between the groups (P>.05).¹⁷

Smith et al¹⁸ randomized 43 male patients aged 15 to 25 years with facial acne into 2 cohorts for 12 weeks, each consuming either a low-glycemic diet (25% protein, 45% low-glycemic food [fruits, whole grains], and 30% fat) or a carbohydrate-dense diet of foods with medium to high GI based on prior documentation of the original diet. Patients were instructed to use a noncomedogenic cleanser as their only acne treatment. At 12 weeks, patients consuming the low-glycemic diet had an average of 23.5 fewer inflammatory lesions, while those in the intervention group had 12.0 fewer lesions (P=.03).¹⁸

In another controlled study by Kwon et al,²¹ 32 male and female acne patients were randomized to a low-glycemic diet (25% protein, 45% low-glycemic food, and 30% fat) or a standard diet for 10 weeks. Patients on the low-glycemic diet experienced a 70.9% reduction in inflammatory lesions (P<.05). Hematoxylin and eosin staining and image analysis were performed to measure sebaceous gland surface area in the low-glycemic diet group, which decreased from 0.32 to 0.24 mm² (P=.03). The sebaceous gland surface area in the control group was not reported. Moreover, patients on the low-glycemic diet had reduced IL-8 immunohistochemical staining (decreasing from 2.9 to 1.7 [P=.03]) and sterol regulatory element-binding protein 1 levels (decreasing from 2.6 to 1.3 [P=.03]), suggesting suppression of ongoing inflammation. Patients on the low-glycemic diet had no significant difference in transforming growth factor β1(P=.83). In the control group, there was no difference in IL-8, sterol regulatory element binding protein 1, or transforming growth factor β1 (P>.05) on immunohistochemical staining.²¹

Psoriasis—Psoriasis is a systemic inflammatory disease characterized by hyperproliferation and aberrant keratinocyte plaque formation. The innate immune response of keratinocytes in response to epidermal damage or infection begins with neutrophil recruitment and dendritic cell activation. Dendritic cell secretion of IL-23 promotes T-cell differentiation into helper T cells (T_H1) that subsequently secrete IL-17 and IL-22, thereby stimulating keratinocyte proliferation and eventual plaque formation. The relationship between diet and psoriasis is poorly understood; however, hyperinsulinemia is associated with greater severity of psoriasis.³¹ 

Four observational studies examined sugar intake in psoriasis patients. Barrea et al²³ conducted a survey-based study of 82 male participants (41 with psoriasis and 41 healthy controls), reporting that PASI score was correlated with intake of simple carbohydrates (percentage of total kilocalorie)(r=0.564, P<.001). Another study by Yamashita et al²⁷ found higher sugar intake in psoriasis patients than controls (P=.003) based on surveys from 70 patients with psoriasis and 70 matched healthy controls.

These findings contrast with 2 survey-based studies by Johnson et al²² and Afifi et al²⁵ of sugar intake in psoriasis patients using the National Health and Nutrition Examination Survey. Johnson et al²² reported reduced sugar intake among 156 psoriasis patients compared with 6104 unmatched controls (odds ratio, 0.998; CI, 0.996-1 [P=.04]) from 2003 to 2006. Similarly, Afifi et al²⁵ reported decreased sugar intake in 1206 psoriasis patients compared with sex- and age-matched controls (P<.0001) in 2009 and 2010. When patients were asked about dietary triggers, 13.8% of psoriasis patients reported sugar as the most common trigger, which was more frequent than alcohol (13.6%), gluten (7.2%), and dairy (6%).²⁵

Castaldo et al^29,30 published 2 nonrandomized clinical intervention studies in 2020 and 2021 evaluating the impact of the ketogenic diet on psoriasis. In the first study, 37 psoriasis patients followed a 10-week diet consisting of 4 weeks on a ketogenic diet (500 kcal/d) followed by 6 weeks on a low-caloric Mediterranean diet.²⁹ At the end of the intervention, there was a 17.4% reduction in PASI score, a 33.2-point reduction in itch severity score, and a 13.4-point reduction in the dermatology life quality index score; however, this study did not include a control diet group for comparison.²⁹ The second study included 30 psoriasis patients on a ketogenic diet and 30 control patients without psoriasis on a regular diet.³⁰ The ketogenic diet consisted of 400 to 500 g of vegetables, 20 to 30 g of fat, and a proportion of protein based on body weight with at least 12 g of whey protein and various amino acids. Patients on the ketogenic diet had significant reduction in PASI scores (value relative to clinical features, 1.4916 [P=.007]). Furthermore, concentrations of cytokines IL-2 (P=.04) and IL-1β (P=.006) decreased following the ketogenic diet but were not measured in the control group.³⁰

Seborrheic Dermatitis—Seborrheic dermatitis is associated with overcolonization of Malassezia species near lipid-rich sebaceous glands. Malassezia hydrolyzes free fatty acids, yielding oleic acids and leading to T-cell release of IL-8 and IL-17.³² Literature is sparse regarding how dietary modifications may play a role in disease severity. In a survey study, Bett et al¹⁷ compared 16 SD patients to 1:2 matched controls (N=29) to investigate the relationship between sugar consumption and presence of disease. Two control cohorts were selected, 1 from clinic patients diagnosed with verruca and 1 matched by age and sex from a survey-based study at a facility in London, England. Sugar intake was measured both in total grams per day and in “beverage sugar” per day, defined as sugar taken in tea and coffee. There was higher total sugar and higher beverage sugar intake among the SD group compared with both control groups (P<.05).¹⁷

Atopic Dermatitis—Atopic dermatitis is a disease of epidermal barrier dysfunction and IgE-mediated allergic sensitization.³³ There are several mechanisms by which skin structure may be disrupted. It is well established that filaggrin mutations inhibit stratum corneum maturation and lamellar matrix deposition.³⁴ Upregulation of IL-4–, IL-13–, and IL-17–secreting T_H2 cells also is associated with disruption of tight junctions and reduction of filaggrin.^35,36 Given that a T cell–mediated inflammatory response is involved in disease pathogenesis, glycemic control is hypothesized to have therapeutic potential.

Nosrati et al²⁴ surveyed 169 AD patients about their perceived dietary triggers through a 61-question survey based on the National Health and Nutrition Examination Survey. Respondents were queried about their perceptions and dietary changes, such as removal or addition of specific food groups and trial of specific diets. Overall, 16.5% of patients reported sugar being a trigger, making it the fourth most common among those surveyed and less common than dairy (24.8%), gluten (18.3%), and alcohol (17.1%).²⁴

Hidradenitis Suppurativa—Hidradenitis suppurativa is driven by hyperkeratosis, dilatation, and occlusion of pilosebaceous follicular ducts, whose eventual rupture evokes a local acute inflammatory response.³⁷ The inciting event for both acne and HS involves mTOR complex–mediated follicular hyperproliferation andinsulinlike growth factor 1 stimulation of androgen receptors in pilosebaceous glands. Given the similarities between the pathogenesis of acne and HS, it is hypothesized that lifestyle changes, including diet modification, may have a beneficial effect on HS.^38-40

Comment

Acne—Overall, there is strong evidence supporting the efficacy of a low-glycemic diet in the treatment of acne. Notably, among the 6 observational studies identified, there was 1 conflicting study by Bett et al¹⁷ that did not find a statistically significant difference in glucose intake between acne and control patients. However, this study included only 16 acne patients, whereas the other 5 observational studies included 32 to 2255 patients.¹⁷ The strongest evidence supporting low-glycemic dietary interventions in acne treatment is from 2 rigorous randomized clinical trials by Kwon et al²¹ and Smith et al.¹⁸ These trials used intention-to-treat models and maintained consistency in gender, age, and acne treatment protocols across both control and treatment groups. To ensure compliance with dietary interventions, daily telephone calls, food logs, and 24-hour urea sampling were utilized. Acne outcomes were assessed by a dermatologist who remained blinded with well-defined outcome measures. An important limitation of these studies is the difficulty in attributing the observed results solely to reduced glucose intake, as low-glycemic diets often lead to other dietary changes, including reduced fat intake and increased nutrient consumption.^18,21

A 2022 systematic review of acne by Meixiong et al⁴¹ further reinforced the beneficial effects of low-glycemic diets in the management of acne patients. The group reviewed 6 interventional studies and 28 observational studies to investigate the relationship among acne, dairy, and glycemic content and found an association between decreased glucose and dairy on reduction of acne.⁴¹

It is likely that the ketogenic diet, which limits glucose, would be beneficial for acne patients. There may be added benefit through elevated ketone bodies and substantially reduced insulin secretion. However, because there are no observational or interventional studies, further research is needed to draw firm conclusions regarding diet for acne treatment. A randomized clinical trial investigating the effects of the ketogenic diet compared to the low-glycemic diet compared to a regular diet would be valuable.

Psoriasis—Among psoriasis studies, there was a lack of consensus regarding glucose intake and correlation with disease. Among the 4 observational studies, 2 reported increased glucose intake among psoriasis patients and 2 reported decreased glucose intake. It is plausible that the variability in studies is due to differences in sample size and diet heterogeneity among study populations. More specifically, Johnson et al²² and Afifi et al²⁵ analyzed large sample sizes of 6260 and 2412 US participants, respectively, and found decreased sugar intake among psoriasis patients compared to controls. In comparison, Barrea et al²³ and Yamashita et al²⁷ analyzed substantially smaller and more specific populations consisting of 82 Italian and 140 Japanese participants, respectively; both reported increased glucose intake among psoriasis patients compared to controls. These seemingly antithetical results may be explained by regional dietary differences, with varying proportions of meats, vegetables, antioxidants, and vitamins.

Moreover, the variation among studies may be further explained by the high prevalence of comorbidities among psoriasis patients. In the study by Barrea et al,²³ psoriasis patients had higher fasting glucose (P=.004) and insulin (P=.022) levels than healthy patients. After adjusting for body mass index and metabolic syndrome, the correlation coefficient measuring the relationship between the PASI score and intake of simple carbohydrates changed from r=0.564 (P<.001) to r=0.352 (P=.028). The confounding impact of these comorbidities was further highlighted by Yamashita et al,²⁷ who found statistically significant differences in glucose intake between psoriasis and healthy patients (P=.003). However, they reported diminished significance on additional subgroup analysis accounting for potential comorbidities (P=.994).²⁷ Johnson et al²² and Afifi et al²⁵ did not account for comorbidities; therefore, the 4 observational study results must be interpreted cautiously.

The 2 randomized clinical trials by Castaldo et al^29,30 weakly suggest that a ketogenic diet may be beneficial for psoriasis patients. The studies have several notable limitations, including insufficient sample sizes and control groups. Thus, the decreased PASI scores reported in psoriasis patients on the ketogenic diets are challenging to interpret. Additionally, both studies placed patients on highly restrictive diets of 500 kcal/d for 4 weeks. The feasibility of recommending such a diet to patients in clinical practice is questionable. Diets of less than 500 kcal/d may be dangerous for patients with underlying comorbidities and are unlikely to serve as long-term solutions.²³ To contextualize our findings, a 2022 review by Chung et al⁴² examined the impact of various diets—low-caloric, gluten-free, Mediterranean, Western, and ketogenic—on psoriasis and reported insufficient evidence to suggest a benefit to the ketogenic diet for psoriasis patients, though the Mediterranean diet may be well suited for psoriasis patients because of improved cardiovascular health and reduced mortality.

Seborrheic Dermatitis—Sanders et al⁴³ found that patients with a high-fruit diet had lower odds of having SD, while those on a Western diet had higher odds of having SD. Although the study did not measure glycemic load, it is conceivable that the high glycemic load characteristic of the Western diet contributed to these findings.⁴³ However, no studies have investigated the direct link between low-glycemic or ketogenic diets and SD, leaving this area open for further study.

Atopic Dermatitis—It has been hypothesized that mitigating T cell–mediated inflammation via glucose control may contribute to the improvement in AD.^35,36 However, in one study, 16.5% of AD patients self-identified sugar as a dietary trigger, ranking fourth among other dietary triggers.²⁴ Thus, the connection between glucose levels and AD warrants further exploration.

Hidradenitis Suppurativa—Given the role of metabolic and hormonal influence in HS as well as the overlapping pathophysiology with acne, it is possible that low-glycemic and ketogenic diets may have a role in improving HS.^38-40 However, there is a gap in observation and controlled studies investigating the link between low-glycemic or ketogenic diets and HS.

Conclusion

Our analysis focused on interventional and observational research exploring the effects of low-glycemic and ketogenic diets on associations and treatment of inflammatory skin conditions. There is sufficient evidence to counsel acne patients on the benefits of a low-glycemic diet as an adjunctive treatment for acne. Currently, there is insufficient evidence to recommend a low-glycemic or ketogenic diet as a treatment for patients with any other inflammatory skin disease. Prospective and controlled clinical trials are needed to clarify the utility of dietary interventions for treating inflammatory skin conditions.

Inflammatory skin conditions often have a relapsing and remitting course and represent a large proportion of chronic skin diseases. Common inflammatory skin disorders include acne, psoriasis, hidradenitis suppurativa (HS), atopic dermatitis (AD), and seborrheic dermatitis (SD).¹ Although each of these conditions has a unique pathogenesis, they all are driven by a background of chronic inflammation. It has been reported that diets with high levels of refined carbohydrates and saturated or trans-fatty acids may exacerbate existing inflammation.² Consequently, dietary interventions, such as the ketogenic and low-glycemic diets, have potential anti-inflammatory and metabolic effects that are being assessed as stand-alone or adjunctive therapies for dermatologic diseases.

Diet may partially influence systemic inflammation through its effect on weight. Higher body mass index and obesity are linked to a low-grade inflammatory state and higher levels of circulating inflammatory markers. Therefore, weight loss leads to decreases in inflammatory cytokines, including C-reactive protein, tumor necrosis factor α, and IL-6.³ These cytokines and metabolic effects overlap with inflammatory skin condition pathways. It also is posited that decreased insulin release associated with weight loss results in decreased sebaceous lipogenesis and androgens, which drive keratinocyte proliferation and acne development.^4,5 For instance, in a 2015 meta-analysis of 5 randomized controlled trials on psoriasis, patients in the weight loss intervention group had more substantial reductions in psoriasis area and severity index (PASI) scores compared with controls receiving usual care (P=.004).⁶ However, in a systematic review of 35 studies on acne vulgaris, overweight and obese patients (defined by a body mass index of ≥23 kg/m²) had similar odds of having acne compared with normal-weight individuals (P=.671).⁷

Similar to weight loss, ketogenesis acts as a negative feedback mechanism to reduce insulin release, leading to decreased inflammation and androgens that often exacerbate inflammatory skin diseases.⁸ Ketogenesis ensues when daily carbohydrate intake is limited to less than 50 g, and long-term adherence to a ketogenic diet results in metabolic reliance on ketone bodies such as acetoacetate, β-hydroxybutyrate, and acetone.⁹ These metabolites may decrease free radical damage and consequently improve signs and symptoms of acne, psoriasis, and other inflammatory skin diseases.^10-12 Similarly, increased ketones also may decrease activation of the NLRP3 (NOD-, LRR-, and Pyrin domain-containing protein 3) inflammasome and therefore reduce inflammatory markers such as IL-1β and IL-1.^4,13 Several proposed mechanisms are outlined in the Table.

Collectively, low-glycemic and ketogenic diets have been proposed as potential interventions for reducing inflammatory skin conditions. These dietary approaches are hypothesized to exert their effects by facilitating weight loss, elevating ketone levels, and reducing systemic inflammation. The current review summarizes the existing evidence on ketogenic and low-glycemic diets as treatments for inflammatory skin conditions and evaluates the potential benefits of these dietary interventions in managing and improving outcomes for individuals with inflammatory skin conditions.

Methods

Using PubMed for articles indexed for MEDLINE and Google Scholar, a review of the literature was conducted with a combination of the following search terms: low-glycemic diet, inflammatory, dermatologic, ketogenic diet, inflammation, dermatology, acne, psoriasis, eczema, seborrheic dermatitis, and hidradenitis suppurativa. Reference citations in identified works also were reviewed. Interventional (experimental studies or clinical trials), survey-based, and observational studies that investigated the effects of low-glycemic or ketogenic diets for the treatment of inflammatory skin conditions were included. Inclusion criteria were studies assessing acne, psoriasis, SD, AD, and HS. Exclusion criteria were studies published before 1965; those written in languages other than English; and those analyzing other diets, such as the Mediterranean or low-fat diets. The search yielded a total of 11 observational studies and 4 controlled studies published between 1966 and January 2023. Because this analysis utilized publicly available data and did not qualify as human subject research, institutional review board approval was not required.

Results

Acne Vulgaris—Acne vulgaris is a disease of chronic pilosebaceous inflammation and follicular epithelial proliferation associated with Propionibacterium acnes. The association between acne and low-glycemic diets has been examined in several studies. Diet quality is measured and assessed using the glycemic index (GI), which is the effect of a single food on postprandial blood glucose, and the glycemic load, which is the GI adjusted for carbohydrates per serving.¹⁴ High levels of GI and glycemic load are associated with hyperinsulinemia and an increase in insulinlike growth factor 1 concentration that promotes mechanistic target of rapamycin (mTOR) complex 1–mediated follicular lipogenesis, sebum fatty acid production, and androgen synthesis.¹⁵Propionibacterium acnes directly activates toll-like receptor 2 on monocytes through damage-associated molecular patterns and indirectly through products of triglyceride catalysis, causing release of IL-12, IL-6, tumor necrosis factor α, and other proinflammatory cytokines.¹⁶ Therefore, lifestyle modifications focused on strict glucose control have been postulated to reduce acne severity via modulation of lipogenesis, androgen concentration, and inflammation.

Six survey-based studies evaluated sugar intake in patients with acne compared to healthy matched controls (eTable). Among these studies, 5 reported higher glycemic loads or daily sugar intake in acne patients compared to individuals without acne.^{12,19,20,26,28} The remaining study was conducted in 1967 and enrolled 16 acne patients and 32 matched controls. It reported no significant difference in sugar intake between the groups (P>.05).¹⁷

Smith et al¹⁸ randomized 43 male patients aged 15 to 25 years with facial acne into 2 cohorts for 12 weeks, each consuming either a low-glycemic diet (25% protein, 45% low-glycemic food [fruits, whole grains], and 30% fat) or a carbohydrate-dense diet of foods with medium to high GI based on prior documentation of the original diet. Patients were instructed to use a noncomedogenic cleanser as their only acne treatment. At 12 weeks, patients consuming the low-glycemic diet had an average of 23.5 fewer inflammatory lesions, while those in the intervention group had 12.0 fewer lesions (P=.03).¹⁸

In another controlled study by Kwon et al,²¹ 32 male and female acne patients were randomized to a low-glycemic diet (25% protein, 45% low-glycemic food, and 30% fat) or a standard diet for 10 weeks. Patients on the low-glycemic diet experienced a 70.9% reduction in inflammatory lesions (P<.05). Hematoxylin and eosin staining and image analysis were performed to measure sebaceous gland surface area in the low-glycemic diet group, which decreased from 0.32 to 0.24 mm² (P=.03). The sebaceous gland surface area in the control group was not reported. Moreover, patients on the low-glycemic diet had reduced IL-8 immunohistochemical staining (decreasing from 2.9 to 1.7 [P=.03]) and sterol regulatory element-binding protein 1 levels (decreasing from 2.6 to 1.3 [P=.03]), suggesting suppression of ongoing inflammation. Patients on the low-glycemic diet had no significant difference in transforming growth factor β1(P=.83). In the control group, there was no difference in IL-8, sterol regulatory element binding protein 1, or transforming growth factor β1 (P>.05) on immunohistochemical staining.²¹

Psoriasis—Psoriasis is a systemic inflammatory disease characterized by hyperproliferation and aberrant keratinocyte plaque formation. The innate immune response of keratinocytes in response to epidermal damage or infection begins with neutrophil recruitment and dendritic cell activation. Dendritic cell secretion of IL-23 promotes T-cell differentiation into helper T cells (T_H1) that subsequently secrete IL-17 and IL-22, thereby stimulating keratinocyte proliferation and eventual plaque formation. The relationship between diet and psoriasis is poorly understood; however, hyperinsulinemia is associated with greater severity of psoriasis.³¹ 

Four observational studies examined sugar intake in psoriasis patients. Barrea et al²³ conducted a survey-based study of 82 male participants (41 with psoriasis and 41 healthy controls), reporting that PASI score was correlated with intake of simple carbohydrates (percentage of total kilocalorie)(r=0.564, P<.001). Another study by Yamashita et al²⁷ found higher sugar intake in psoriasis patients than controls (P=.003) based on surveys from 70 patients with psoriasis and 70 matched healthy controls.

These findings contrast with 2 survey-based studies by Johnson et al²² and Afifi et al²⁵ of sugar intake in psoriasis patients using the National Health and Nutrition Examination Survey. Johnson et al²² reported reduced sugar intake among 156 psoriasis patients compared with 6104 unmatched controls (odds ratio, 0.998; CI, 0.996-1 [P=.04]) from 2003 to 2006. Similarly, Afifi et al²⁵ reported decreased sugar intake in 1206 psoriasis patients compared with sex- and age-matched controls (P<.0001) in 2009 and 2010. When patients were asked about dietary triggers, 13.8% of psoriasis patients reported sugar as the most common trigger, which was more frequent than alcohol (13.6%), gluten (7.2%), and dairy (6%).²⁵

Castaldo et al^29,30 published 2 nonrandomized clinical intervention studies in 2020 and 2021 evaluating the impact of the ketogenic diet on psoriasis. In the first study, 37 psoriasis patients followed a 10-week diet consisting of 4 weeks on a ketogenic diet (500 kcal/d) followed by 6 weeks on a low-caloric Mediterranean diet.²⁹ At the end of the intervention, there was a 17.4% reduction in PASI score, a 33.2-point reduction in itch severity score, and a 13.4-point reduction in the dermatology life quality index score; however, this study did not include a control diet group for comparison.²⁹ The second study included 30 psoriasis patients on a ketogenic diet and 30 control patients without psoriasis on a regular diet.³⁰ The ketogenic diet consisted of 400 to 500 g of vegetables, 20 to 30 g of fat, and a proportion of protein based on body weight with at least 12 g of whey protein and various amino acids. Patients on the ketogenic diet had significant reduction in PASI scores (value relative to clinical features, 1.4916 [P=.007]). Furthermore, concentrations of cytokines IL-2 (P=.04) and IL-1β (P=.006) decreased following the ketogenic diet but were not measured in the control group.³⁰

Seborrheic Dermatitis—Seborrheic dermatitis is associated with overcolonization of Malassezia species near lipid-rich sebaceous glands. Malassezia hydrolyzes free fatty acids, yielding oleic acids and leading to T-cell release of IL-8 and IL-17.³² Literature is sparse regarding how dietary modifications may play a role in disease severity. In a survey study, Bett et al¹⁷ compared 16 SD patients to 1:2 matched controls (N=29) to investigate the relationship between sugar consumption and presence of disease. Two control cohorts were selected, 1 from clinic patients diagnosed with verruca and 1 matched by age and sex from a survey-based study at a facility in London, England. Sugar intake was measured both in total grams per day and in “beverage sugar” per day, defined as sugar taken in tea and coffee. There was higher total sugar and higher beverage sugar intake among the SD group compared with both control groups (P<.05).¹⁷

Atopic Dermatitis—Atopic dermatitis is a disease of epidermal barrier dysfunction and IgE-mediated allergic sensitization.³³ There are several mechanisms by which skin structure may be disrupted. It is well established that filaggrin mutations inhibit stratum corneum maturation and lamellar matrix deposition.³⁴ Upregulation of IL-4–, IL-13–, and IL-17–secreting T_H2 cells also is associated with disruption of tight junctions and reduction of filaggrin.^35,36 Given that a T cell–mediated inflammatory response is involved in disease pathogenesis, glycemic control is hypothesized to have therapeutic potential.

Nosrati et al²⁴ surveyed 169 AD patients about their perceived dietary triggers through a 61-question survey based on the National Health and Nutrition Examination Survey. Respondents were queried about their perceptions and dietary changes, such as removal or addition of specific food groups and trial of specific diets. Overall, 16.5% of patients reported sugar being a trigger, making it the fourth most common among those surveyed and less common than dairy (24.8%), gluten (18.3%), and alcohol (17.1%).²⁴

Hidradenitis Suppurativa—Hidradenitis suppurativa is driven by hyperkeratosis, dilatation, and occlusion of pilosebaceous follicular ducts, whose eventual rupture evokes a local acute inflammatory response.³⁷ The inciting event for both acne and HS involves mTOR complex–mediated follicular hyperproliferation andinsulinlike growth factor 1 stimulation of androgen receptors in pilosebaceous glands. Given the similarities between the pathogenesis of acne and HS, it is hypothesized that lifestyle changes, including diet modification, may have a beneficial effect on HS.^38-40

Comment

Acne—Overall, there is strong evidence supporting the efficacy of a low-glycemic diet in the treatment of acne. Notably, among the 6 observational studies identified, there was 1 conflicting study by Bett et al¹⁷ that did not find a statistically significant difference in glucose intake between acne and control patients. However, this study included only 16 acne patients, whereas the other 5 observational studies included 32 to 2255 patients.¹⁷ The strongest evidence supporting low-glycemic dietary interventions in acne treatment is from 2 rigorous randomized clinical trials by Kwon et al²¹ and Smith et al.¹⁸ These trials used intention-to-treat models and maintained consistency in gender, age, and acne treatment protocols across both control and treatment groups. To ensure compliance with dietary interventions, daily telephone calls, food logs, and 24-hour urea sampling were utilized. Acne outcomes were assessed by a dermatologist who remained blinded with well-defined outcome measures. An important limitation of these studies is the difficulty in attributing the observed results solely to reduced glucose intake, as low-glycemic diets often lead to other dietary changes, including reduced fat intake and increased nutrient consumption.^18,21

A 2022 systematic review of acne by Meixiong et al⁴¹ further reinforced the beneficial effects of low-glycemic diets in the management of acne patients. The group reviewed 6 interventional studies and 28 observational studies to investigate the relationship among acne, dairy, and glycemic content and found an association between decreased glucose and dairy on reduction of acne.⁴¹

It is likely that the ketogenic diet, which limits glucose, would be beneficial for acne patients. There may be added benefit through elevated ketone bodies and substantially reduced insulin secretion. However, because there are no observational or interventional studies, further research is needed to draw firm conclusions regarding diet for acne treatment. A randomized clinical trial investigating the effects of the ketogenic diet compared to the low-glycemic diet compared to a regular diet would be valuable.

Psoriasis—Among psoriasis studies, there was a lack of consensus regarding glucose intake and correlation with disease. Among the 4 observational studies, 2 reported increased glucose intake among psoriasis patients and 2 reported decreased glucose intake. It is plausible that the variability in studies is due to differences in sample size and diet heterogeneity among study populations. More specifically, Johnson et al²² and Afifi et al²⁵ analyzed large sample sizes of 6260 and 2412 US participants, respectively, and found decreased sugar intake among psoriasis patients compared to controls. In comparison, Barrea et al²³ and Yamashita et al²⁷ analyzed substantially smaller and more specific populations consisting of 82 Italian and 140 Japanese participants, respectively; both reported increased glucose intake among psoriasis patients compared to controls. These seemingly antithetical results may be explained by regional dietary differences, with varying proportions of meats, vegetables, antioxidants, and vitamins.

Moreover, the variation among studies may be further explained by the high prevalence of comorbidities among psoriasis patients. In the study by Barrea et al,²³ psoriasis patients had higher fasting glucose (P=.004) and insulin (P=.022) levels than healthy patients. After adjusting for body mass index and metabolic syndrome, the correlation coefficient measuring the relationship between the PASI score and intake of simple carbohydrates changed from r=0.564 (P<.001) to r=0.352 (P=.028). The confounding impact of these comorbidities was further highlighted by Yamashita et al,²⁷ who found statistically significant differences in glucose intake between psoriasis and healthy patients (P=.003). However, they reported diminished significance on additional subgroup analysis accounting for potential comorbidities (P=.994).²⁷ Johnson et al²² and Afifi et al²⁵ did not account for comorbidities; therefore, the 4 observational study results must be interpreted cautiously.

The 2 randomized clinical trials by Castaldo et al^29,30 weakly suggest that a ketogenic diet may be beneficial for psoriasis patients. The studies have several notable limitations, including insufficient sample sizes and control groups. Thus, the decreased PASI scores reported in psoriasis patients on the ketogenic diets are challenging to interpret. Additionally, both studies placed patients on highly restrictive diets of 500 kcal/d for 4 weeks. The feasibility of recommending such a diet to patients in clinical practice is questionable. Diets of less than 500 kcal/d may be dangerous for patients with underlying comorbidities and are unlikely to serve as long-term solutions.²³ To contextualize our findings, a 2022 review by Chung et al⁴² examined the impact of various diets—low-caloric, gluten-free, Mediterranean, Western, and ketogenic—on psoriasis and reported insufficient evidence to suggest a benefit to the ketogenic diet for psoriasis patients, though the Mediterranean diet may be well suited for psoriasis patients because of improved cardiovascular health and reduced mortality.

Seborrheic Dermatitis—Sanders et al⁴³ found that patients with a high-fruit diet had lower odds of having SD, while those on a Western diet had higher odds of having SD. Although the study did not measure glycemic load, it is conceivable that the high glycemic load characteristic of the Western diet contributed to these findings.⁴³ However, no studies have investigated the direct link between low-glycemic or ketogenic diets and SD, leaving this area open for further study.

Atopic Dermatitis—It has been hypothesized that mitigating T cell–mediated inflammation via glucose control may contribute to the improvement in AD.^35,36 However, in one study, 16.5% of AD patients self-identified sugar as a dietary trigger, ranking fourth among other dietary triggers.²⁴ Thus, the connection between glucose levels and AD warrants further exploration.

Hidradenitis Suppurativa—Given the role of metabolic and hormonal influence in HS as well as the overlapping pathophysiology with acne, it is possible that low-glycemic and ketogenic diets may have a role in improving HS.^38-40 However, there is a gap in observation and controlled studies investigating the link between low-glycemic or ketogenic diets and HS.

Conclusion

Our analysis focused on interventional and observational research exploring the effects of low-glycemic and ketogenic diets on associations and treatment of inflammatory skin conditions. There is sufficient evidence to counsel acne patients on the benefits of a low-glycemic diet as an adjunctive treatment for acne. Currently, there is insufficient evidence to recommend a low-glycemic or ketogenic diet as a treatment for patients with any other inflammatory skin disease. Prospective and controlled clinical trials are needed to clarify the utility of dietary interventions for treating inflammatory skin conditions.

Inflammatory skin conditions often have a relapsing and remitting course and represent a large proportion of chronic skin diseases. Common inflammatory skin disorders include acne, psoriasis, hidradenitis suppurativa (HS), atopic dermatitis (AD), and seborrheic dermatitis (SD).¹ Although each of these conditions has a unique pathogenesis, they all are driven by a background of chronic inflammation. It has been reported that diets with high levels of refined carbohydrates and saturated or trans-fatty acids may exacerbate existing inflammation.² Consequently, dietary interventions, such as the ketogenic and low-glycemic diets, have potential anti-inflammatory and metabolic effects that are being assessed as stand-alone or adjunctive therapies for dermatologic diseases.

Diet may partially influence systemic inflammation through its effect on weight. Higher body mass index and obesity are linked to a low-grade inflammatory state and higher levels of circulating inflammatory markers. Therefore, weight loss leads to decreases in inflammatory cytokines, including C-reactive protein, tumor necrosis factor α, and IL-6.³ These cytokines and metabolic effects overlap with inflammatory skin condition pathways. It also is posited that decreased insulin release associated with weight loss results in decreased sebaceous lipogenesis and androgens, which drive keratinocyte proliferation and acne development.^4,5 For instance, in a 2015 meta-analysis of 5 randomized controlled trials on psoriasis, patients in the weight loss intervention group had more substantial reductions in psoriasis area and severity index (PASI) scores compared with controls receiving usual care (P=.004).⁶ However, in a systematic review of 35 studies on acne vulgaris, overweight and obese patients (defined by a body mass index of ≥23 kg/m²) had similar odds of having acne compared with normal-weight individuals (P=.671).⁷

Similar to weight loss, ketogenesis acts as a negative feedback mechanism to reduce insulin release, leading to decreased inflammation and androgens that often exacerbate inflammatory skin diseases.⁸ Ketogenesis ensues when daily carbohydrate intake is limited to less than 50 g, and long-term adherence to a ketogenic diet results in metabolic reliance on ketone bodies such as acetoacetate, β-hydroxybutyrate, and acetone.⁹ These metabolites may decrease free radical damage and consequently improve signs and symptoms of acne, psoriasis, and other inflammatory skin diseases.^10-12 Similarly, increased ketones also may decrease activation of the NLRP3 (NOD-, LRR-, and Pyrin domain-containing protein 3) inflammasome and therefore reduce inflammatory markers such as IL-1β and IL-1.^4,13 Several proposed mechanisms are outlined in the Table.

Collectively, low-glycemic and ketogenic diets have been proposed as potential interventions for reducing inflammatory skin conditions. These dietary approaches are hypothesized to exert their effects by facilitating weight loss, elevating ketone levels, and reducing systemic inflammation. The current review summarizes the existing evidence on ketogenic and low-glycemic diets as treatments for inflammatory skin conditions and evaluates the potential benefits of these dietary interventions in managing and improving outcomes for individuals with inflammatory skin conditions.

Methods

Using PubMed for articles indexed for MEDLINE and Google Scholar, a review of the literature was conducted with a combination of the following search terms: low-glycemic diet, inflammatory, dermatologic, ketogenic diet, inflammation, dermatology, acne, psoriasis, eczema, seborrheic dermatitis, and hidradenitis suppurativa. Reference citations in identified works also were reviewed. Interventional (experimental studies or clinical trials), survey-based, and observational studies that investigated the effects of low-glycemic or ketogenic diets for the treatment of inflammatory skin conditions were included. Inclusion criteria were studies assessing acne, psoriasis, SD, AD, and HS. Exclusion criteria were studies published before 1965; those written in languages other than English; and those analyzing other diets, such as the Mediterranean or low-fat diets. The search yielded a total of 11 observational studies and 4 controlled studies published between 1966 and January 2023. Because this analysis utilized publicly available data and did not qualify as human subject research, institutional review board approval was not required.

Results

Acne Vulgaris—Acne vulgaris is a disease of chronic pilosebaceous inflammation and follicular epithelial proliferation associated with Propionibacterium acnes. The association between acne and low-glycemic diets has been examined in several studies. Diet quality is measured and assessed using the glycemic index (GI), which is the effect of a single food on postprandial blood glucose, and the glycemic load, which is the GI adjusted for carbohydrates per serving.¹⁴ High levels of GI and glycemic load are associated with hyperinsulinemia and an increase in insulinlike growth factor 1 concentration that promotes mechanistic target of rapamycin (mTOR) complex 1–mediated follicular lipogenesis, sebum fatty acid production, and androgen synthesis.¹⁵Propionibacterium acnes directly activates toll-like receptor 2 on monocytes through damage-associated molecular patterns and indirectly through products of triglyceride catalysis, causing release of IL-12, IL-6, tumor necrosis factor α, and other proinflammatory cytokines.¹⁶ Therefore, lifestyle modifications focused on strict glucose control have been postulated to reduce acne severity via modulation of lipogenesis, androgen concentration, and inflammation.

Six survey-based studies evaluated sugar intake in patients with acne compared to healthy matched controls (eTable). Among these studies, 5 reported higher glycemic loads or daily sugar intake in acne patients compared to individuals without acne.^{12,19,20,26,28} The remaining study was conducted in 1967 and enrolled 16 acne patients and 32 matched controls. It reported no significant difference in sugar intake between the groups (P>.05).¹⁷

Smith et al¹⁸ randomized 43 male patients aged 15 to 25 years with facial acne into 2 cohorts for 12 weeks, each consuming either a low-glycemic diet (25% protein, 45% low-glycemic food [fruits, whole grains], and 30% fat) or a carbohydrate-dense diet of foods with medium to high GI based on prior documentation of the original diet. Patients were instructed to use a noncomedogenic cleanser as their only acne treatment. At 12 weeks, patients consuming the low-glycemic diet had an average of 23.5 fewer inflammatory lesions, while those in the intervention group had 12.0 fewer lesions (P=.03).¹⁸

In another controlled study by Kwon et al,²¹ 32 male and female acne patients were randomized to a low-glycemic diet (25% protein, 45% low-glycemic food, and 30% fat) or a standard diet for 10 weeks. Patients on the low-glycemic diet experienced a 70.9% reduction in inflammatory lesions (P<.05). Hematoxylin and eosin staining and image analysis were performed to measure sebaceous gland surface area in the low-glycemic diet group, which decreased from 0.32 to 0.24 mm² (P=.03). The sebaceous gland surface area in the control group was not reported. Moreover, patients on the low-glycemic diet had reduced IL-8 immunohistochemical staining (decreasing from 2.9 to 1.7 [P=.03]) and sterol regulatory element-binding protein 1 levels (decreasing from 2.6 to 1.3 [P=.03]), suggesting suppression of ongoing inflammation. Patients on the low-glycemic diet had no significant difference in transforming growth factor β1(P=.83). In the control group, there was no difference in IL-8, sterol regulatory element binding protein 1, or transforming growth factor β1 (P>.05) on immunohistochemical staining.²¹

Psoriasis—Psoriasis is a systemic inflammatory disease characterized by hyperproliferation and aberrant keratinocyte plaque formation. The innate immune response of keratinocytes in response to epidermal damage or infection begins with neutrophil recruitment and dendritic cell activation. Dendritic cell secretion of IL-23 promotes T-cell differentiation into helper T cells (T_H1) that subsequently secrete IL-17 and IL-22, thereby stimulating keratinocyte proliferation and eventual plaque formation. The relationship between diet and psoriasis is poorly understood; however, hyperinsulinemia is associated with greater severity of psoriasis.³¹ 

Four observational studies examined sugar intake in psoriasis patients. Barrea et al²³ conducted a survey-based study of 82 male participants (41 with psoriasis and 41 healthy controls), reporting that PASI score was correlated with intake of simple carbohydrates (percentage of total kilocalorie)(r=0.564, P<.001). Another study by Yamashita et al²⁷ found higher sugar intake in psoriasis patients than controls (P=.003) based on surveys from 70 patients with psoriasis and 70 matched healthy controls.

These findings contrast with 2 survey-based studies by Johnson et al²² and Afifi et al²⁵ of sugar intake in psoriasis patients using the National Health and Nutrition Examination Survey. Johnson et al²² reported reduced sugar intake among 156 psoriasis patients compared with 6104 unmatched controls (odds ratio, 0.998; CI, 0.996-1 [P=.04]) from 2003 to 2006. Similarly, Afifi et al²⁵ reported decreased sugar intake in 1206 psoriasis patients compared with sex- and age-matched controls (P<.0001) in 2009 and 2010. When patients were asked about dietary triggers, 13.8% of psoriasis patients reported sugar as the most common trigger, which was more frequent than alcohol (13.6%), gluten (7.2%), and dairy (6%).²⁵

Castaldo et al^29,30 published 2 nonrandomized clinical intervention studies in 2020 and 2021 evaluating the impact of the ketogenic diet on psoriasis. In the first study, 37 psoriasis patients followed a 10-week diet consisting of 4 weeks on a ketogenic diet (500 kcal/d) followed by 6 weeks on a low-caloric Mediterranean diet.²⁹ At the end of the intervention, there was a 17.4% reduction in PASI score, a 33.2-point reduction in itch severity score, and a 13.4-point reduction in the dermatology life quality index score; however, this study did not include a control diet group for comparison.²⁹ The second study included 30 psoriasis patients on a ketogenic diet and 30 control patients without psoriasis on a regular diet.³⁰ The ketogenic diet consisted of 400 to 500 g of vegetables, 20 to 30 g of fat, and a proportion of protein based on body weight with at least 12 g of whey protein and various amino acids. Patients on the ketogenic diet had significant reduction in PASI scores (value relative to clinical features, 1.4916 [P=.007]). Furthermore, concentrations of cytokines IL-2 (P=.04) and IL-1β (P=.006) decreased following the ketogenic diet but were not measured in the control group.³⁰

Seborrheic Dermatitis—Seborrheic dermatitis is associated with overcolonization of Malassezia species near lipid-rich sebaceous glands. Malassezia hydrolyzes free fatty acids, yielding oleic acids and leading to T-cell release of IL-8 and IL-17.³² Literature is sparse regarding how dietary modifications may play a role in disease severity. In a survey study, Bett et al¹⁷ compared 16 SD patients to 1:2 matched controls (N=29) to investigate the relationship between sugar consumption and presence of disease. Two control cohorts were selected, 1 from clinic patients diagnosed with verruca and 1 matched by age and sex from a survey-based study at a facility in London, England. Sugar intake was measured both in total grams per day and in “beverage sugar” per day, defined as sugar taken in tea and coffee. There was higher total sugar and higher beverage sugar intake among the SD group compared with both control groups (P<.05).¹⁷

Atopic Dermatitis—Atopic dermatitis is a disease of epidermal barrier dysfunction and IgE-mediated allergic sensitization.³³ There are several mechanisms by which skin structure may be disrupted. It is well established that filaggrin mutations inhibit stratum corneum maturation and lamellar matrix deposition.³⁴ Upregulation of IL-4–, IL-13–, and IL-17–secreting T_H2 cells also is associated with disruption of tight junctions and reduction of filaggrin.^35,36 Given that a T cell–mediated inflammatory response is involved in disease pathogenesis, glycemic control is hypothesized to have therapeutic potential.

Nosrati et al²⁴ surveyed 169 AD patients about their perceived dietary triggers through a 61-question survey based on the National Health and Nutrition Examination Survey. Respondents were queried about their perceptions and dietary changes, such as removal or addition of specific food groups and trial of specific diets. Overall, 16.5% of patients reported sugar being a trigger, making it the fourth most common among those surveyed and less common than dairy (24.8%), gluten (18.3%), and alcohol (17.1%).²⁴

Hidradenitis Suppurativa—Hidradenitis suppurativa is driven by hyperkeratosis, dilatation, and occlusion of pilosebaceous follicular ducts, whose eventual rupture evokes a local acute inflammatory response.³⁷ The inciting event for both acne and HS involves mTOR complex–mediated follicular hyperproliferation andinsulinlike growth factor 1 stimulation of androgen receptors in pilosebaceous glands. Given the similarities between the pathogenesis of acne and HS, it is hypothesized that lifestyle changes, including diet modification, may have a beneficial effect on HS.^38-40

Comment

Acne—Overall, there is strong evidence supporting the efficacy of a low-glycemic diet in the treatment of acne. Notably, among the 6 observational studies identified, there was 1 conflicting study by Bett et al¹⁷ that did not find a statistically significant difference in glucose intake between acne and control patients. However, this study included only 16 acne patients, whereas the other 5 observational studies included 32 to 2255 patients.¹⁷ The strongest evidence supporting low-glycemic dietary interventions in acne treatment is from 2 rigorous randomized clinical trials by Kwon et al²¹ and Smith et al.¹⁸ These trials used intention-to-treat models and maintained consistency in gender, age, and acne treatment protocols across both control and treatment groups. To ensure compliance with dietary interventions, daily telephone calls, food logs, and 24-hour urea sampling were utilized. Acne outcomes were assessed by a dermatologist who remained blinded with well-defined outcome measures. An important limitation of these studies is the difficulty in attributing the observed results solely to reduced glucose intake, as low-glycemic diets often lead to other dietary changes, including reduced fat intake and increased nutrient consumption.^18,21

A 2022 systematic review of acne by Meixiong et al⁴¹ further reinforced the beneficial effects of low-glycemic diets in the management of acne patients. The group reviewed 6 interventional studies and 28 observational studies to investigate the relationship among acne, dairy, and glycemic content and found an association between decreased glucose and dairy on reduction of acne.⁴¹

It is likely that the ketogenic diet, which limits glucose, would be beneficial for acne patients. There may be added benefit through elevated ketone bodies and substantially reduced insulin secretion. However, because there are no observational or interventional studies, further research is needed to draw firm conclusions regarding diet for acne treatment. A randomized clinical trial investigating the effects of the ketogenic diet compared to the low-glycemic diet compared to a regular diet would be valuable.

Psoriasis—Among psoriasis studies, there was a lack of consensus regarding glucose intake and correlation with disease. Among the 4 observational studies, 2 reported increased glucose intake among psoriasis patients and 2 reported decreased glucose intake. It is plausible that the variability in studies is due to differences in sample size and diet heterogeneity among study populations. More specifically, Johnson et al²² and Afifi et al²⁵ analyzed large sample sizes of 6260 and 2412 US participants, respectively, and found decreased sugar intake among psoriasis patients compared to controls. In comparison, Barrea et al²³ and Yamashita et al²⁷ analyzed substantially smaller and more specific populations consisting of 82 Italian and 140 Japanese participants, respectively; both reported increased glucose intake among psoriasis patients compared to controls. These seemingly antithetical results may be explained by regional dietary differences, with varying proportions of meats, vegetables, antioxidants, and vitamins.

Moreover, the variation among studies may be further explained by the high prevalence of comorbidities among psoriasis patients. In the study by Barrea et al,²³ psoriasis patients had higher fasting glucose (P=.004) and insulin (P=.022) levels than healthy patients. After adjusting for body mass index and metabolic syndrome, the correlation coefficient measuring the relationship between the PASI score and intake of simple carbohydrates changed from r=0.564 (P<.001) to r=0.352 (P=.028). The confounding impact of these comorbidities was further highlighted by Yamashita et al,²⁷ who found statistically significant differences in glucose intake between psoriasis and healthy patients (P=.003). However, they reported diminished significance on additional subgroup analysis accounting for potential comorbidities (P=.994).²⁷ Johnson et al²² and Afifi et al²⁵ did not account for comorbidities; therefore, the 4 observational study results must be interpreted cautiously.

The 2 randomized clinical trials by Castaldo et al^29,30 weakly suggest that a ketogenic diet may be beneficial for psoriasis patients. The studies have several notable limitations, including insufficient sample sizes and control groups. Thus, the decreased PASI scores reported in psoriasis patients on the ketogenic diets are challenging to interpret. Additionally, both studies placed patients on highly restrictive diets of 500 kcal/d for 4 weeks. The feasibility of recommending such a diet to patients in clinical practice is questionable. Diets of less than 500 kcal/d may be dangerous for patients with underlying comorbidities and are unlikely to serve as long-term solutions.²³ To contextualize our findings, a 2022 review by Chung et al⁴² examined the impact of various diets—low-caloric, gluten-free, Mediterranean, Western, and ketogenic—on psoriasis and reported insufficient evidence to suggest a benefit to the ketogenic diet for psoriasis patients, though the Mediterranean diet may be well suited for psoriasis patients because of improved cardiovascular health and reduced mortality.

Seborrheic Dermatitis—Sanders et al⁴³ found that patients with a high-fruit diet had lower odds of having SD, while those on a Western diet had higher odds of having SD. Although the study did not measure glycemic load, it is conceivable that the high glycemic load characteristic of the Western diet contributed to these findings.⁴³ However, no studies have investigated the direct link between low-glycemic or ketogenic diets and SD, leaving this area open for further study.

Atopic Dermatitis—It has been hypothesized that mitigating T cell–mediated inflammation via glucose control may contribute to the improvement in AD.^35,36 However, in one study, 16.5% of AD patients self-identified sugar as a dietary trigger, ranking fourth among other dietary triggers.²⁴ Thus, the connection between glucose levels and AD warrants further exploration.

Hidradenitis Suppurativa—Given the role of metabolic and hormonal influence in HS as well as the overlapping pathophysiology with acne, it is possible that low-glycemic and ketogenic diets may have a role in improving HS.^38-40 However, there is a gap in observation and controlled studies investigating the link between low-glycemic or ketogenic diets and HS.

Conclusion

Our analysis focused on interventional and observational research exploring the effects of low-glycemic and ketogenic diets on associations and treatment of inflammatory skin conditions. There is sufficient evidence to counsel acne patients on the benefits of a low-glycemic diet as an adjunctive treatment for acne. Currently, there is insufficient evidence to recommend a low-glycemic or ketogenic diet as a treatment for patients with any other inflammatory skin disease. Prospective and controlled clinical trials are needed to clarify the utility of dietary interventions for treating inflammatory skin conditions.

Practice Gap

Punch biopsies are utilized frequently by dermatologists to aid in the diagnosis of various skin diseases.¹ When performing a punch biopsy, dermatologists are taught to use either forceps or skin hooks in addition to scissors to extract the tissue from the skin.² However, the use of these sterile instruments for a simple biopsy adds extra costs to the procedure. Herein, a cheaper and often faster method of obtaining the specimen from the patient is described.

The Technique

A 3- or 4-mm disposable punch biopsy tool is employed for this method. After locally anesthetizing the skin, the skin is punched to a subcutaneous depth utilizing the full length of the blade and a little extra pressure is applied downward while stretching the skin around (Figure, A). This may be helpful to dislodge the punch specimen from the surrounding skin. The specimen now can be easily removed by gently grasping it with the thumb and index finger (Figure, B and C). It then can be transferred immediately to the formalin container.

Practice Implications

This technique saves time as well as financial and environmental costs associated with the use of sterile instruments. An additional advantage to this simple method is avoiding specimen crush injuries, which are common when using forceps. This solution works in most cases but may not be suitable for certain special anatomic locations such as the scalp, nose, and ears.

Practice Gap

Punch biopsies are utilized frequently by dermatologists to aid in the diagnosis of various skin diseases.¹ When performing a punch biopsy, dermatologists are taught to use either forceps or skin hooks in addition to scissors to extract the tissue from the skin.² However, the use of these sterile instruments for a simple biopsy adds extra costs to the procedure. Herein, a cheaper and often faster method of obtaining the specimen from the patient is described.

The Technique

A 3- or 4-mm disposable punch biopsy tool is employed for this method. After locally anesthetizing the skin, the skin is punched to a subcutaneous depth utilizing the full length of the blade and a little extra pressure is applied downward while stretching the skin around (Figure, A). This may be helpful to dislodge the punch specimen from the surrounding skin. The specimen now can be easily removed by gently grasping it with the thumb and index finger (Figure, B and C). It then can be transferred immediately to the formalin container.

Practice Implications

This technique saves time as well as financial and environmental costs associated with the use of sterile instruments. An additional advantage to this simple method is avoiding specimen crush injuries, which are common when using forceps. This solution works in most cases but may not be suitable for certain special anatomic locations such as the scalp, nose, and ears.

Practice Gap

Punch biopsies are utilized frequently by dermatologists to aid in the diagnosis of various skin diseases.¹ When performing a punch biopsy, dermatologists are taught to use either forceps or skin hooks in addition to scissors to extract the tissue from the skin.² However, the use of these sterile instruments for a simple biopsy adds extra costs to the procedure. Herein, a cheaper and often faster method of obtaining the specimen from the patient is described.

The Technique

A 3- or 4-mm disposable punch biopsy tool is employed for this method. After locally anesthetizing the skin, the skin is punched to a subcutaneous depth utilizing the full length of the blade and a little extra pressure is applied downward while stretching the skin around (Figure, A). This may be helpful to dislodge the punch specimen from the surrounding skin. The specimen now can be easily removed by gently grasping it with the thumb and index finger (Figure, B and C). It then can be transferred immediately to the formalin container.

Practice Implications

This technique saves time as well as financial and environmental costs associated with the use of sterile instruments. An additional advantage to this simple method is avoiding specimen crush injuries, which are common when using forceps. This solution works in most cases but may not be suitable for certain special anatomic locations such as the scalp, nose, and ears.

If you feel like the day doesn’t hold enough hours for you to get your work done, you’re right: A new study found primary care physicians (PCPs) now need 27 hours a day to complete their clinical and nonclinical tasks — thanks in large part to the ever-growing burden of electronic health records (EHRs).

Investigators followed 141 academic PCPs between May 2019 and March 2023 and found they spent considerably more time engaging in EHR tasks during the final year of the study than in the prepandemic period. EHR time increased by over 8% on days with scheduled appointments and almost 20% on days without scheduled appointments.

“Physicians spend an unsustainable amount of time on EHR-based work, and that amount has increased steadily from 2019 to 2023,” Christine Sinsky, MD, vice president of professional satisfaction at the American Medical Association (AMA) and the senior author of the study, told this news organization. “It is imperative for healthcare systems to develop strategies to change the overall EHR workload trajectory to minimize PCPs’ occupational stress, including improved workflows, where the work is more appropriately distributed amongst the team.”

The study was published online on January 22, 2024, in the Annals of Family Medicine.
 

‘Pajama Time’

Dr. Sinsky said the motivation for conducting the current study was that PCPs have reported an increase in their workload, especially EHR tasks outside of work (“pajama time”) since the onset of the pandemic.

The research followed up on a 2017 analysis from the same group and other findings showing an increase in the time physicians spend in EHR tasks and the number of Inbox messages they receive from patients seeking medical advice increased during the months following the start of the pandemic.

“As a busy practicing PCP with a large panel of patients, my sense was that the workload was increasing even more, which is what our study confirmed,” said Brian G. Arndt, MD, of the Department of Family Medicine and Community Heath at the University of Wisconsin School of Medicine and Public Health, in Madison, Wisconsin, who led the new study.

The researchers analyzed EHR usage of 141 academic PCPs practicing family medicine, internal medicine, and general pediatrics, two thirds (66.7%) of whom were female. They compared the amount of time spent on EHR tasks during four timespans:

• May 2019 to February 2020
• June 2020 to March 2021
• May 2021 to March 2022
• April 2022 to March 2023

Each PCP’s time and Inbox message volume were calculated and then normalized over 8 hours of scheduled clinic appointments.
 

Increased Time, Increased Burnout

The study found evidence PCPs have reduced their clinical hours in response to their growing digital workload.

“We have a serious shortage of primary care physicians,” Dr. Sinsky said. “When PCPs cut back their clinical [work] as a coping mechanism for an unmanageable workload, this further exacerbates the primary care shortage, reducing access to care for patients.”

The researchers found increases from the first prepandemic period to the final period of their study in average time that PCPs spent at the EHR per 8 hours of scheduled clinic appointments (Table).

Tips for Reducing EHR Time

Arndt noted that some “brief investments” of time with patients “lead to high rates of return on decreased MyChart messaging.” For example, he has said to patients: “In the future, there’s no need to respond in MyChart with a ‘Thank you.’” Or “In the future, if you have questions from preappointment labs, no need to send me a separate message in MyChart prior to your visit since they’re typically just a few days out. I look closely at your labs and would always pick up the phone and call you if there was anything more urgent or pressing that needs more immediate action.”

Sinsky recommended two “high-yield opportunities” to reduce EHR-associated workload. The AMA offers a brief Inbox reduction checklist as well as a detailed toolkit to guide physicians and operational leaders in reducing the volume of unnecessary Inbox messages, she said.

Distribution of work among the team also can reduce the time physicians spent on order entry. “It doesn’t take a medical school education to enter orders for flu shots, lipid profiles, mammograms, and other tests, and yet we have primary care physicians around the country spending an hour or more per 8 hours of patient visits on this task,” she said.

‘Growing Mountain’

Sally Baxter, MD, assistant professor of ophthalmology and division chief for Ophthalmology Informatics and Data Sciences at University of California San Diego, said, “Studies like this ... are important for continuing to quantify the burden of EHR work and to evaluate potential interventions to reduce this burden and subsequent burnout.”

Baxter’s health system allows physicians to bill for asynchronous messaging when certain eligibility criteria are met. “This can deter frivolous messaging and also provide some compensation for the work involved,” she said.

“In addition, we’ve recently piloted using AI tools to help draft replies to patient messages in the EHR as another approach to tackling this important issue,” said Baxter, who wasn’t involved with the current study.

Eve Rittenberg, MD, an assistant professor at Harvard Medical School and a PCP at Brigham and Women’s Hospital Fish Center for Women’s Health, in Boston, recommended that healthcare systems “monitor EHR workload across gender, specialty, and other variables to develop equitable support and compensation models.”

Dr. Rittenberg, who wasn’t involved with the current study, said healthcare systems should consider supporting physicians by blocking out time during clinic sessions to manage their EHR work. “Cross-coverage systems are vital so that on their days off, physicians can unplug from the computer and know that their patients’ needs are being met,” she added.

This work was supported in part by the AMA Practice Transformation Initiative: EHR-Use Metrics Research which provided grant funding to several of the authors. Sinsky is employed by the AMA. Dr. Arndt and coauthors disclosed no relevant financial information. Dr. Baxter received nonfinancial support from Optonmed and Topcon for research studies and collaborated with some of the study authors on other research but not this particular study. Dr. Rittenberg received internal funding from the Brigham Care Redesign Incubator and Startup Program, Brigham and Women’s Hospital, for a previous pilot project of inbasket cross-coverage. She had no relevant current disclosures.
 

A version of this article appeared on Medscape.com.

If you feel like the day doesn’t hold enough hours for you to get your work done, you’re right: A new study found primary care physicians (PCPs) now need 27 hours a day to complete their clinical and nonclinical tasks — thanks in large part to the ever-growing burden of electronic health records (EHRs).

Investigators followed 141 academic PCPs between May 2019 and March 2023 and found they spent considerably more time engaging in EHR tasks during the final year of the study than in the prepandemic period. EHR time increased by over 8% on days with scheduled appointments and almost 20% on days without scheduled appointments.

“Physicians spend an unsustainable amount of time on EHR-based work, and that amount has increased steadily from 2019 to 2023,” Christine Sinsky, MD, vice president of professional satisfaction at the American Medical Association (AMA) and the senior author of the study, told this news organization. “It is imperative for healthcare systems to develop strategies to change the overall EHR workload trajectory to minimize PCPs’ occupational stress, including improved workflows, where the work is more appropriately distributed amongst the team.”

The study was published online on January 22, 2024, in the Annals of Family Medicine.
 

‘Pajama Time’

Dr. Sinsky said the motivation for conducting the current study was that PCPs have reported an increase in their workload, especially EHR tasks outside of work (“pajama time”) since the onset of the pandemic.

The research followed up on a 2017 analysis from the same group and other findings showing an increase in the time physicians spend in EHR tasks and the number of Inbox messages they receive from patients seeking medical advice increased during the months following the start of the pandemic.

“As a busy practicing PCP with a large panel of patients, my sense was that the workload was increasing even more, which is what our study confirmed,” said Brian G. Arndt, MD, of the Department of Family Medicine and Community Heath at the University of Wisconsin School of Medicine and Public Health, in Madison, Wisconsin, who led the new study.

The researchers analyzed EHR usage of 141 academic PCPs practicing family medicine, internal medicine, and general pediatrics, two thirds (66.7%) of whom were female. They compared the amount of time spent on EHR tasks during four timespans:

• May 2019 to February 2020
• June 2020 to March 2021
• May 2021 to March 2022
• April 2022 to March 2023

Each PCP’s time and Inbox message volume were calculated and then normalized over 8 hours of scheduled clinic appointments.
 

Increased Time, Increased Burnout

The study found evidence PCPs have reduced their clinical hours in response to their growing digital workload.

“We have a serious shortage of primary care physicians,” Dr. Sinsky said. “When PCPs cut back their clinical [work] as a coping mechanism for an unmanageable workload, this further exacerbates the primary care shortage, reducing access to care for patients.”

The researchers found increases from the first prepandemic period to the final period of their study in average time that PCPs spent at the EHR per 8 hours of scheduled clinic appointments (Table).

Tips for Reducing EHR Time

Arndt noted that some “brief investments” of time with patients “lead to high rates of return on decreased MyChart messaging.” For example, he has said to patients: “In the future, there’s no need to respond in MyChart with a ‘Thank you.’” Or “In the future, if you have questions from preappointment labs, no need to send me a separate message in MyChart prior to your visit since they’re typically just a few days out. I look closely at your labs and would always pick up the phone and call you if there was anything more urgent or pressing that needs more immediate action.”

Sinsky recommended two “high-yield opportunities” to reduce EHR-associated workload. The AMA offers a brief Inbox reduction checklist as well as a detailed toolkit to guide physicians and operational leaders in reducing the volume of unnecessary Inbox messages, she said.

Distribution of work among the team also can reduce the time physicians spent on order entry. “It doesn’t take a medical school education to enter orders for flu shots, lipid profiles, mammograms, and other tests, and yet we have primary care physicians around the country spending an hour or more per 8 hours of patient visits on this task,” she said.

‘Growing Mountain’

Sally Baxter, MD, assistant professor of ophthalmology and division chief for Ophthalmology Informatics and Data Sciences at University of California San Diego, said, “Studies like this ... are important for continuing to quantify the burden of EHR work and to evaluate potential interventions to reduce this burden and subsequent burnout.”

Baxter’s health system allows physicians to bill for asynchronous messaging when certain eligibility criteria are met. “This can deter frivolous messaging and also provide some compensation for the work involved,” she said.

“In addition, we’ve recently piloted using AI tools to help draft replies to patient messages in the EHR as another approach to tackling this important issue,” said Baxter, who wasn’t involved with the current study.

Eve Rittenberg, MD, an assistant professor at Harvard Medical School and a PCP at Brigham and Women’s Hospital Fish Center for Women’s Health, in Boston, recommended that healthcare systems “monitor EHR workload across gender, specialty, and other variables to develop equitable support and compensation models.”

Dr. Rittenberg, who wasn’t involved with the current study, said healthcare systems should consider supporting physicians by blocking out time during clinic sessions to manage their EHR work. “Cross-coverage systems are vital so that on their days off, physicians can unplug from the computer and know that their patients’ needs are being met,” she added.

This work was supported in part by the AMA Practice Transformation Initiative: EHR-Use Metrics Research which provided grant funding to several of the authors. Sinsky is employed by the AMA. Dr. Arndt and coauthors disclosed no relevant financial information. Dr. Baxter received nonfinancial support from Optonmed and Topcon for research studies and collaborated with some of the study authors on other research but not this particular study. Dr. Rittenberg received internal funding from the Brigham Care Redesign Incubator and Startup Program, Brigham and Women’s Hospital, for a previous pilot project of inbasket cross-coverage. She had no relevant current disclosures.
 

A version of this article appeared on Medscape.com.

If you feel like the day doesn’t hold enough hours for you to get your work done, you’re right: A new study found primary care physicians (PCPs) now need 27 hours a day to complete their clinical and nonclinical tasks — thanks in large part to the ever-growing burden of electronic health records (EHRs).

Investigators followed 141 academic PCPs between May 2019 and March 2023 and found they spent considerably more time engaging in EHR tasks during the final year of the study than in the prepandemic period. EHR time increased by over 8% on days with scheduled appointments and almost 20% on days without scheduled appointments.

“Physicians spend an unsustainable amount of time on EHR-based work, and that amount has increased steadily from 2019 to 2023,” Christine Sinsky, MD, vice president of professional satisfaction at the American Medical Association (AMA) and the senior author of the study, told this news organization. “It is imperative for healthcare systems to develop strategies to change the overall EHR workload trajectory to minimize PCPs’ occupational stress, including improved workflows, where the work is more appropriately distributed amongst the team.”

The study was published online on January 22, 2024, in the Annals of Family Medicine.
 

‘Pajama Time’

Dr. Sinsky said the motivation for conducting the current study was that PCPs have reported an increase in their workload, especially EHR tasks outside of work (“pajama time”) since the onset of the pandemic.

The research followed up on a 2017 analysis from the same group and other findings showing an increase in the time physicians spend in EHR tasks and the number of Inbox messages they receive from patients seeking medical advice increased during the months following the start of the pandemic.

“As a busy practicing PCP with a large panel of patients, my sense was that the workload was increasing even more, which is what our study confirmed,” said Brian G. Arndt, MD, of the Department of Family Medicine and Community Heath at the University of Wisconsin School of Medicine and Public Health, in Madison, Wisconsin, who led the new study.

The researchers analyzed EHR usage of 141 academic PCPs practicing family medicine, internal medicine, and general pediatrics, two thirds (66.7%) of whom were female. They compared the amount of time spent on EHR tasks during four timespans:

• May 2019 to February 2020
• June 2020 to March 2021
• May 2021 to March 2022
• April 2022 to March 2023

Each PCP’s time and Inbox message volume were calculated and then normalized over 8 hours of scheduled clinic appointments.
 

Increased Time, Increased Burnout

The study found evidence PCPs have reduced their clinical hours in response to their growing digital workload.

“We have a serious shortage of primary care physicians,” Dr. Sinsky said. “When PCPs cut back their clinical [work] as a coping mechanism for an unmanageable workload, this further exacerbates the primary care shortage, reducing access to care for patients.”

The researchers found increases from the first prepandemic period to the final period of their study in average time that PCPs spent at the EHR per 8 hours of scheduled clinic appointments (Table).

Tips for Reducing EHR Time

Arndt noted that some “brief investments” of time with patients “lead to high rates of return on decreased MyChart messaging.” For example, he has said to patients: “In the future, there’s no need to respond in MyChart with a ‘Thank you.’” Or “In the future, if you have questions from preappointment labs, no need to send me a separate message in MyChart prior to your visit since they’re typically just a few days out. I look closely at your labs and would always pick up the phone and call you if there was anything more urgent or pressing that needs more immediate action.”

Sinsky recommended two “high-yield opportunities” to reduce EHR-associated workload. The AMA offers a brief Inbox reduction checklist as well as a detailed toolkit to guide physicians and operational leaders in reducing the volume of unnecessary Inbox messages, she said.

Distribution of work among the team also can reduce the time physicians spent on order entry. “It doesn’t take a medical school education to enter orders for flu shots, lipid profiles, mammograms, and other tests, and yet we have primary care physicians around the country spending an hour or more per 8 hours of patient visits on this task,” she said.

‘Growing Mountain’

Sally Baxter, MD, assistant professor of ophthalmology and division chief for Ophthalmology Informatics and Data Sciences at University of California San Diego, said, “Studies like this ... are important for continuing to quantify the burden of EHR work and to evaluate potential interventions to reduce this burden and subsequent burnout.”

Baxter’s health system allows physicians to bill for asynchronous messaging when certain eligibility criteria are met. “This can deter frivolous messaging and also provide some compensation for the work involved,” she said.

“In addition, we’ve recently piloted using AI tools to help draft replies to patient messages in the EHR as another approach to tackling this important issue,” said Baxter, who wasn’t involved with the current study.

Eve Rittenberg, MD, an assistant professor at Harvard Medical School and a PCP at Brigham and Women’s Hospital Fish Center for Women’s Health, in Boston, recommended that healthcare systems “monitor EHR workload across gender, specialty, and other variables to develop equitable support and compensation models.”

Dr. Rittenberg, who wasn’t involved with the current study, said healthcare systems should consider supporting physicians by blocking out time during clinic sessions to manage their EHR work. “Cross-coverage systems are vital so that on their days off, physicians can unplug from the computer and know that their patients’ needs are being met,” she added.

This work was supported in part by the AMA Practice Transformation Initiative: EHR-Use Metrics Research which provided grant funding to several of the authors. Sinsky is employed by the AMA. Dr. Arndt and coauthors disclosed no relevant financial information. Dr. Baxter received nonfinancial support from Optonmed and Topcon for research studies and collaborated with some of the study authors on other research but not this particular study. Dr. Rittenberg received internal funding from the Brigham Care Redesign Incubator and Startup Program, Brigham and Women’s Hospital, for a previous pilot project of inbasket cross-coverage. She had no relevant current disclosures.
 

A version of this article appeared on Medscape.com.

A pair of dueling editorials in the journal Hypertension debate whether our focus should be on sodium or its often neglected partner, potassium.

Should we cut sodium from our diet or eat more potassium to lower blood pressure? The answer requires an intricate understanding of renal physiology that is fascinating. To nephrologists. A meta-analysis of 85 trials showed a consistent and linear. It may also depend on where you live and whether your concern is treating individuals or implementing effective food policy.

The Case for Sodium Restriction

Stephen Juraschek, MD, PhD, of the Beth Israel Deaconess Medical Center, Boston, Massachusetts, co-author of one editorial, told me in a zoom interview that he believes his side of the debate clearly has the stronger argument. Of the two cations in question, there has been infinitely more ink spilled about sodium.

Studies such as INTERSALT, the DASH diet, and TOHP may be the most well-known, but there are many, many intervention studies of sodium restriction’s effect on blood pressure. A meta-analysis of 85 trials of showed a consistent and linear relationship between sodium reduction and blood pressure. In contrast, the evidence base for potassium is more limited and less consistent. There are half as many trials with potassium, and its ability to lower blood pressure may depend on how much sodium is present in the diet.

An outlier in the sodium restriction evidence base is the PURE study, which suggested that extreme sodium restriction could increase cardiovascular mortality, but the trial suffered from two potential issues. First, it used a single spot urine specimen to measure sodium rather than the generally accepted more accurate 24-hour urine collection. A reanalysis of the TOHP study using a spot urine rather than a 24-hour urine collection changed the relationship between sodium intake and mortality and possibly explained the U-shaped association observed in PURE. Second, PURE was an observational cohort and was prone to confounding, or in this case, reverse causation. Why did people who consumed very little salt have an increased risk for cardiovascular disease? It is very possible that people with a high risk for cardiovascular disease were told to consume less salt to begin with. Hence B led to A rather than A leading to B.

The debate on sodium restriction has been bitter at times. Opposing camps formed, and people took sides in the “salt wars.” A group of researchers, termed the Jackson 6, met and decided to end the controversy by running a randomized trial in US prisons (having discounted the options of long-term care homes and military bases). They detailed their plan in an editorial in Hypertension. The study never came to fruition for two reasons: the obvious ethical problems of experimenting on prisoners and the revelation of undisclosed salt industry funding.

More recent studies have mercifully been more conventional. The SSaSS study, a randomized controlled trial of a salt substitute, provided the cardiovascular outcomes data that many were waiting for. And CARDIA-SSBP, a cross-over randomized trial recently presented at the American Heart Association meeting, showed that reducing dietary sodium was on par with medication when it came to lowering blood pressure.

For Dr. Juraschek, the evidence is clear: “If you were going to choose one, I would say the weight of the evidence is still really heavily on the sodium side.”

The Case for Potassium Supplementation

The evidence for salt restriction notwithstanding, Swapnil Hiremath, MD, MPH, from the University of Ottawa, Ontario, Canada, argued in his editorial that potassium supplementation has gotten short shrift. Though he admits the studies for potassium supplementation have been smaller and sometimes rely on observational evidence, the evidence is there. In the distal convoluted tubule, the sodium chloride cotransporter (NCC), aka the potassium switch, is turned on by low potassium levels and leads to sodium reabsorption by the kidney even in settings of high sodium intake (Figure). To nonnephrologists, renal physiology may be a black box. But if you quickly brush up on the mechanism of action of thiazide diuretics, the preceding descriptor will make more sense.

Medscape

Realistic Diets and Taste Issues

“We know that increasing potassium, decreasing sodium is useful. The question is how do we do that?” says Dr. Hiremath. Should we encourage fruit and vegetable consumption in a healthy diet, give potassium supplements, or encourage the use of low-sodium salt substitutes?

Recommending a healthier diet with more fruits and vegetables is a no-brainer. But getting people to do it is hard. In a world where fruit is more expensive than junk food is, economic realities may drive food choice regardless of our best efforts. The 4700 mg of potassium in the DASH eating plan is the equivalent of eleven bananas daily; although not impossible, it would require a substantive shift in eating patterns for most people.

Given that we prescribe iron, vitamin B12, calcium, and vitamin D to patients who need them, why not potassium tablets to help with blood pressure? Granted, there are concerns about inducing hyperkalemia. Also, why not just prescribe a proven anti-hypertensive, such as ramipril, which has the added benefit of helping with renal protection or cardiac remodeling? Dr. Hiremath points out that patients are far less reluctant to take dietary supplements. Medication is something you take when sick. A supplement is seen as “natural” and “healthy” and might be more attractive to people resistant to prescription meds.

Another drawback of oral potassium supplementation is taste. In a Consumer Reports taste test, potassium chloride fared poorly. It was bitter and had a metallic aftertaste. At least one tester wouldn’t ever consume it again. Potassium citrate is slightly more palpable.

Salt substitutes, like the 75:25 ratio of sodium to potassium used in SSaSS, may be as high as you can go for potassium in any low-sodium salt alternative. If you go any higher than that, the taste will just turn people off, suggests Dr. Hiremath.

But SsaSS, which was done in China, may not be relevant to North America. In China, most sodium is added during cooking at home, and the consumption of processed foods is low. For the typical North American, roughly three quarters of the sodium eaten is added to their food by someone else; only about 15% is added during cooking at home or at the dinner table. If you aren’t someone who cooks, buying a salt substitute is probably not going to have much impact.

Given that reality, Dr. Juraschek thinks we need to target the sodium in processed foods. “There’s just so much sodium in so many products,” he says. “When you think about public policy, it’s most expeditious for there to be more regulation about how much is added to our food supply vs trying to get people to consume eight to 12 servings of fruit.”

No Salt War Here

Despite their different editorial takes, Dr. Hiremath and Dr. Juraschek largely agree on the broad strokes of the problem. This isn’t X (or Twitter) after all. Potassium supplementation may be useful in some parts of the world but may not address the underlying problem in countries where processed foods are the source of most dietary sodium.

The CARDIA-SSBP trial showed that a very low–sodium diet had the same blood pressure–lowering effect as a first-line antihypertensive, but most people will not be able to limit themselves to 500 mg of dietary sodium per day. In CARDIA-SSBP, just as in DASH, participants were provided with meals from study kitchens. They were not just told to eat less salt, which would almost certainly have failed.

“We should aim for stuff that is practical and doable rather than aim for stuff that cannot be done,” according to Dr. Hiremath. Whether that should be salt substitutes or policy change may depend on which part of the planet you live on.

One recent positive change may herald the beginning of a policy change, at least in the United States. In March 2023, the US Food and Drug Administration proposed a rule change to allow salt substitutes to be labeled as salt. This would make it easier for food manufacturers to swap out sodium chloride for a low-sodium alternative and reduce the amount of sodium in the US diet without having a large impact on taste and consumer uptake. Both Dr. Hiremath and Dr. Juraschek agree that it may not be enough on its own but that it’s a start.

Christopher Labos is a cardiologist with a degree in epidemiology. He spends most of his time doing things that he doesn’t get paid for, like research, teaching, and podcasting. Occasionally, he finds time to practice cardiology to pay the rent. He realizes that half of his research findings will be disproved in 5 years; he just doesn’t know which half. He is a regular contributor to the Montreal Gazette, CJAD radio, and CTV television in Montreal, and is host of the award-winning podcast The Body of Evidence.

A version of this article appeared on Medscape.com.

A pair of dueling editorials in the journal Hypertension debate whether our focus should be on sodium or its often neglected partner, potassium.

Should we cut sodium from our diet or eat more potassium to lower blood pressure? The answer requires an intricate understanding of renal physiology that is fascinating. To nephrologists. A meta-analysis of 85 trials showed a consistent and linear. It may also depend on where you live and whether your concern is treating individuals or implementing effective food policy.

The Case for Sodium Restriction

Stephen Juraschek, MD, PhD, of the Beth Israel Deaconess Medical Center, Boston, Massachusetts, co-author of one editorial, told me in a zoom interview that he believes his side of the debate clearly has the stronger argument. Of the two cations in question, there has been infinitely more ink spilled about sodium.

Studies such as INTERSALT, the DASH diet, and TOHP may be the most well-known, but there are many, many intervention studies of sodium restriction’s effect on blood pressure. A meta-analysis of 85 trials of showed a consistent and linear relationship between sodium reduction and blood pressure. In contrast, the evidence base for potassium is more limited and less consistent. There are half as many trials with potassium, and its ability to lower blood pressure may depend on how much sodium is present in the diet.

An outlier in the sodium restriction evidence base is the PURE study, which suggested that extreme sodium restriction could increase cardiovascular mortality, but the trial suffered from two potential issues. First, it used a single spot urine specimen to measure sodium rather than the generally accepted more accurate 24-hour urine collection. A reanalysis of the TOHP study using a spot urine rather than a 24-hour urine collection changed the relationship between sodium intake and mortality and possibly explained the U-shaped association observed in PURE. Second, PURE was an observational cohort and was prone to confounding, or in this case, reverse causation. Why did people who consumed very little salt have an increased risk for cardiovascular disease? It is very possible that people with a high risk for cardiovascular disease were told to consume less salt to begin with. Hence B led to A rather than A leading to B.

The debate on sodium restriction has been bitter at times. Opposing camps formed, and people took sides in the “salt wars.” A group of researchers, termed the Jackson 6, met and decided to end the controversy by running a randomized trial in US prisons (having discounted the options of long-term care homes and military bases). They detailed their plan in an editorial in Hypertension. The study never came to fruition for two reasons: the obvious ethical problems of experimenting on prisoners and the revelation of undisclosed salt industry funding.

More recent studies have mercifully been more conventional. The SSaSS study, a randomized controlled trial of a salt substitute, provided the cardiovascular outcomes data that many were waiting for. And CARDIA-SSBP, a cross-over randomized trial recently presented at the American Heart Association meeting, showed that reducing dietary sodium was on par with medication when it came to lowering blood pressure.

For Dr. Juraschek, the evidence is clear: “If you were going to choose one, I would say the weight of the evidence is still really heavily on the sodium side.”

The Case for Potassium Supplementation

The evidence for salt restriction notwithstanding, Swapnil Hiremath, MD, MPH, from the University of Ottawa, Ontario, Canada, argued in his editorial that potassium supplementation has gotten short shrift. Though he admits the studies for potassium supplementation have been smaller and sometimes rely on observational evidence, the evidence is there. In the distal convoluted tubule, the sodium chloride cotransporter (NCC), aka the potassium switch, is turned on by low potassium levels and leads to sodium reabsorption by the kidney even in settings of high sodium intake (Figure). To nonnephrologists, renal physiology may be a black box. But if you quickly brush up on the mechanism of action of thiazide diuretics, the preceding descriptor will make more sense.

Medscape

Realistic Diets and Taste Issues

“We know that increasing potassium, decreasing sodium is useful. The question is how do we do that?” says Dr. Hiremath. Should we encourage fruit and vegetable consumption in a healthy diet, give potassium supplements, or encourage the use of low-sodium salt substitutes?

Recommending a healthier diet with more fruits and vegetables is a no-brainer. But getting people to do it is hard. In a world where fruit is more expensive than junk food is, economic realities may drive food choice regardless of our best efforts. The 4700 mg of potassium in the DASH eating plan is the equivalent of eleven bananas daily; although not impossible, it would require a substantive shift in eating patterns for most people.

Given that we prescribe iron, vitamin B12, calcium, and vitamin D to patients who need them, why not potassium tablets to help with blood pressure? Granted, there are concerns about inducing hyperkalemia. Also, why not just prescribe a proven anti-hypertensive, such as ramipril, which has the added benefit of helping with renal protection or cardiac remodeling? Dr. Hiremath points out that patients are far less reluctant to take dietary supplements. Medication is something you take when sick. A supplement is seen as “natural” and “healthy” and might be more attractive to people resistant to prescription meds.

Another drawback of oral potassium supplementation is taste. In a Consumer Reports taste test, potassium chloride fared poorly. It was bitter and had a metallic aftertaste. At least one tester wouldn’t ever consume it again. Potassium citrate is slightly more palpable.

Salt substitutes, like the 75:25 ratio of sodium to potassium used in SSaSS, may be as high as you can go for potassium in any low-sodium salt alternative. If you go any higher than that, the taste will just turn people off, suggests Dr. Hiremath.

But SsaSS, which was done in China, may not be relevant to North America. In China, most sodium is added during cooking at home, and the consumption of processed foods is low. For the typical North American, roughly three quarters of the sodium eaten is added to their food by someone else; only about 15% is added during cooking at home or at the dinner table. If you aren’t someone who cooks, buying a salt substitute is probably not going to have much impact.

Given that reality, Dr. Juraschek thinks we need to target the sodium in processed foods. “There’s just so much sodium in so many products,” he says. “When you think about public policy, it’s most expeditious for there to be more regulation about how much is added to our food supply vs trying to get people to consume eight to 12 servings of fruit.”

No Salt War Here

Despite their different editorial takes, Dr. Hiremath and Dr. Juraschek largely agree on the broad strokes of the problem. This isn’t X (or Twitter) after all. Potassium supplementation may be useful in some parts of the world but may not address the underlying problem in countries where processed foods are the source of most dietary sodium.

The CARDIA-SSBP trial showed that a very low–sodium diet had the same blood pressure–lowering effect as a first-line antihypertensive, but most people will not be able to limit themselves to 500 mg of dietary sodium per day. In CARDIA-SSBP, just as in DASH, participants were provided with meals from study kitchens. They were not just told to eat less salt, which would almost certainly have failed.

“We should aim for stuff that is practical and doable rather than aim for stuff that cannot be done,” according to Dr. Hiremath. Whether that should be salt substitutes or policy change may depend on which part of the planet you live on.

One recent positive change may herald the beginning of a policy change, at least in the United States. In March 2023, the US Food and Drug Administration proposed a rule change to allow salt substitutes to be labeled as salt. This would make it easier for food manufacturers to swap out sodium chloride for a low-sodium alternative and reduce the amount of sodium in the US diet without having a large impact on taste and consumer uptake. Both Dr. Hiremath and Dr. Juraschek agree that it may not be enough on its own but that it’s a start.

Christopher Labos is a cardiologist with a degree in epidemiology. He spends most of his time doing things that he doesn’t get paid for, like research, teaching, and podcasting. Occasionally, he finds time to practice cardiology to pay the rent. He realizes that half of his research findings will be disproved in 5 years; he just doesn’t know which half. He is a regular contributor to the Montreal Gazette, CJAD radio, and CTV television in Montreal, and is host of the award-winning podcast The Body of Evidence.

A version of this article appeared on Medscape.com.

A pair of dueling editorials in the journal Hypertension debate whether our focus should be on sodium or its often neglected partner, potassium.

Should we cut sodium from our diet or eat more potassium to lower blood pressure? The answer requires an intricate understanding of renal physiology that is fascinating. To nephrologists. A meta-analysis of 85 trials showed a consistent and linear. It may also depend on where you live and whether your concern is treating individuals or implementing effective food policy.

The Case for Sodium Restriction

Stephen Juraschek, MD, PhD, of the Beth Israel Deaconess Medical Center, Boston, Massachusetts, co-author of one editorial, told me in a zoom interview that he believes his side of the debate clearly has the stronger argument. Of the two cations in question, there has been infinitely more ink spilled about sodium.

Studies such as INTERSALT, the DASH diet, and TOHP may be the most well-known, but there are many, many intervention studies of sodium restriction’s effect on blood pressure. A meta-analysis of 85 trials of showed a consistent and linear relationship between sodium reduction and blood pressure. In contrast, the evidence base for potassium is more limited and less consistent. There are half as many trials with potassium, and its ability to lower blood pressure may depend on how much sodium is present in the diet.

An outlier in the sodium restriction evidence base is the PURE study, which suggested that extreme sodium restriction could increase cardiovascular mortality, but the trial suffered from two potential issues. First, it used a single spot urine specimen to measure sodium rather than the generally accepted more accurate 24-hour urine collection. A reanalysis of the TOHP study using a spot urine rather than a 24-hour urine collection changed the relationship between sodium intake and mortality and possibly explained the U-shaped association observed in PURE. Second, PURE was an observational cohort and was prone to confounding, or in this case, reverse causation. Why did people who consumed very little salt have an increased risk for cardiovascular disease? It is very possible that people with a high risk for cardiovascular disease were told to consume less salt to begin with. Hence B led to A rather than A leading to B.

The debate on sodium restriction has been bitter at times. Opposing camps formed, and people took sides in the “salt wars.” A group of researchers, termed the Jackson 6, met and decided to end the controversy by running a randomized trial in US prisons (having discounted the options of long-term care homes and military bases). They detailed their plan in an editorial in Hypertension. The study never came to fruition for two reasons: the obvious ethical problems of experimenting on prisoners and the revelation of undisclosed salt industry funding.

More recent studies have mercifully been more conventional. The SSaSS study, a randomized controlled trial of a salt substitute, provided the cardiovascular outcomes data that many were waiting for. And CARDIA-SSBP, a cross-over randomized trial recently presented at the American Heart Association meeting, showed that reducing dietary sodium was on par with medication when it came to lowering blood pressure.

For Dr. Juraschek, the evidence is clear: “If you were going to choose one, I would say the weight of the evidence is still really heavily on the sodium side.”

The Case for Potassium Supplementation

The evidence for salt restriction notwithstanding, Swapnil Hiremath, MD, MPH, from the University of Ottawa, Ontario, Canada, argued in his editorial that potassium supplementation has gotten short shrift. Though he admits the studies for potassium supplementation have been smaller and sometimes rely on observational evidence, the evidence is there. In the distal convoluted tubule, the sodium chloride cotransporter (NCC), aka the potassium switch, is turned on by low potassium levels and leads to sodium reabsorption by the kidney even in settings of high sodium intake (Figure). To nonnephrologists, renal physiology may be a black box. But if you quickly brush up on the mechanism of action of thiazide diuretics, the preceding descriptor will make more sense.

Medscape

Realistic Diets and Taste Issues

“We know that increasing potassium, decreasing sodium is useful. The question is how do we do that?” says Dr. Hiremath. Should we encourage fruit and vegetable consumption in a healthy diet, give potassium supplements, or encourage the use of low-sodium salt substitutes?

Recommending a healthier diet with more fruits and vegetables is a no-brainer. But getting people to do it is hard. In a world where fruit is more expensive than junk food is, economic realities may drive food choice regardless of our best efforts. The 4700 mg of potassium in the DASH eating plan is the equivalent of eleven bananas daily; although not impossible, it would require a substantive shift in eating patterns for most people.

Given that we prescribe iron, vitamin B12, calcium, and vitamin D to patients who need them, why not potassium tablets to help with blood pressure? Granted, there are concerns about inducing hyperkalemia. Also, why not just prescribe a proven anti-hypertensive, such as ramipril, which has the added benefit of helping with renal protection or cardiac remodeling? Dr. Hiremath points out that patients are far less reluctant to take dietary supplements. Medication is something you take when sick. A supplement is seen as “natural” and “healthy” and might be more attractive to people resistant to prescription meds.

Another drawback of oral potassium supplementation is taste. In a Consumer Reports taste test, potassium chloride fared poorly. It was bitter and had a metallic aftertaste. At least one tester wouldn’t ever consume it again. Potassium citrate is slightly more palpable.

Salt substitutes, like the 75:25 ratio of sodium to potassium used in SSaSS, may be as high as you can go for potassium in any low-sodium salt alternative. If you go any higher than that, the taste will just turn people off, suggests Dr. Hiremath.

But SsaSS, which was done in China, may not be relevant to North America. In China, most sodium is added during cooking at home, and the consumption of processed foods is low. For the typical North American, roughly three quarters of the sodium eaten is added to their food by someone else; only about 15% is added during cooking at home or at the dinner table. If you aren’t someone who cooks, buying a salt substitute is probably not going to have much impact.

Given that reality, Dr. Juraschek thinks we need to target the sodium in processed foods. “There’s just so much sodium in so many products,” he says. “When you think about public policy, it’s most expeditious for there to be more regulation about how much is added to our food supply vs trying to get people to consume eight to 12 servings of fruit.”

No Salt War Here

Despite their different editorial takes, Dr. Hiremath and Dr. Juraschek largely agree on the broad strokes of the problem. This isn’t X (or Twitter) after all. Potassium supplementation may be useful in some parts of the world but may not address the underlying problem in countries where processed foods are the source of most dietary sodium.

The CARDIA-SSBP trial showed that a very low–sodium diet had the same blood pressure–lowering effect as a first-line antihypertensive, but most people will not be able to limit themselves to 500 mg of dietary sodium per day. In CARDIA-SSBP, just as in DASH, participants were provided with meals from study kitchens. They were not just told to eat less salt, which would almost certainly have failed.

“We should aim for stuff that is practical and doable rather than aim for stuff that cannot be done,” according to Dr. Hiremath. Whether that should be salt substitutes or policy change may depend on which part of the planet you live on.

One recent positive change may herald the beginning of a policy change, at least in the United States. In March 2023, the US Food and Drug Administration proposed a rule change to allow salt substitutes to be labeled as salt. This would make it easier for food manufacturers to swap out sodium chloride for a low-sodium alternative and reduce the amount of sodium in the US diet without having a large impact on taste and consumer uptake. Both Dr. Hiremath and Dr. Juraschek agree that it may not be enough on its own but that it’s a start.

Christopher Labos is a cardiologist with a degree in epidemiology. He spends most of his time doing things that he doesn’t get paid for, like research, teaching, and podcasting. Occasionally, he finds time to practice cardiology to pay the rent. He realizes that half of his research findings will be disproved in 5 years; he just doesn’t know which half. He is a regular contributor to the Montreal Gazette, CJAD radio, and CTV television in Montreal, and is host of the award-winning podcast The Body of Evidence.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

From the year 2000 until around 2016, the incidence of breast cancer among young women — those under age 50 — rose steadily, if slowly.

JAMA Network Open

JAMA Network Open

JAMA Network Open

Dr. F. Perry Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

From the year 2000 until around 2016, the incidence of breast cancer among young women — those under age 50 — rose steadily, if slowly.

JAMA Network Open

JAMA Network Open

JAMA Network Open

Dr. F. Perry Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

From the year 2000 until around 2016, the incidence of breast cancer among young women — those under age 50 — rose steadily, if slowly.

JAMA Network Open

JAMA Network Open

JAMA Network Open

Dr. F. Perry Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Have patients who want to lose weight? Tell them to put on their dancing shoes. 

Dancing can be an effective fat-loss tool for people who are overweight or have obesity, according to a recent meta-analysis in PLOS One. People who danced regularly lost about four more pounds — including three and a half pounds of fat — than those who didn’t dance. They also shaved an extra inch off their waists. 

Participants who danced three times a week for at least 3 months reaped maximum benefits. And the more they let loose, the better — more creative dance forms led to more pronounced improvements in body composition. 

The study builds on previous research that suggests dance can be beneficial for weight loss and overall health. A 2017 meta-analysis found that dance significantly improved body composition, blood biomarkers, and musculoskeletal function. Other research has linked dance with improvements in cognitive function, mental health, and quality of life.  

What makes dance special? It’s a full-body workout that might be easier to stick with than other exercises. “Enjoyment” is key for sustainability, the researchers wrote: “As a form of physical activity that integrates exercise, entertainment, and sociality, dance possesses innate advantages in fostering motivation for exercise.”

“The best exercise is the one you’ll do every day, and something that you like to do,” said Nicholas Pennings, DO, chair and associate professor of family medicine at Campbell University, Buies Creek, NC. (Dr. Pennings was not involved in the study.) For patients who enjoy dancing, dance could be that thing — or at least one workout to add to the mix. 

Help your patients get started with these tips. 

Frame it as a hobby, not exercise. Ask what hobbies they used to enjoy in high school, suggests Deirdre Mattina, MD, a cardiologist at the Cleveland Clinic and a former professional dancer. “ This can sometimes evoke happy memories of younger years and perhaps hobbies that they’d given up because they thought they were too old,” she said. If they used to play sports or dance, that’s your in. “I usually talk about hot yoga as a transition to get back their flexibility and then something like a dance aerobics or Zumba class to start.”

Recommend a group class. “Any intervention promoting social relationships is expected to increase adherence,” said Giulio Marchesini Reggiani, MD, a recently retired professor of internal medicine and dietetics at the University of Bologna in Italy. “You are motivated by the group, and you create a relationship among participants, and this means that you are no longer alone.” Try local gyms, health clubs, or even dance studios (yes, where kids go — they offer adult classes, too).

Help patients find their unique groove. Dr. Mattina has some patients who take cardio dance classes, some who line dance, and others who pole dance or heels dance. “Those are the things that keep it fun,” she said. “It doesn’t seem like exercise. It seems more like going out and hanging out.” 

Encourage those who “don’t know how to dance.” You don’t need fancy choreography or the grace of a prima ballerina.”Simply move aided by the music,” said Dr. Reggiani. “As long as you start engaging in physical activity, you improve your health, and you improve your movement.” Suggest patients start with beginner Zumba or a step class to get the hang of moving to a beat. Or try a home dance video, like Barre Blend by BODi (which offers a 14-day free trial). “You can try taking a couple classes in the privacy of your own home first, so you feel comfortable getting out there and doing it with a group,” said Dr. Mattina.

Modify as needed. If a patient has mobility limitations or lower-body pain, they can still dance — just do the upper-body portion of the moves. “Dance involves both upper and lower body movement, and so many dance activities could easily be performed in a chair,” said Dr. Pennings. A good joint-friendly option: Some health clubs offer dance classes that take place in a swimming pool.

Involve the whole family. Support from a partner can help patients stick with exercise, said Dr. Reggiani, and dance can also help a couple strengthen their bond. Invite kids and grandparents to join, too. “Dancing is something that can be done at any age,” said Dr. Reggiani. “For kids, it is important to make it fun,” said Dr. Pennings. “Start when they are young with music they are familiar with and enjoy.” For skeptical partners? “Keep it simple and nonjudgmental,” he said.

Remind patients to warm up. We lose flexibility with age, so ease into it, said Dr. Mattina. Many classes include warmups, but if you’re at home, do a few minutes of light, low-impact cardio — jumping jacks, mountain climbers, jogging, or brisk walking — before stretching. Or just put on a slow song and start lightly bouncing to the beat or stepping your feet to one side, together, then to the other side and together.

Tell them to take dance breaks. No time to join a class? Break up the workday with a few 10-minute dance parties. (That’s about three songs.) “Short bursts of exercise throughout the day, like if you do 10 minutes of exercise six times a day, actually has a greater health benefit than doing 60 minutes of continuous exercise,” said Dr. Pennings. It helps counter the negative effects of prolonged sitting “by increasing blood flow and increasing utilization of your muscles.”

Manage expectations about weight loss. Patients often have outsized expectations about how much weight they’ll lose when starting a new exercise regimen, Dr. Pennings said. Dancing burns about 300 calories per hour, so it takes roughly 12 hours to lose one pound. Consistency over time is the key. “My goal is to both emphasize the health benefits of exercise while maintaining realistic expectations about weight loss,” said Dr. Pennings. Focus less on the weight part and highlight other benefits: Dancing builds strength, balance, and coordination, said Dr. Pennings. It can help improve blood pressure and other heart health markers and boost cognition in older adults. And it’s fun.  
 

A version of this article appeared on Medscape.com.

Have patients who want to lose weight? Tell them to put on their dancing shoes. 

Dancing can be an effective fat-loss tool for people who are overweight or have obesity, according to a recent meta-analysis in PLOS One. People who danced regularly lost about four more pounds — including three and a half pounds of fat — than those who didn’t dance. They also shaved an extra inch off their waists. 

Participants who danced three times a week for at least 3 months reaped maximum benefits. And the more they let loose, the better — more creative dance forms led to more pronounced improvements in body composition. 

The study builds on previous research that suggests dance can be beneficial for weight loss and overall health. A 2017 meta-analysis found that dance significantly improved body composition, blood biomarkers, and musculoskeletal function. Other research has linked dance with improvements in cognitive function, mental health, and quality of life.  

What makes dance special? It’s a full-body workout that might be easier to stick with than other exercises. “Enjoyment” is key for sustainability, the researchers wrote: “As a form of physical activity that integrates exercise, entertainment, and sociality, dance possesses innate advantages in fostering motivation for exercise.”

“The best exercise is the one you’ll do every day, and something that you like to do,” said Nicholas Pennings, DO, chair and associate professor of family medicine at Campbell University, Buies Creek, NC. (Dr. Pennings was not involved in the study.) For patients who enjoy dancing, dance could be that thing — or at least one workout to add to the mix. 

Help your patients get started with these tips. 

Frame it as a hobby, not exercise. Ask what hobbies they used to enjoy in high school, suggests Deirdre Mattina, MD, a cardiologist at the Cleveland Clinic and a former professional dancer. “ This can sometimes evoke happy memories of younger years and perhaps hobbies that they’d given up because they thought they were too old,” she said. If they used to play sports or dance, that’s your in. “I usually talk about hot yoga as a transition to get back their flexibility and then something like a dance aerobics or Zumba class to start.”

Recommend a group class. “Any intervention promoting social relationships is expected to increase adherence,” said Giulio Marchesini Reggiani, MD, a recently retired professor of internal medicine and dietetics at the University of Bologna in Italy. “You are motivated by the group, and you create a relationship among participants, and this means that you are no longer alone.” Try local gyms, health clubs, or even dance studios (yes, where kids go — they offer adult classes, too).

Help patients find their unique groove. Dr. Mattina has some patients who take cardio dance classes, some who line dance, and others who pole dance or heels dance. “Those are the things that keep it fun,” she said. “It doesn’t seem like exercise. It seems more like going out and hanging out.” 

Encourage those who “don’t know how to dance.” You don’t need fancy choreography or the grace of a prima ballerina.”Simply move aided by the music,” said Dr. Reggiani. “As long as you start engaging in physical activity, you improve your health, and you improve your movement.” Suggest patients start with beginner Zumba or a step class to get the hang of moving to a beat. Or try a home dance video, like Barre Blend by BODi (which offers a 14-day free trial). “You can try taking a couple classes in the privacy of your own home first, so you feel comfortable getting out there and doing it with a group,” said Dr. Mattina.

Modify as needed. If a patient has mobility limitations or lower-body pain, they can still dance — just do the upper-body portion of the moves. “Dance involves both upper and lower body movement, and so many dance activities could easily be performed in a chair,” said Dr. Pennings. A good joint-friendly option: Some health clubs offer dance classes that take place in a swimming pool.

Involve the whole family. Support from a partner can help patients stick with exercise, said Dr. Reggiani, and dance can also help a couple strengthen their bond. Invite kids and grandparents to join, too. “Dancing is something that can be done at any age,” said Dr. Reggiani. “For kids, it is important to make it fun,” said Dr. Pennings. “Start when they are young with music they are familiar with and enjoy.” For skeptical partners? “Keep it simple and nonjudgmental,” he said.

Remind patients to warm up. We lose flexibility with age, so ease into it, said Dr. Mattina. Many classes include warmups, but if you’re at home, do a few minutes of light, low-impact cardio — jumping jacks, mountain climbers, jogging, or brisk walking — before stretching. Or just put on a slow song and start lightly bouncing to the beat or stepping your feet to one side, together, then to the other side and together.

Tell them to take dance breaks. No time to join a class? Break up the workday with a few 10-minute dance parties. (That’s about three songs.) “Short bursts of exercise throughout the day, like if you do 10 minutes of exercise six times a day, actually has a greater health benefit than doing 60 minutes of continuous exercise,” said Dr. Pennings. It helps counter the negative effects of prolonged sitting “by increasing blood flow and increasing utilization of your muscles.”

Manage expectations about weight loss. Patients often have outsized expectations about how much weight they’ll lose when starting a new exercise regimen, Dr. Pennings said. Dancing burns about 300 calories per hour, so it takes roughly 12 hours to lose one pound. Consistency over time is the key. “My goal is to both emphasize the health benefits of exercise while maintaining realistic expectations about weight loss,” said Dr. Pennings. Focus less on the weight part and highlight other benefits: Dancing builds strength, balance, and coordination, said Dr. Pennings. It can help improve blood pressure and other heart health markers and boost cognition in older adults. And it’s fun.  
 

A version of this article appeared on Medscape.com.

Have patients who want to lose weight? Tell them to put on their dancing shoes. 

Dancing can be an effective fat-loss tool for people who are overweight or have obesity, according to a recent meta-analysis in PLOS One. People who danced regularly lost about four more pounds — including three and a half pounds of fat — than those who didn’t dance. They also shaved an extra inch off their waists. 

Participants who danced three times a week for at least 3 months reaped maximum benefits. And the more they let loose, the better — more creative dance forms led to more pronounced improvements in body composition. 

The study builds on previous research that suggests dance can be beneficial for weight loss and overall health. A 2017 meta-analysis found that dance significantly improved body composition, blood biomarkers, and musculoskeletal function. Other research has linked dance with improvements in cognitive function, mental health, and quality of life.  

What makes dance special? It’s a full-body workout that might be easier to stick with than other exercises. “Enjoyment” is key for sustainability, the researchers wrote: “As a form of physical activity that integrates exercise, entertainment, and sociality, dance possesses innate advantages in fostering motivation for exercise.”

“The best exercise is the one you’ll do every day, and something that you like to do,” said Nicholas Pennings, DO, chair and associate professor of family medicine at Campbell University, Buies Creek, NC. (Dr. Pennings was not involved in the study.) For patients who enjoy dancing, dance could be that thing — or at least one workout to add to the mix. 

Help your patients get started with these tips. 

Frame it as a hobby, not exercise. Ask what hobbies they used to enjoy in high school, suggests Deirdre Mattina, MD, a cardiologist at the Cleveland Clinic and a former professional dancer. “ This can sometimes evoke happy memories of younger years and perhaps hobbies that they’d given up because they thought they were too old,” she said. If they used to play sports or dance, that’s your in. “I usually talk about hot yoga as a transition to get back their flexibility and then something like a dance aerobics or Zumba class to start.”

Recommend a group class. “Any intervention promoting social relationships is expected to increase adherence,” said Giulio Marchesini Reggiani, MD, a recently retired professor of internal medicine and dietetics at the University of Bologna in Italy. “You are motivated by the group, and you create a relationship among participants, and this means that you are no longer alone.” Try local gyms, health clubs, or even dance studios (yes, where kids go — they offer adult classes, too).

Help patients find their unique groove. Dr. Mattina has some patients who take cardio dance classes, some who line dance, and others who pole dance or heels dance. “Those are the things that keep it fun,” she said. “It doesn’t seem like exercise. It seems more like going out and hanging out.” 

Encourage those who “don’t know how to dance.” You don’t need fancy choreography or the grace of a prima ballerina.”Simply move aided by the music,” said Dr. Reggiani. “As long as you start engaging in physical activity, you improve your health, and you improve your movement.” Suggest patients start with beginner Zumba or a step class to get the hang of moving to a beat. Or try a home dance video, like Barre Blend by BODi (which offers a 14-day free trial). “You can try taking a couple classes in the privacy of your own home first, so you feel comfortable getting out there and doing it with a group,” said Dr. Mattina.

Modify as needed. If a patient has mobility limitations or lower-body pain, they can still dance — just do the upper-body portion of the moves. “Dance involves both upper and lower body movement, and so many dance activities could easily be performed in a chair,” said Dr. Pennings. A good joint-friendly option: Some health clubs offer dance classes that take place in a swimming pool.

Involve the whole family. Support from a partner can help patients stick with exercise, said Dr. Reggiani, and dance can also help a couple strengthen their bond. Invite kids and grandparents to join, too. “Dancing is something that can be done at any age,” said Dr. Reggiani. “For kids, it is important to make it fun,” said Dr. Pennings. “Start when they are young with music they are familiar with and enjoy.” For skeptical partners? “Keep it simple and nonjudgmental,” he said.

Remind patients to warm up. We lose flexibility with age, so ease into it, said Dr. Mattina. Many classes include warmups, but if you’re at home, do a few minutes of light, low-impact cardio — jumping jacks, mountain climbers, jogging, or brisk walking — before stretching. Or just put on a slow song and start lightly bouncing to the beat or stepping your feet to one side, together, then to the other side and together.

Tell them to take dance breaks. No time to join a class? Break up the workday with a few 10-minute dance parties. (That’s about three songs.) “Short bursts of exercise throughout the day, like if you do 10 minutes of exercise six times a day, actually has a greater health benefit than doing 60 minutes of continuous exercise,” said Dr. Pennings. It helps counter the negative effects of prolonged sitting “by increasing blood flow and increasing utilization of your muscles.”

Manage expectations about weight loss. Patients often have outsized expectations about how much weight they’ll lose when starting a new exercise regimen, Dr. Pennings said. Dancing burns about 300 calories per hour, so it takes roughly 12 hours to lose one pound. Consistency over time is the key. “My goal is to both emphasize the health benefits of exercise while maintaining realistic expectations about weight loss,” said Dr. Pennings. Focus less on the weight part and highlight other benefits: Dancing builds strength, balance, and coordination, said Dr. Pennings. It can help improve blood pressure and other heart health markers and boost cognition in older adults. And it’s fun.  
 

A version of this article appeared on Medscape.com.

Modern technology for recording deep-brain activity involves sharp metal electrodes that penetrate the tissue, causing damage that can compromise the signal and limiting how often they can be used. 

A rapidly growing area in materials science and engineering aims to fix the problem by designing electrodes that are softer, smaller, and flexible — safer for use inside the delicate tissues of the brain. On January 17, researchers from the University of California, San Diego, reported the development of a thin, flexible electrode that can be inserted deep within the brain and communicate with sensors on the surface. 

But what if you could record detailed deep-brain activity without piercing the brain? 

A team of researchers (as it happens, also from UC San Diego) have developed a thin, flexible implant that “resides on the brain’s surface” and “can infer neural activity from deeper layers,” said Duygu Kuzum, PhD, a professor of electrical and computer engineering, who led the research. 

By combining electrical and optical imaging methods, and artificial intelligence, the researchers used the device — a polymer strip packed with graphene electrodes — to predict deep calcium activity from surface signals, according to a proof-of-concept study published this month in Nature Nanotechnology. 

“Almost everything we know about how neurons behave in living brains comes from data collected with either electrophysiology or two-photon imaging,” said neuroscientist Joshua H. Siegle, PhD, of the Allen Institute for Neural Dynamics in Seattle , who not involved in the study. “ Until now, these two methods have rarely been used simultaneously.”

The technology, which has been tested in mice, could help advance our knowledge of how the brain works and may lead to new minimally invasive treatments for neurologic disorders. 
 

Multimodal Neurotech: The Power of 2-in-1

Electrical and optical methods for recording brain activity have been crucial in advancing neurophysiologic science, but each technique has its limits. Electrical recordings provide high “temporal resolution”; they reveal when activation is happening, but not really where. Optical imaging, on the other hand, offers high “spatial resolution,” showing which area of the brain is lighting up, but its measurements may not correspond with the activity’s timing. 

Research over the past decade has explored how to combine and harness the strengths of both methods. One potential solution is to use electrodes made of transparent materials such as graphene, allowing a clear field of view for a microscope during imaging. Recently, University of Pennsylvania scientists used graphene electrodes to illuminate the neural dynamics of seizures. 

But there are challenges. If graphene electrodes are very small — in this case, 20 µm in diameter — they become more resistant to the flow of electricity. Dr. Kuzum and colleagues addressed this by adding tiny platinum particles to improve electrical conductivity. Long graphene wires connect electrodes to the circuit board, but defects in graphene can interrupt the signal, so they made each wire with two layers; any defects in one wire could be hidden by the other.

By combining the two methods (microelectrode arrays and two-photon imaging), the researchers could see both when brain activity was happening and where, including in deeper layers. They discovered a correlation between electrical responses on the surface and cellular calcium activity deeper down. The team used these data to create a neural network (a type of artificial intelligence that learns to recognize patterns) that predicts deep calcium activity from surface-level readings.

The tech could help scientists study brain activity “in a way not possible with current single-function tools,” said Luyao Lu, PhD, professor of biomedical engineering at George Washington University in Washington, DC, who was not involved in the study. It could shed light on interactions between vascular and electrical activity, or explain how place cells (neurons in the hippocampus) are so efficient at creating spatial memory. 

It could also pave the way for minimally invasive neural prosthetics or targeted treatments for neurologic disorders, the researchers say. Implanting the device would be a “straightforward process” similar to placing electrocorticography grids in patients with epilepsy, said Dr. Kuzum. 

But first, the team plans to do more studies in animal models before testing the tech in clinical settings, Dr. Kuzum added.

A version of this article appeared on Medscape.com.

Modern technology for recording deep-brain activity involves sharp metal electrodes that penetrate the tissue, causing damage that can compromise the signal and limiting how often they can be used. 

A rapidly growing area in materials science and engineering aims to fix the problem by designing electrodes that are softer, smaller, and flexible — safer for use inside the delicate tissues of the brain. On January 17, researchers from the University of California, San Diego, reported the development of a thin, flexible electrode that can be inserted deep within the brain and communicate with sensors on the surface. 

But what if you could record detailed deep-brain activity without piercing the brain? 

A team of researchers (as it happens, also from UC San Diego) have developed a thin, flexible implant that “resides on the brain’s surface” and “can infer neural activity from deeper layers,” said Duygu Kuzum, PhD, a professor of electrical and computer engineering, who led the research. 

By combining electrical and optical imaging methods, and artificial intelligence, the researchers used the device — a polymer strip packed with graphene electrodes — to predict deep calcium activity from surface signals, according to a proof-of-concept study published this month in Nature Nanotechnology. 

“Almost everything we know about how neurons behave in living brains comes from data collected with either electrophysiology or two-photon imaging,” said neuroscientist Joshua H. Siegle, PhD, of the Allen Institute for Neural Dynamics in Seattle , who not involved in the study. “ Until now, these two methods have rarely been used simultaneously.”

The technology, which has been tested in mice, could help advance our knowledge of how the brain works and may lead to new minimally invasive treatments for neurologic disorders. 
 

Multimodal Neurotech: The Power of 2-in-1

Electrical and optical methods for recording brain activity have been crucial in advancing neurophysiologic science, but each technique has its limits. Electrical recordings provide high “temporal resolution”; they reveal when activation is happening, but not really where. Optical imaging, on the other hand, offers high “spatial resolution,” showing which area of the brain is lighting up, but its measurements may not correspond with the activity’s timing. 

Research over the past decade has explored how to combine and harness the strengths of both methods. One potential solution is to use electrodes made of transparent materials such as graphene, allowing a clear field of view for a microscope during imaging. Recently, University of Pennsylvania scientists used graphene electrodes to illuminate the neural dynamics of seizures. 

But there are challenges. If graphene electrodes are very small — in this case, 20 µm in diameter — they become more resistant to the flow of electricity. Dr. Kuzum and colleagues addressed this by adding tiny platinum particles to improve electrical conductivity. Long graphene wires connect electrodes to the circuit board, but defects in graphene can interrupt the signal, so they made each wire with two layers; any defects in one wire could be hidden by the other.

By combining the two methods (microelectrode arrays and two-photon imaging), the researchers could see both when brain activity was happening and where, including in deeper layers. They discovered a correlation between electrical responses on the surface and cellular calcium activity deeper down. The team used these data to create a neural network (a type of artificial intelligence that learns to recognize patterns) that predicts deep calcium activity from surface-level readings.

The tech could help scientists study brain activity “in a way not possible with current single-function tools,” said Luyao Lu, PhD, professor of biomedical engineering at George Washington University in Washington, DC, who was not involved in the study. It could shed light on interactions between vascular and electrical activity, or explain how place cells (neurons in the hippocampus) are so efficient at creating spatial memory. 

It could also pave the way for minimally invasive neural prosthetics or targeted treatments for neurologic disorders, the researchers say. Implanting the device would be a “straightforward process” similar to placing electrocorticography grids in patients with epilepsy, said Dr. Kuzum. 

But first, the team plans to do more studies in animal models before testing the tech in clinical settings, Dr. Kuzum added.

A version of this article appeared on Medscape.com.

Modern technology for recording deep-brain activity involves sharp metal electrodes that penetrate the tissue, causing damage that can compromise the signal and limiting how often they can be used. 

A rapidly growing area in materials science and engineering aims to fix the problem by designing electrodes that are softer, smaller, and flexible — safer for use inside the delicate tissues of the brain. On January 17, researchers from the University of California, San Diego, reported the development of a thin, flexible electrode that can be inserted deep within the brain and communicate with sensors on the surface. 

But what if you could record detailed deep-brain activity without piercing the brain? 

A team of researchers (as it happens, also from UC San Diego) have developed a thin, flexible implant that “resides on the brain’s surface” and “can infer neural activity from deeper layers,” said Duygu Kuzum, PhD, a professor of electrical and computer engineering, who led the research. 

By combining electrical and optical imaging methods, and artificial intelligence, the researchers used the device — a polymer strip packed with graphene electrodes — to predict deep calcium activity from surface signals, according to a proof-of-concept study published this month in Nature Nanotechnology. 

“Almost everything we know about how neurons behave in living brains comes from data collected with either electrophysiology or two-photon imaging,” said neuroscientist Joshua H. Siegle, PhD, of the Allen Institute for Neural Dynamics in Seattle , who not involved in the study. “ Until now, these two methods have rarely been used simultaneously.”

The technology, which has been tested in mice, could help advance our knowledge of how the brain works and may lead to new minimally invasive treatments for neurologic disorders. 
 

Multimodal Neurotech: The Power of 2-in-1

Electrical and optical methods for recording brain activity have been crucial in advancing neurophysiologic science, but each technique has its limits. Electrical recordings provide high “temporal resolution”; they reveal when activation is happening, but not really where. Optical imaging, on the other hand, offers high “spatial resolution,” showing which area of the brain is lighting up, but its measurements may not correspond with the activity’s timing. 

Research over the past decade has explored how to combine and harness the strengths of both methods. One potential solution is to use electrodes made of transparent materials such as graphene, allowing a clear field of view for a microscope during imaging. Recently, University of Pennsylvania scientists used graphene electrodes to illuminate the neural dynamics of seizures. 

But there are challenges. If graphene electrodes are very small — in this case, 20 µm in diameter — they become more resistant to the flow of electricity. Dr. Kuzum and colleagues addressed this by adding tiny platinum particles to improve electrical conductivity. Long graphene wires connect electrodes to the circuit board, but defects in graphene can interrupt the signal, so they made each wire with two layers; any defects in one wire could be hidden by the other.

By combining the two methods (microelectrode arrays and two-photon imaging), the researchers could see both when brain activity was happening and where, including in deeper layers. They discovered a correlation between electrical responses on the surface and cellular calcium activity deeper down. The team used these data to create a neural network (a type of artificial intelligence that learns to recognize patterns) that predicts deep calcium activity from surface-level readings.

The tech could help scientists study brain activity “in a way not possible with current single-function tools,” said Luyao Lu, PhD, professor of biomedical engineering at George Washington University in Washington, DC, who was not involved in the study. It could shed light on interactions between vascular and electrical activity, or explain how place cells (neurons in the hippocampus) are so efficient at creating spatial memory. 

It could also pave the way for minimally invasive neural prosthetics or targeted treatments for neurologic disorders, the researchers say. Implanting the device would be a “straightforward process” similar to placing electrocorticography grids in patients with epilepsy, said Dr. Kuzum. 

But first, the team plans to do more studies in animal models before testing the tech in clinical settings, Dr. Kuzum added.

A version of this article appeared on Medscape.com.

Bone health begins in childhood, particularly during the rapid bone accrual phase of puberty, which is essential for attaining optimal peak bone mass. Peak bone mass is achieved in early adult life and affects both immediate and future fracture risk. Genetic, nutritional, exercise-related, and hormonal factors, and certain diseases and medications, have deleterious effects on bone health.

In addition, emerging data suggest that certain manmade chemicals known as per- and polyfluoroalkyl substances (PFAS) may affect bone accrual during this important period and potentially increase the risk for osteoporosis in adulthood. Osteoporosis refers to increased fracture risk because of low bone density and affects a large proportion of postmenopausal women and older men.

New evidence comes from a recent study conducted by investigators from the Keck School of Medicine, who examined the impact of exposure to PFAS on skeletal outcomes in youth. Of note, participants were primarily Hispanic; this population has a higher risk for osteoporosis in adulthood. PFAS are manmade chemicals with water- and grease-resistant properties. They are used in a variety of products, such as nonstick cookware, food packaging, water-repellent clothing, stain-resistant fabrics, carpets, and in certain industrial processes. They are pervasive in the environment, in wildlife, and in humans.

Use and production of certain PFAS, such as perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA),  have decreased over the past two decades, with a significant reduction in blood concentrations of these chemicals. However, they can be resistant to degradation and have very long half-lives. As a consequence, these «forever chemicals» continue to linger in the environment. Also, the risk for exposure to other PFAS persists, and almost every individual has detectable levels of PFAS in blood.

Scientists are still learning about the impact of environmental chemicals on bone health. In contrast, other factors that may jeopardize pubertal bone accrual and peak bone mass acquisition have been studied extensively, with guidelines for management of the consequent poor skeletal health.

For PFAS, studies have reported deleterious effects on various body systems, such as the liver, immune system, thyroid, and the developing brain. The limited data related to bone suggest negative associations between certain, but not all, PFAS and bone density — ie, the higher the exposure, the worse the impact on bone health.

PFAS may affect health through alterations in the endocrine system. They have been associated with lower levels of testosterone and downregulation of its receptor (and testosterone is known to modulate bone formation and bone loss). On the other hand, some PFAS are estrogenic, which should be beneficial to bone. A direct impact of PFAS on pathways regulating activity of osteoblasts (bone-forming cells) and osteoclasts (bone-resorbing cells) has also been postulated, with conflicting results.

Previous research on PFAS and human bone health has found mixed results. In adolescents, Xiong and colleagues  reported negative associations of PFOS, PFOA, and perfluorononanoic acid (PFNA), but not perfluorohexane sulfonic acid (PFHxS), levels with bone density at various sites, mostly in females. Carwile and associates  reported similar negative associations of blood concentrations of PFOA and PFOS and urinary concentrations of phthalates with bone density in adolescents, but only in males. Lin and coworkers also reported negative associations of PFOA and bone density in adult premenopausal women, but found no associations of PFOA and PFOS concentrations with self-reported fractures, suggesting questionable biological significance of these findings. These were all cross-sectional studies and did not report on the impact of these chemicals on longitudinal bone accrual.

In the recent study, Beglarian and colleagues examined the impact of PFAS on longitudinal changes in bone density in adolescents, drawn from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR) cohort and young adults from the Southern California Children’s Health Study (CHS) cohort. They found that in adolescents, higher baseline concentrations of PFOS predicted lower bone accrual over time. In young adults, there was a similar negative association of PFOS concentrations and bone density at baseline, but not with longitudinal bone accrual. In this study, other PFAS were not associated with bone outcomes.

Overall, research appears to suggest that PFOA, PFOS, and PFNA may have deleterious effects on bone density and bone accrual over time. However, data are not consistent across studies and across sexes, and more research is necessary to conclusively define the impact of these chemicals on skeletal health, particularly during the critical pubertal years of maximal bone accrual. In the meantime, continued efforts are necessary to reduce to concentrations of these PFAS in the environment.

Dr. Misra disclosed ties with AbbVie, Sanofi, and Ipsen.
 

A version of this article appeared on Medscape.com.

Bone health begins in childhood, particularly during the rapid bone accrual phase of puberty, which is essential for attaining optimal peak bone mass. Peak bone mass is achieved in early adult life and affects both immediate and future fracture risk. Genetic, nutritional, exercise-related, and hormonal factors, and certain diseases and medications, have deleterious effects on bone health.

In addition, emerging data suggest that certain manmade chemicals known as per- and polyfluoroalkyl substances (PFAS) may affect bone accrual during this important period and potentially increase the risk for osteoporosis in adulthood. Osteoporosis refers to increased fracture risk because of low bone density and affects a large proportion of postmenopausal women and older men.

New evidence comes from a recent study conducted by investigators from the Keck School of Medicine, who examined the impact of exposure to PFAS on skeletal outcomes in youth. Of note, participants were primarily Hispanic; this population has a higher risk for osteoporosis in adulthood. PFAS are manmade chemicals with water- and grease-resistant properties. They are used in a variety of products, such as nonstick cookware, food packaging, water-repellent clothing, stain-resistant fabrics, carpets, and in certain industrial processes. They are pervasive in the environment, in wildlife, and in humans.

Use and production of certain PFAS, such as perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA),  have decreased over the past two decades, with a significant reduction in blood concentrations of these chemicals. However, they can be resistant to degradation and have very long half-lives. As a consequence, these «forever chemicals» continue to linger in the environment. Also, the risk for exposure to other PFAS persists, and almost every individual has detectable levels of PFAS in blood.

Scientists are still learning about the impact of environmental chemicals on bone health. In contrast, other factors that may jeopardize pubertal bone accrual and peak bone mass acquisition have been studied extensively, with guidelines for management of the consequent poor skeletal health.

For PFAS, studies have reported deleterious effects on various body systems, such as the liver, immune system, thyroid, and the developing brain. The limited data related to bone suggest negative associations between certain, but not all, PFAS and bone density — ie, the higher the exposure, the worse the impact on bone health.

PFAS may affect health through alterations in the endocrine system. They have been associated with lower levels of testosterone and downregulation of its receptor (and testosterone is known to modulate bone formation and bone loss). On the other hand, some PFAS are estrogenic, which should be beneficial to bone. A direct impact of PFAS on pathways regulating activity of osteoblasts (bone-forming cells) and osteoclasts (bone-resorbing cells) has also been postulated, with conflicting results.

Previous research on PFAS and human bone health has found mixed results. In adolescents, Xiong and colleagues  reported negative associations of PFOS, PFOA, and perfluorononanoic acid (PFNA), but not perfluorohexane sulfonic acid (PFHxS), levels with bone density at various sites, mostly in females. Carwile and associates  reported similar negative associations of blood concentrations of PFOA and PFOS and urinary concentrations of phthalates with bone density in adolescents, but only in males. Lin and coworkers also reported negative associations of PFOA and bone density in adult premenopausal women, but found no associations of PFOA and PFOS concentrations with self-reported fractures, suggesting questionable biological significance of these findings. These were all cross-sectional studies and did not report on the impact of these chemicals on longitudinal bone accrual.

In the recent study, Beglarian and colleagues examined the impact of PFAS on longitudinal changes in bone density in adolescents, drawn from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR) cohort and young adults from the Southern California Children’s Health Study (CHS) cohort. They found that in adolescents, higher baseline concentrations of PFOS predicted lower bone accrual over time. In young adults, there was a similar negative association of PFOS concentrations and bone density at baseline, but not with longitudinal bone accrual. In this study, other PFAS were not associated with bone outcomes.

Overall, research appears to suggest that PFOA, PFOS, and PFNA may have deleterious effects on bone density and bone accrual over time. However, data are not consistent across studies and across sexes, and more research is necessary to conclusively define the impact of these chemicals on skeletal health, particularly during the critical pubertal years of maximal bone accrual. In the meantime, continued efforts are necessary to reduce to concentrations of these PFAS in the environment.

Dr. Misra disclosed ties with AbbVie, Sanofi, and Ipsen.
 

A version of this article appeared on Medscape.com.

Bone health begins in childhood, particularly during the rapid bone accrual phase of puberty, which is essential for attaining optimal peak bone mass. Peak bone mass is achieved in early adult life and affects both immediate and future fracture risk. Genetic, nutritional, exercise-related, and hormonal factors, and certain diseases and medications, have deleterious effects on bone health.

In addition, emerging data suggest that certain manmade chemicals known as per- and polyfluoroalkyl substances (PFAS) may affect bone accrual during this important period and potentially increase the risk for osteoporosis in adulthood. Osteoporosis refers to increased fracture risk because of low bone density and affects a large proportion of postmenopausal women and older men.

New evidence comes from a recent study conducted by investigators from the Keck School of Medicine, who examined the impact of exposure to PFAS on skeletal outcomes in youth. Of note, participants were primarily Hispanic; this population has a higher risk for osteoporosis in adulthood. PFAS are manmade chemicals with water- and grease-resistant properties. They are used in a variety of products, such as nonstick cookware, food packaging, water-repellent clothing, stain-resistant fabrics, carpets, and in certain industrial processes. They are pervasive in the environment, in wildlife, and in humans.

Use and production of certain PFAS, such as perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA),  have decreased over the past two decades, with a significant reduction in blood concentrations of these chemicals. However, they can be resistant to degradation and have very long half-lives. As a consequence, these «forever chemicals» continue to linger in the environment. Also, the risk for exposure to other PFAS persists, and almost every individual has detectable levels of PFAS in blood.

Scientists are still learning about the impact of environmental chemicals on bone health. In contrast, other factors that may jeopardize pubertal bone accrual and peak bone mass acquisition have been studied extensively, with guidelines for management of the consequent poor skeletal health.

For PFAS, studies have reported deleterious effects on various body systems, such as the liver, immune system, thyroid, and the developing brain. The limited data related to bone suggest negative associations between certain, but not all, PFAS and bone density — ie, the higher the exposure, the worse the impact on bone health.

PFAS may affect health through alterations in the endocrine system. They have been associated with lower levels of testosterone and downregulation of its receptor (and testosterone is known to modulate bone formation and bone loss). On the other hand, some PFAS are estrogenic, which should be beneficial to bone. A direct impact of PFAS on pathways regulating activity of osteoblasts (bone-forming cells) and osteoclasts (bone-resorbing cells) has also been postulated, with conflicting results.

Previous research on PFAS and human bone health has found mixed results. In adolescents, Xiong and colleagues  reported negative associations of PFOS, PFOA, and perfluorononanoic acid (PFNA), but not perfluorohexane sulfonic acid (PFHxS), levels with bone density at various sites, mostly in females. Carwile and associates  reported similar negative associations of blood concentrations of PFOA and PFOS and urinary concentrations of phthalates with bone density in adolescents, but only in males. Lin and coworkers also reported negative associations of PFOA and bone density in adult premenopausal women, but found no associations of PFOA and PFOS concentrations with self-reported fractures, suggesting questionable biological significance of these findings. These were all cross-sectional studies and did not report on the impact of these chemicals on longitudinal bone accrual.

In the recent study, Beglarian and colleagues examined the impact of PFAS on longitudinal changes in bone density in adolescents, drawn from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR) cohort and young adults from the Southern California Children’s Health Study (CHS) cohort. They found that in adolescents, higher baseline concentrations of PFOS predicted lower bone accrual over time. In young adults, there was a similar negative association of PFOS concentrations and bone density at baseline, but not with longitudinal bone accrual. In this study, other PFAS were not associated with bone outcomes.

Overall, research appears to suggest that PFOA, PFOS, and PFNA may have deleterious effects on bone density and bone accrual over time. However, data are not consistent across studies and across sexes, and more research is necessary to conclusively define the impact of these chemicals on skeletal health, particularly during the critical pubertal years of maximal bone accrual. In the meantime, continued efforts are necessary to reduce to concentrations of these PFAS in the environment.

Dr. Misra disclosed ties with AbbVie, Sanofi, and Ipsen.
 

A version of this article appeared on Medscape.com.

Psoriasis is a chronic inflammatory disease that affects approximately 3% of the US population.¹ Plaque psoriasis comprises 80% to 90% of cases, while pustular, erythrodermic, guttate, inverse, and palmoplantar disease are less common variants (Figure 1). Psoriatic skin manifestations range from localized to widespread or generalized disease with recurrent flares. Body surface area or psoriasis area and severity index (PASI) measurements primarily focus on skin manifestations and are important for evaluating disease activity and response to treatment, but they have inherent limitations: they do not capture extracutaneous disease activity, systemic inflammation, comorbid conditions, quality of life impact, or the economic burden of psoriasis.

A common manifestation of psoriasis is psoriatic arthritis (PsA), which can involve the nails, joints, ligaments, or tendons in 30% to 41% of affected individuals (Figure 2).^2,3 A growing number of psoriasis-associated comorbidities also have been reported including metabolic syndrome⁴; hyperlipidemia⁵; cardiovascular disease⁶; stroke⁷; hypertension⁸; obesity⁹; sleep disorders¹⁰; malignancy¹¹; infections¹²; inflammatory bowel disease¹³; and mental health disorders such as depression,¹⁴ anxiety,¹⁵ and suicidal ideation.¹⁵ Psoriatic disease also interferes with daily life activities and a patient’s overall quality of life, including interpersonal relationships, intimacy, employment, and work productivity.¹⁶ Finally, the total estimated cost of psoriasis-related health care is more than $35 billion annually,¹⁷ representing a substantial economic burden to our health care system and individual patients.

The overall burden of psoriatic disease has declined markedly in the last 2 decades due to revolutionary advances in our understanding of the immunopathogenesis of psoriasis and the subsequent development of improved therapies that predominantly interrupt IL-23/IL-17 cytokine signaling; however, critical knowledge and treatment gaps persist, underscoring the importance of ongoing clinical and research efforts in psoriatic disease. We review the working immune model of psoriasis, summarize related immune discoveries, and highlight recent therapeutic innovations that are shaping psoriatic disease management.

Current Immune Model of Psoriatic Disease

Psoriasis is an autoinflammatory T cell–mediated disease with negligible contributions from the humoral immune response. Early clinical observations reported increased inflammatory infiltrates in psoriatic skin lesions primarily consisting of both CD4⁺ and CD8⁺ T-cell populations.^18,19 Additionally, patients treated with broad-acting, systemic immunosuppressive medications (eg, cyclosporine, oral corticosteroids) experienced improvement of psoriatic lesions and normalization of the immune infiltrates observed in skin biopsy specimens.^20,21 These early clinical findings led to more sophisticated experimentation in xenotransplant models of psoriasis,^22,23 which explored the clinical efficacy of several less immunosuppressive (eg, methotrexate, anti–tumor necrosis factor [TNF] biologics)²⁴ or T cell–specific agents (eg, alefacept, abatacept, efalizumab).^25-27 The results of these translational studies provided indisputable evidence for the role of the dysregulated immune response as the primary pathogenic process driving plaque formation; they also led to a paradigm shift in how the immunopathogenesis of psoriatic disease was viewed and paved the way for the identification and targeting of other specific proinflammatory signals produced by activated dendritic cell (DC) and T-lymphocyte populations. Among the psoriasis-associated cytokines subsequently identified and studied, elevated IL-23 and IL-17 cytokine levels in psoriatic skin were most closely associated with disease activity, and rapid normalization of IL-23/IL-17 signaling in response to effective oral or injectable antipsoriatic treatments was the hallmark of skin clearance.²⁸ The predominant role of IL-23/IL-17 signaling in the development and maintenance of psoriatic disease is the central feature of all working immune models for this disease (Figure 3).

Psoriasis-Associated Genetic and Environmental Risk Factors

The exact sequence of events that lead to the initiation and formation of plaque psoriasis in susceptible individuals is still poorly understood; however, several important risk factors and key immune events have been identified. First, decades of genetic research have reported more than 80 known psoriasis-associated susceptibility loci,²⁹ which explains approximately 50% of psoriasis heritability. The major genetic determinant of psoriasis, HLA-C*06:02 (formerly HLA-Cw6), resides in the major histocompatibility complex class I region on chromosome 6p21.3 (psoriasis susceptibility gene 1, PSORS1) and is most strongly associated with psoriatic disease.³⁰ Less common psoriasis-associated susceptibility genes also are known to directly or indirectly impact innate and adaptive immune functions that contribute to the pathogenesis of psoriasis.

Second, several nongenetic environmental risk factors for psoriasis have been reported across diverse patient populations, including skin trauma/injury, infections, alcohol/tobacco use, obesity, medication exposure (eg, lithium, antimalarials, beta-blockers), and stress.³¹ These genetic and/or environmental risk factors can trigger the onset of psoriatic disease at any stage of life, though most patients develop disease in early adulthood or later (age range, 50–60 years). Some patients never develop psoriasis despite exposure to environmental risk factors and/or a genetic makeup that is similar to affected first-degree relatives, which requires further study.

Prepsoriatic Skin and Initiation of Plaque Development

In response to environmental stimuli and/or other triggers of the immune system, DC and resident IL-17–producing T-cell (T17) populations become activated in predisposed individuals. Dendritic cell activation leads to the upregulation and increase of several proinflammatory cytokines, including TNF, interferon (IFN) α, IFN-γ, IL-12, and IL-23. Tumor necrosis factor and IL-23 play a vital role in psoriasis by helping to regulate the polarization and expansion of T22 and T17 cells in the skin, whereas IL-12 promotes a corresponding type 1 inflammatory response.³² Increased IL-17 and IL-22 result in alteration of the terminal differentiation and proliferative potential of epidermal keratinocytes, leading to the early clinical hallmarks of psoriatic plaques. The potential contribution of overexpressed psoriasis-related autoantigens, such as LL-37/cathelicidin, ADAMTSL5, and PLA2G4D,³³ in the initiation of psoriatic plaques has been suggested but is poorly characterized.³⁴ Whether these specific autoantigens or others presented by HLA-C variants found on antigen-presenting cells are required for the breakdown of immune tolerance and psoriatic disease initiation is highly relevant but requires further investigation and validation.

In response to the upstream production of IL-23 by dermal DCs, high levels of IL-17 cytokines can be found in mature psoriatic plaques. The IL-17 family consists of 6 dimeric cytokines (IL-17A through IL-17F) that provide innate cutaneous protection against bacterial, viral, and fungal infectious agents, such as Candida albicans. Unlike other IL-17 isoforms, IL-17A and IL-17F share the same receptor complex and have the highest structural homology of any pair (approximately 50% similar).³⁵ The relative expression of IL-17F is higher than IL-17A in psoriasis,³⁶ though IL-17A has been considered as the predominant IL-17 cytokine found in psoriatic skin lesions due to its higher potency.

Binding of IL-17A/F with the IL-17 receptor (IL-17R) on keratinocytes contributes to the development of psoriatic plaques by inducing epidermal hyperplasia via activation of CCAAT/enhancer-binding proteins β and δ, nuclear factor κB, and signal transducer and activator of transcription 1 gene (STAT1).^37,38 This also increases the expression of other keratinocyte-derived proteins (eg, human β-defensins, S-100 proteins, LL-37, other antimicrobial peptides, IL-19, IL-36, IL-17C) that act as reinforcing proinflammatory signals or chemotactic factors (eg, chemokine [C-C motif] ligand 20 [CCL20], chemokine [C-C motif] ligand 1/2/3/5 [CXCL1/2/3/5], CXCL8, IL-8) that facilitate the recruitment of additional immune cells to the skin including polymorphonuclear neutrophils (PMNs), macrophages, and DCs.^39-41 Routine immunohistochemical staining for these keratinocyte-derived proteins reveals a striking epidermal gene expression gradient wherein levels of IL-17–induced proteins are most highly expressed in the uppermost layers of keratinocytes and facilitate the recruitment of immune cells into the epidermis. Activated T17 cells also stimulate the production of keratinocyte-derived chemokines (eg, CXCL9/10/11), which recruit type 1 inflammatory T-cell populations into developing psoriatic plaques.^42,43 Finally, TNF, IL-36, and IL-17C cytokines act synergistically with IL-17A/F to amplify the proinflammatory effects of IL-17 signaling and further stimulate their production from T17 cell populations.⁴⁰ This inflammatory circuit in the skin creates and supports a self-amplifying or positive feedback loop between the skin and immune system that commonly is referred to as feed-forward inflammation (Figure 3).³⁴ The feed-forward inflammatory loop in psoriasis—predominantly driven by increased IL-23/IL-17 signaling—best characterizes the mature psoriatic plaque.

Several findings suggest that the influx of persistent, long-lived resident memory T cells (Trms) may contribute to the mature psoriatic plaque. It is believed that CD8⁺CD103⁺CD49a⁻ Trm cell populations may be responsible for the sharply demarcated borders of untreated psoriasis plaques or their recurrence at specific body sites such as the scalp, buttocks, extremity extensor surfaces, umbilicus, or acral skin following specific stimuli or trauma (Koebner phenomenon or isomorphic response).^44,45 It is not known if repeated stimuli or trauma induce disease formation via the activation of Trm cell populations; further study in large patient cohorts is needed, but this remains an intriguing area of study for durable treatment responses and potential cures for psoriasis.

Recent Discoveries in Psoriatic Disease

Remarkable treatment outcomes for psoriasis have been achieved with multiple selective IL-17 and IL-23 inhibitors (eTable). As demonstrated in several pivotal phase 3 clinical trials for members of these classes of medications, the majority of treated psoriasis patients achieved PASI90 clearance.⁴⁶ Due to their more favorable dosing schedule (ie, fewer injections) and ability to induce a durable remissionlike treatment response, IL-23 inhibitors have become the preferred treatment class for cutaneous disease, while IL-17 inhibitors may be preferred when treating patients with both plaque psoriasis and PsA.^47,48 Nevertheless, the complexity of this disease is punctuated by treated patients who do not adequately respond to selective IL-23/IL-17 blockade.⁴⁹ Recent and emerging treatments may shed light on these recalcitrant cases and will add to the rapidly growing arsenal of available psoriasis therapies.

The Role of IL-17F in Psoriasis and Other Inflammatory Skin Diseases

Dysregulation of IL-17A and IL-17F is associated with several chronic inflammatory conditions, such as psoriasis and PsA.^35,50 Both cytokines, either as homodimers or heterodimers, can selectively bind to the heterodimeric IL-17R formed by the IL-17RA and IL-17RC subunits.³⁵ IL-17F and IL-17C also can synergize with TNF and other cytokines to promote and support the self-sustaining inflammatory circuits in mature psoriatic plaques, though their inflammatory effects in the skin are more limited than IL-17A.^51,52 Therefore, incomplete blockade of IL-17 signaling (ie, unopposed IL-17F and IL-17C) represents a potential mechanism to explain the persistence of psoriasis in patients treated with selective IL-17A inhibitors. This hypothesis is supported by reports of psoriasis patients who have inadequate clinical responses to selective IL-17A inhibition but subsequently improve with IL-17R blockade, which results in disruption of IL-17A as well as IL-17C/E/F cytokine signaling. This formed the basis for further study into the specific role of IL-17F in psoriatic disease and any potential therapeutic benefits associated with its inhibition.

Recently approved in the European Union, Canada, Australia, Japan, the United Kingdom, and the United States for moderate to severe psoriasis, bimekizumab is a novel humanized IgG antibody that selectively inhibits both IL-17A and IL-17F cytokines.⁵³ Specifically, bimekizumab simultaneously prevents binding of IL-17A/A, IL-17A/F, and IL-17F/F dimers with the IL-17R. Compared to other IL-17 and IL-23 biologic therapies, bimekizumab (320 mg) achieved relatively higher response rates for PASI75, PASI90, and PASI100.⁴⁹ Neutralization of IL-17A and IL-17F by bimekizumab also resulted in more complete suppression of cytokine responses and PMN chemotaxis than either cytokine alone in treated PsA patients,⁵⁴ which is notable because of the incremental benefits of recent IL-23 and IL-17 inhibitors on inflammatory arthritis symptoms in contrast to the substantial improvements observed for cutaneous disease with those same agents.

The primary disadvantage of bimekizumab and its more complete blockade of the IL-17 signaling pathway is that treated patients have a substantially increased risk for oral candidiasis (>10%).⁵⁵ However, the precise link between candidiasis and IL-17 blockade is not yet fully understood because other targeted agents that also broadly suppress IL-17 signaling (ie, IL-17R, IL-23 inhibitors) are associated with much lower rates of candidiasis.^56-58 Bimekizumab also is being investigated as a novel therapy for hidradenitis suppurativa and will provide important reference information regarding the role for bispecific biologic agents in the treatment of chronic inflammatory skin diseases.⁵⁹

Recent genetic and clinical studies have expanded our understanding of the role of IL-36 signaling in the immunopathogenesis of pustular psoriasis variants. Generalized pustular psoriasis (GPP) is a rare distinct psoriasis subtype characterized by the recurrent development of widespread erythema, superficial sterile pustules, and desquamation. Systemic symptoms such as fever, malaise, itching, and skin pain accompany acute GPP flares.⁶⁰ Generalized pustular psoriasis is more common in female patients (in contrast with plaque psoriasis), and acute flares may be caused by multiple stimuli including infections, hypocalcemia, initiation or discontinuation of medications (eg, oral corticosteroids), pregnancy, or stress.^61,62 Flares of GPP often require emergency or in-patient care, as untreated symptoms increase the risk for severe health complications such as secondary infections, sepsis, or multisystem organ failure.⁶³ The prevalence of GPP is estimated to be approximately 1 in 10,000 individuals in the United States,^64-67 with mortality rates ranging from 0 to 3.3 deaths per 100 patient-years.⁶⁷

In contrast to plaque psoriasis, aberrant IL-36 signaling is the predominant driver of GPP. IL-36 is a member of the IL-1 cytokine family that includes three IL-36 agonists (IL-36α, IL-36β, IL-36γ) and 1 endogenous antagonist (IL-36Ra, encoded by IL36RN).⁶⁸ The immunopathogenesis of GPP involves dysregulation of the IL-36–chemokine–PMN axis, resulting in unopposed IL-36 signaling and the subsequent recruitment and influx of PMNs into the epidermis. IL36RN mutations are strongly associated with GPP and result in impaired function of the IL-36Ra protein, leading to unopposed IL-36 signaling.⁶⁹ However, approximately two-thirds of GPP patients lack identifiable gene mutations, suggesting other immune mechanisms or triggers causing upregulated IL-36 signaling.⁷⁰ In response to these triggers, increased IL-36 cytokines released by keratinocytes bind to the IL-36R, resulting in substantial keratinocyte hyperproliferation, increased IL-36 levels, and the expression of hundreds of additional inflammatory signals (eg, IL-17C, antimicrobial peptides, TNF, IL-6).⁷¹ Increased IL-36 levels also drive the production of PMN chemotactic proteins (eg, CXCL1/2/3/5/6/8 and CXCR1/2) and act synergistically with IL-17 cytokines to create an autoamplifying circuit that is analogous to the feed-forward inflammatory loop in plaque psoriasis.⁷² Biopsies of involved GPP skin reveal increased expression of IL-36 in the uppermost layers of the epidermis, which creates a gene expression gradient that acts as a strong attractant for PMNs and forms the basis for the hallmark pustular lesions observed in GPP patients.

Until recently, treatment strategies for GPP involved the off-label use of topical, oral, or biologic therapies approved for plaque psoriasis, which often was associated with variable or incomplete disease control. In September 2022, the US Food and Drug Administration (FDA) approved intravenous spesolimab as a first-in-class humanized monoclonal IgG1 antibody for the treatment of GPP flares in adults. Spesolimab binds to IL-36R and prevents its activation by its endogenous agonists. A phase 2, randomized, 12-week clinical trial (Effisayil-1) evaluated the efficacy and safety of a single 900-mg intravenous dose of spesolimab followed by an optional second dose 1 week later for inadequate treatment responses in 53 enrolled GPP patients (2:1 treatment to placebo randomization).⁷³ Remarkably, more than half (19/35 [54%]) of GPP patients experienced complete resolution of pustules (GPP physician global assessment subscore of 0 [range, 0–4]) and showed sustained efficacy out to week 12 after just 1 or 2 doses of spesolimab. Overall, the safety profile of spesolimab was good; asthenia, fatigue, nausea, vomiting, headache, pruritus, infusion-related reaction and symptoms, and mild infections (eg, urinary tract infection) were the most common adverse events reported.⁷³

Imsidolimab, a high-affinity humanized IgG4 monoclonal antibody that binds and blocks activation of IL-36R, also has completed phase 2 testing,⁷⁴ with phase 3 study results expected in early 2024. The rapid onset of action and overall safety of imsidolimab was in line with and similar to spesolimab. Future approval of imsidolimab would add to the limited treatment options available for GPP and has the additional convenience of being administered to patients subcutaneously. Overall, the development of selective IL-36R inhibitors offers a much-needed therapeutic option for GPP and illustrates the importance of translational research.

Role of Tyrosine Kinase in Psoriatic Disease

The Janus kinase (JAK) enzyme family consists of 4 enzymes—tyrosine kinase 2 (TYK2), JAK1, JAK2, and JAK3—that function as intracellular transduction signals that mediate the biologic response of most extracellular cytokines and growth factors.⁷⁵ Critical psoriasis-related cytokines are dependent on intact JAK-STAT signaling, including IL-23, IL-12, and type I IFNs. In 2010, a genome-wide association identified TYK2 as a psoriasis susceptibility locus,⁷⁶ and loss-of-function TYK2 mutations confer a reduced risk for psoriasis.⁷⁷ Unlike other JAK isoforms, TYK2 mediates biologic functions that are highly restricted to the immune responses associated with IL-23, IL-12, and type I IFN signaling.^78,79 For these reasons, blockade of TYK2 signaling is an attractive therapeutic target for the potential treatment of psoriatic disease.

In September 2022, the FDA approved deucravacitinib as a first-in-class, oral, selective TYK2 inhibitor for the treatment of adult patients with moderate to severe plaque psoriasis. It was the first FDA approval of an oral small-molecule treatment for plaque psoriasis in nearly a decade. Deucravacitinib inhibits TYK2 signaling via selective binding of its unique regulatory domain, resulting in a conformational (allosteric) change that interferes with its active domain.⁸⁰ This novel mechanism of action limits the unwanted blockade of other broad biologic processes mediated by JAK1/2/3. Of note, the FDA did not issue any boxed warnings for deucravacitinib as it did for other FDA-approved JAK inhibitors.

In a head-to-head, 52-week, double-blind, prospective, randomized, phase 3 study, deucravacitinib showed clear superiority over apremilast for PASI75 at week 16 (53.0% [271/511] vs 39.8% [101/254]) and week 24 (58.7% [296/504] vs 37.8% [96/254]).⁸¹ Clinical responses were sustained through week 52 and showed efficacy for difficult-to-treat areas such as the scalp, acral sites, and nails. Other advantages of deucravacitinib include once-daily dosing with no need for dose titration or adjustments for renal insufficiency as well as the absence of statistically significant differences in gastrointestinal tract symptoms compared to placebo. The most common adverse effects included nasopharyngitis, upper respiratory tract infections, headache, diarrhea, and herpes infections.⁸¹ The potential benefit of deucravacitinib for PsA and psoriasis comorbidities remains to be seen, but it is promising due to its simultaneous disruption of multiple psoriasis-related cytokine networks. Several other TYK2 inhibitors are being developed for psoriatic disease and related inflammatory conditions, underscoring the promise of targeting this intracellular pathway.

Topical steroids are the mainstay treatment option for localized or limited plaque psoriasis due to their potent immunosuppressive effect on the skin and relatively low cost. Combined with vitamin D analogs, topical steroids result in marked improvements in disease severity and improved tolerability.⁸² However, chronic use of topical steroids is limited by the need for twice-daily application, resulting in poor treatment compliance; loss of efficacy over time; risk for steroid-induced skin atrophy on special body sites; and patient concerns of potential systemic effects. The discovery of novel drug targets amenable to topical inhibition is needed.

Dysregulated aryl hydrocarbon receptor (AHR) levels have been reported in atopic dermatitis and psoriasis.⁸³ Aryl hydrocarbon receptors are ubiquitously expressed in many cell types and play an integral role in immune homeostasis within the skin, skin barrier function, protection against oxidative stressors, and regulation of proliferating melanocytes and keratinocytes.^84,85 They are widely expressed in multiple immune cell types (eg, antigen-presenting cells, T lymphocytes, fibroblasts) and modulate the differentiation of T17 and T22 cells as well as their balance with regulatory T-cell populations.⁸⁶ In keratinocytes, AHR helps to regulate terminal differentiation, enhance skin barrier integrity via AHR-dependent filaggrin (FLG) expression, and prevent transepidermal water loss.^87,88 The mechanisms by which AHR ligands lead to the upregulation or downregulation of specific genes is intricate and highly context dependent, such as the specific ligand and cell type involved. In preclinical studies, AHR-deficient mice develop psoriasiform skin inflammation, increased IL-17 and IL-22 expression, and abnormal skin barrier function.⁸⁹ Keratinocytes treated with AHR ligands in vitro modulated psoriasis-associated inflammatory cytokines, such as IL-6, IL-8, and type I and II IFNs.^89,90 The use of coal tar, one of the earliest historical treatments for psoriasis, is thought to activate AHRs in the skin via organic compound mixtures containing polyaromatic hydrocarbons that help normalize the proinflammatory environment in psoriatic skin.⁹¹

In June 2022, the FDA approved tapinarof as a first-in-class, topical, nonsteroidal AHR agonist for the treatment of plaque psoriasis in adults. Although the exact mechanism of action for tapinarof has not been fully elucidated, early studies suggest that its primary function is the activation of AHR, leading to reduced T-cell expansion and T17 cell differentiation. In the imiquimod mouse model, cytokine expression of IL-17A, IL-17F, IL-19, IL-22, IL-23A, and IL-lβ in psoriasiform skin lesions were downregulated following tapinarof treatment.⁹² In humans, tapinarof treatment is associated with a remittive effect, in which the average time for tapinarof-treated psoriasis lesions to remain clear was approximately 4 months.⁹³ Preliminary research investigating the mechanism by which tapinarof induces this remittive effect is ongoing and may involve the reduced activation and influx of T17 and Trm populations into the skin.⁹⁴ However, these preclinical studies were performed on healthy dermatome-derived skin tissue cultured in T17-skewing conditions and needs to be replicated in larger samples sizes using human-derived psoriatic tissue. Alternatively, a strong inhibitory effect on IL-23 cytokine signaling may, in part, explain the remittive effect of tapinarof, as an analogous response is observed in patients who start and discontinue treatment with selective IL-23 antagonists. Regardless, the once-daily dosing of tapinarof and sustained treatment response is appealing to psoriasis patients. Tapinarof generally is well tolerated with mild folliculitis (>20% of patients) and contact dermatitis (5% of patients) reported as the most common skin-related adverse events.

New Roles for Phosphodiesterase 4 Inhibition

Phosphodiesterases (PDEs) are enzymes that hydrolyze cyclic nucleotides (eg, cyclic adenosine monophosphate) to regulate intracellular secondary messengers involved in the inflammatory response. One of several enzymes in the PDE family, PDE4, has been shown to have greater activity in psoriatic skin compared to healthy skin.⁹⁵ Phosphodiesterase inhibitors decrease the degradation of cyclic adenosine monophosphate, which triggers protein kinase A to downregulate proinflammatory (eg, TNF-α, IL-6, IL-17, IL-12, IL-23) cytokines and increased expression of anti-inflammatory signals such as IL-10.^96,97 Apremilast, the first oral PDE4 inhibitor approved by the FDA for psoriasis, offered a safe alternative to traditional oral immunosuppressive agents that had extensive risks and potential end-organ adverse effects. Unfortunately, apremilast demonstrated modest efficacy for psoriatic disease (better efficacy in the skin vs joint manifestations) and was supplanted easily by next-generation targeted biologic agents that were more efficacious and lacked the troublesome gastrointestinal tract adverse effects of PDE4 inhibition.⁹⁸

Crisaborole became the first topical PDE4 inhibitor approved in the United States in December 2016 for twice-daily treatment of atopic dermatitis. Although phase 2 trial results were reported in psoriasis, this indication was never pursued, presumably due to similar improvements in primary outcome measures at week 12, compared to placebo (ClinicalTrials.gov Identifier NCT01300052).

In July 2022, the first topical PDE4 inhibitor indicated for plaque psoriasis was approved by the FDA—­roflumilast cream 0.3% for once-daily use in individuals 12 years and older. Roflumilast was found to be clinically efficacious as early as 2 weeks after its use in an early-phase clinical trial.⁹⁹ In 2 phase 3 clinical trials (DERMIS-1 and DERMIS-2), roflumilast significantly increased the proportion of patients achieving PASI75 at week 8 compared to vehicle (39%–41.6% vs 5.3%–7.6%, respectively)(P<.001).¹⁰⁰ Overall, this nonsteroidal topical therapy was found to be well tolerated, with infrequent reports of application site pain or irritation as adverse events. Similar to tapinarof, patients can apply roflumilast on all body surface areas including the face, external genitalia, and other intertriginous areas.¹⁰⁰ Importantly, the broad immune impact of PDE4 inhibition suggests that topical roflumilast likely will be an effective treatment for several additional inflammatory conditions, including seborrheic dermatitis and atopic dermatitis, which would expand the clinical utility of this specific medication.

Conclusion

In the last 2 decades, we have witnessed a translational revolution in our understanding of the underlying genetics and immunology of psoriatic disease. Psoriasis is widely considered one of the best-managed inflammatory conditions in all of medicine due to the development and availability of highly targeted, effective topical and systemic therapies that predominantly disrupt IL-23/IL-17 cytokine signaling in affected tissues. However, future clinical studies and laboratory research are necessary to elucidate the precise cause of psoriasis as well as the underlying genetic and immune signaling pathways driving less common clinical variants and recalcitrant disease.

Psoriasis is a chronic inflammatory disease that affects approximately 3% of the US population.¹ Plaque psoriasis comprises 80% to 90% of cases, while pustular, erythrodermic, guttate, inverse, and palmoplantar disease are less common variants (Figure 1). Psoriatic skin manifestations range from localized to widespread or generalized disease with recurrent flares. Body surface area or psoriasis area and severity index (PASI) measurements primarily focus on skin manifestations and are important for evaluating disease activity and response to treatment, but they have inherent limitations: they do not capture extracutaneous disease activity, systemic inflammation, comorbid conditions, quality of life impact, or the economic burden of psoriasis.

A common manifestation of psoriasis is psoriatic arthritis (PsA), which can involve the nails, joints, ligaments, or tendons in 30% to 41% of affected individuals (Figure 2).^2,3 A growing number of psoriasis-associated comorbidities also have been reported including metabolic syndrome⁴; hyperlipidemia⁵; cardiovascular disease⁶; stroke⁷; hypertension⁸; obesity⁹; sleep disorders¹⁰; malignancy¹¹; infections¹²; inflammatory bowel disease¹³; and mental health disorders such as depression,¹⁴ anxiety,¹⁵ and suicidal ideation.¹⁵ Psoriatic disease also interferes with daily life activities and a patient’s overall quality of life, including interpersonal relationships, intimacy, employment, and work productivity.¹⁶ Finally, the total estimated cost of psoriasis-related health care is more than $35 billion annually,¹⁷ representing a substantial economic burden to our health care system and individual patients.

The overall burden of psoriatic disease has declined markedly in the last 2 decades due to revolutionary advances in our understanding of the immunopathogenesis of psoriasis and the subsequent development of improved therapies that predominantly interrupt IL-23/IL-17 cytokine signaling; however, critical knowledge and treatment gaps persist, underscoring the importance of ongoing clinical and research efforts in psoriatic disease. We review the working immune model of psoriasis, summarize related immune discoveries, and highlight recent therapeutic innovations that are shaping psoriatic disease management.

Current Immune Model of Psoriatic Disease

Psoriasis is an autoinflammatory T cell–mediated disease with negligible contributions from the humoral immune response. Early clinical observations reported increased inflammatory infiltrates in psoriatic skin lesions primarily consisting of both CD4⁺ and CD8⁺ T-cell populations.^18,19 Additionally, patients treated with broad-acting, systemic immunosuppressive medications (eg, cyclosporine, oral corticosteroids) experienced improvement of psoriatic lesions and normalization of the immune infiltrates observed in skin biopsy specimens.^20,21 These early clinical findings led to more sophisticated experimentation in xenotransplant models of psoriasis,^22,23 which explored the clinical efficacy of several less immunosuppressive (eg, methotrexate, anti–tumor necrosis factor [TNF] biologics)²⁴ or T cell–specific agents (eg, alefacept, abatacept, efalizumab).^25-27 The results of these translational studies provided indisputable evidence for the role of the dysregulated immune response as the primary pathogenic process driving plaque formation; they also led to a paradigm shift in how the immunopathogenesis of psoriatic disease was viewed and paved the way for the identification and targeting of other specific proinflammatory signals produced by activated dendritic cell (DC) and T-lymphocyte populations. Among the psoriasis-associated cytokines subsequently identified and studied, elevated IL-23 and IL-17 cytokine levels in psoriatic skin were most closely associated with disease activity, and rapid normalization of IL-23/IL-17 signaling in response to effective oral or injectable antipsoriatic treatments was the hallmark of skin clearance.²⁸ The predominant role of IL-23/IL-17 signaling in the development and maintenance of psoriatic disease is the central feature of all working immune models for this disease (Figure 3).

Psoriasis-Associated Genetic and Environmental Risk Factors

The exact sequence of events that lead to the initiation and formation of plaque psoriasis in susceptible individuals is still poorly understood; however, several important risk factors and key immune events have been identified. First, decades of genetic research have reported more than 80 known psoriasis-associated susceptibility loci,²⁹ which explains approximately 50% of psoriasis heritability. The major genetic determinant of psoriasis, HLA-C*06:02 (formerly HLA-Cw6), resides in the major histocompatibility complex class I region on chromosome 6p21.3 (psoriasis susceptibility gene 1, PSORS1) and is most strongly associated with psoriatic disease.³⁰ Less common psoriasis-associated susceptibility genes also are known to directly or indirectly impact innate and adaptive immune functions that contribute to the pathogenesis of psoriasis.

Second, several nongenetic environmental risk factors for psoriasis have been reported across diverse patient populations, including skin trauma/injury, infections, alcohol/tobacco use, obesity, medication exposure (eg, lithium, antimalarials, beta-blockers), and stress.³¹ These genetic and/or environmental risk factors can trigger the onset of psoriatic disease at any stage of life, though most patients develop disease in early adulthood or later (age range, 50–60 years). Some patients never develop psoriasis despite exposure to environmental risk factors and/or a genetic makeup that is similar to affected first-degree relatives, which requires further study.

Prepsoriatic Skin and Initiation of Plaque Development

In response to environmental stimuli and/or other triggers of the immune system, DC and resident IL-17–producing T-cell (T17) populations become activated in predisposed individuals. Dendritic cell activation leads to the upregulation and increase of several proinflammatory cytokines, including TNF, interferon (IFN) α, IFN-γ, IL-12, and IL-23. Tumor necrosis factor and IL-23 play a vital role in psoriasis by helping to regulate the polarization and expansion of T22 and T17 cells in the skin, whereas IL-12 promotes a corresponding type 1 inflammatory response.³² Increased IL-17 and IL-22 result in alteration of the terminal differentiation and proliferative potential of epidermal keratinocytes, leading to the early clinical hallmarks of psoriatic plaques. The potential contribution of overexpressed psoriasis-related autoantigens, such as LL-37/cathelicidin, ADAMTSL5, and PLA2G4D,³³ in the initiation of psoriatic plaques has been suggested but is poorly characterized.³⁴ Whether these specific autoantigens or others presented by HLA-C variants found on antigen-presenting cells are required for the breakdown of immune tolerance and psoriatic disease initiation is highly relevant but requires further investigation and validation.

In response to the upstream production of IL-23 by dermal DCs, high levels of IL-17 cytokines can be found in mature psoriatic plaques. The IL-17 family consists of 6 dimeric cytokines (IL-17A through IL-17F) that provide innate cutaneous protection against bacterial, viral, and fungal infectious agents, such as Candida albicans. Unlike other IL-17 isoforms, IL-17A and IL-17F share the same receptor complex and have the highest structural homology of any pair (approximately 50% similar).³⁵ The relative expression of IL-17F is higher than IL-17A in psoriasis,³⁶ though IL-17A has been considered as the predominant IL-17 cytokine found in psoriatic skin lesions due to its higher potency.

Binding of IL-17A/F with the IL-17 receptor (IL-17R) on keratinocytes contributes to the development of psoriatic plaques by inducing epidermal hyperplasia via activation of CCAAT/enhancer-binding proteins β and δ, nuclear factor κB, and signal transducer and activator of transcription 1 gene (STAT1).^37,38 This also increases the expression of other keratinocyte-derived proteins (eg, human β-defensins, S-100 proteins, LL-37, other antimicrobial peptides, IL-19, IL-36, IL-17C) that act as reinforcing proinflammatory signals or chemotactic factors (eg, chemokine [C-C motif] ligand 20 [CCL20], chemokine [C-C motif] ligand 1/2/3/5 [CXCL1/2/3/5], CXCL8, IL-8) that facilitate the recruitment of additional immune cells to the skin including polymorphonuclear neutrophils (PMNs), macrophages, and DCs.^39-41 Routine immunohistochemical staining for these keratinocyte-derived proteins reveals a striking epidermal gene expression gradient wherein levels of IL-17–induced proteins are most highly expressed in the uppermost layers of keratinocytes and facilitate the recruitment of immune cells into the epidermis. Activated T17 cells also stimulate the production of keratinocyte-derived chemokines (eg, CXCL9/10/11), which recruit type 1 inflammatory T-cell populations into developing psoriatic plaques.^42,43 Finally, TNF, IL-36, and IL-17C cytokines act synergistically with IL-17A/F to amplify the proinflammatory effects of IL-17 signaling and further stimulate their production from T17 cell populations.⁴⁰ This inflammatory circuit in the skin creates and supports a self-amplifying or positive feedback loop between the skin and immune system that commonly is referred to as feed-forward inflammation (Figure 3).³⁴ The feed-forward inflammatory loop in psoriasis—predominantly driven by increased IL-23/IL-17 signaling—best characterizes the mature psoriatic plaque.

Several findings suggest that the influx of persistent, long-lived resident memory T cells (Trms) may contribute to the mature psoriatic plaque. It is believed that CD8⁺CD103⁺CD49a⁻ Trm cell populations may be responsible for the sharply demarcated borders of untreated psoriasis plaques or their recurrence at specific body sites such as the scalp, buttocks, extremity extensor surfaces, umbilicus, or acral skin following specific stimuli or trauma (Koebner phenomenon or isomorphic response).^44,45 It is not known if repeated stimuli or trauma induce disease formation via the activation of Trm cell populations; further study in large patient cohorts is needed, but this remains an intriguing area of study for durable treatment responses and potential cures for psoriasis.

Recent Discoveries in Psoriatic Disease

Remarkable treatment outcomes for psoriasis have been achieved with multiple selective IL-17 and IL-23 inhibitors (eTable). As demonstrated in several pivotal phase 3 clinical trials for members of these classes of medications, the majority of treated psoriasis patients achieved PASI90 clearance.⁴⁶ Due to their more favorable dosing schedule (ie, fewer injections) and ability to induce a durable remissionlike treatment response, IL-23 inhibitors have become the preferred treatment class for cutaneous disease, while IL-17 inhibitors may be preferred when treating patients with both plaque psoriasis and PsA.^47,48 Nevertheless, the complexity of this disease is punctuated by treated patients who do not adequately respond to selective IL-23/IL-17 blockade.⁴⁹ Recent and emerging treatments may shed light on these recalcitrant cases and will add to the rapidly growing arsenal of available psoriasis therapies.

The Role of IL-17F in Psoriasis and Other Inflammatory Skin Diseases

Dysregulation of IL-17A and IL-17F is associated with several chronic inflammatory conditions, such as psoriasis and PsA.^35,50 Both cytokines, either as homodimers or heterodimers, can selectively bind to the heterodimeric IL-17R formed by the IL-17RA and IL-17RC subunits.³⁵ IL-17F and IL-17C also can synergize with TNF and other cytokines to promote and support the self-sustaining inflammatory circuits in mature psoriatic plaques, though their inflammatory effects in the skin are more limited than IL-17A.^51,52 Therefore, incomplete blockade of IL-17 signaling (ie, unopposed IL-17F and IL-17C) represents a potential mechanism to explain the persistence of psoriasis in patients treated with selective IL-17A inhibitors. This hypothesis is supported by reports of psoriasis patients who have inadequate clinical responses to selective IL-17A inhibition but subsequently improve with IL-17R blockade, which results in disruption of IL-17A as well as IL-17C/E/F cytokine signaling. This formed the basis for further study into the specific role of IL-17F in psoriatic disease and any potential therapeutic benefits associated with its inhibition.

Recently approved in the European Union, Canada, Australia, Japan, the United Kingdom, and the United States for moderate to severe psoriasis, bimekizumab is a novel humanized IgG antibody that selectively inhibits both IL-17A and IL-17F cytokines.⁵³ Specifically, bimekizumab simultaneously prevents binding of IL-17A/A, IL-17A/F, and IL-17F/F dimers with the IL-17R. Compared to other IL-17 and IL-23 biologic therapies, bimekizumab (320 mg) achieved relatively higher response rates for PASI75, PASI90, and PASI100.⁴⁹ Neutralization of IL-17A and IL-17F by bimekizumab also resulted in more complete suppression of cytokine responses and PMN chemotaxis than either cytokine alone in treated PsA patients,⁵⁴ which is notable because of the incremental benefits of recent IL-23 and IL-17 inhibitors on inflammatory arthritis symptoms in contrast to the substantial improvements observed for cutaneous disease with those same agents.

The primary disadvantage of bimekizumab and its more complete blockade of the IL-17 signaling pathway is that treated patients have a substantially increased risk for oral candidiasis (>10%).⁵⁵ However, the precise link between candidiasis and IL-17 blockade is not yet fully understood because other targeted agents that also broadly suppress IL-17 signaling (ie, IL-17R, IL-23 inhibitors) are associated with much lower rates of candidiasis.^56-58 Bimekizumab also is being investigated as a novel therapy for hidradenitis suppurativa and will provide important reference information regarding the role for bispecific biologic agents in the treatment of chronic inflammatory skin diseases.⁵⁹

Recent genetic and clinical studies have expanded our understanding of the role of IL-36 signaling in the immunopathogenesis of pustular psoriasis variants. Generalized pustular psoriasis (GPP) is a rare distinct psoriasis subtype characterized by the recurrent development of widespread erythema, superficial sterile pustules, and desquamation. Systemic symptoms such as fever, malaise, itching, and skin pain accompany acute GPP flares.⁶⁰ Generalized pustular psoriasis is more common in female patients (in contrast with plaque psoriasis), and acute flares may be caused by multiple stimuli including infections, hypocalcemia, initiation or discontinuation of medications (eg, oral corticosteroids), pregnancy, or stress.^61,62 Flares of GPP often require emergency or in-patient care, as untreated symptoms increase the risk for severe health complications such as secondary infections, sepsis, or multisystem organ failure.⁶³ The prevalence of GPP is estimated to be approximately 1 in 10,000 individuals in the United States,^64-67 with mortality rates ranging from 0 to 3.3 deaths per 100 patient-years.⁶⁷

In contrast to plaque psoriasis, aberrant IL-36 signaling is the predominant driver of GPP. IL-36 is a member of the IL-1 cytokine family that includes three IL-36 agonists (IL-36α, IL-36β, IL-36γ) and 1 endogenous antagonist (IL-36Ra, encoded by IL36RN).⁶⁸ The immunopathogenesis of GPP involves dysregulation of the IL-36–chemokine–PMN axis, resulting in unopposed IL-36 signaling and the subsequent recruitment and influx of PMNs into the epidermis. IL36RN mutations are strongly associated with GPP and result in impaired function of the IL-36Ra protein, leading to unopposed IL-36 signaling.⁶⁹ However, approximately two-thirds of GPP patients lack identifiable gene mutations, suggesting other immune mechanisms or triggers causing upregulated IL-36 signaling.⁷⁰ In response to these triggers, increased IL-36 cytokines released by keratinocytes bind to the IL-36R, resulting in substantial keratinocyte hyperproliferation, increased IL-36 levels, and the expression of hundreds of additional inflammatory signals (eg, IL-17C, antimicrobial peptides, TNF, IL-6).⁷¹ Increased IL-36 levels also drive the production of PMN chemotactic proteins (eg, CXCL1/2/3/5/6/8 and CXCR1/2) and act synergistically with IL-17 cytokines to create an autoamplifying circuit that is analogous to the feed-forward inflammatory loop in plaque psoriasis.⁷² Biopsies of involved GPP skin reveal increased expression of IL-36 in the uppermost layers of the epidermis, which creates a gene expression gradient that acts as a strong attractant for PMNs and forms the basis for the hallmark pustular lesions observed in GPP patients.

Until recently, treatment strategies for GPP involved the off-label use of topical, oral, or biologic therapies approved for plaque psoriasis, which often was associated with variable or incomplete disease control. In September 2022, the US Food and Drug Administration (FDA) approved intravenous spesolimab as a first-in-class humanized monoclonal IgG1 antibody for the treatment of GPP flares in adults. Spesolimab binds to IL-36R and prevents its activation by its endogenous agonists. A phase 2, randomized, 12-week clinical trial (Effisayil-1) evaluated the efficacy and safety of a single 900-mg intravenous dose of spesolimab followed by an optional second dose 1 week later for inadequate treatment responses in 53 enrolled GPP patients (2:1 treatment to placebo randomization).⁷³ Remarkably, more than half (19/35 [54%]) of GPP patients experienced complete resolution of pustules (GPP physician global assessment subscore of 0 [range, 0–4]) and showed sustained efficacy out to week 12 after just 1 or 2 doses of spesolimab. Overall, the safety profile of spesolimab was good; asthenia, fatigue, nausea, vomiting, headache, pruritus, infusion-related reaction and symptoms, and mild infections (eg, urinary tract infection) were the most common adverse events reported.⁷³

Imsidolimab, a high-affinity humanized IgG4 monoclonal antibody that binds and blocks activation of IL-36R, also has completed phase 2 testing,⁷⁴ with phase 3 study results expected in early 2024. The rapid onset of action and overall safety of imsidolimab was in line with and similar to spesolimab. Future approval of imsidolimab would add to the limited treatment options available for GPP and has the additional convenience of being administered to patients subcutaneously. Overall, the development of selective IL-36R inhibitors offers a much-needed therapeutic option for GPP and illustrates the importance of translational research.

Role of Tyrosine Kinase in Psoriatic Disease

The Janus kinase (JAK) enzyme family consists of 4 enzymes—tyrosine kinase 2 (TYK2), JAK1, JAK2, and JAK3—that function as intracellular transduction signals that mediate the biologic response of most extracellular cytokines and growth factors.⁷⁵ Critical psoriasis-related cytokines are dependent on intact JAK-STAT signaling, including IL-23, IL-12, and type I IFNs. In 2010, a genome-wide association identified TYK2 as a psoriasis susceptibility locus,⁷⁶ and loss-of-function TYK2 mutations confer a reduced risk for psoriasis.⁷⁷ Unlike other JAK isoforms, TYK2 mediates biologic functions that are highly restricted to the immune responses associated with IL-23, IL-12, and type I IFN signaling.^78,79 For these reasons, blockade of TYK2 signaling is an attractive therapeutic target for the potential treatment of psoriatic disease.

In September 2022, the FDA approved deucravacitinib as a first-in-class, oral, selective TYK2 inhibitor for the treatment of adult patients with moderate to severe plaque psoriasis. It was the first FDA approval of an oral small-molecule treatment for plaque psoriasis in nearly a decade. Deucravacitinib inhibits TYK2 signaling via selective binding of its unique regulatory domain, resulting in a conformational (allosteric) change that interferes with its active domain.⁸⁰ This novel mechanism of action limits the unwanted blockade of other broad biologic processes mediated by JAK1/2/3. Of note, the FDA did not issue any boxed warnings for deucravacitinib as it did for other FDA-approved JAK inhibitors.

In a head-to-head, 52-week, double-blind, prospective, randomized, phase 3 study, deucravacitinib showed clear superiority over apremilast for PASI75 at week 16 (53.0% [271/511] vs 39.8% [101/254]) and week 24 (58.7% [296/504] vs 37.8% [96/254]).⁸¹ Clinical responses were sustained through week 52 and showed efficacy for difficult-to-treat areas such as the scalp, acral sites, and nails. Other advantages of deucravacitinib include once-daily dosing with no need for dose titration or adjustments for renal insufficiency as well as the absence of statistically significant differences in gastrointestinal tract symptoms compared to placebo. The most common adverse effects included nasopharyngitis, upper respiratory tract infections, headache, diarrhea, and herpes infections.⁸¹ The potential benefit of deucravacitinib for PsA and psoriasis comorbidities remains to be seen, but it is promising due to its simultaneous disruption of multiple psoriasis-related cytokine networks. Several other TYK2 inhibitors are being developed for psoriatic disease and related inflammatory conditions, underscoring the promise of targeting this intracellular pathway.

Topical steroids are the mainstay treatment option for localized or limited plaque psoriasis due to their potent immunosuppressive effect on the skin and relatively low cost. Combined with vitamin D analogs, topical steroids result in marked improvements in disease severity and improved tolerability.⁸² However, chronic use of topical steroids is limited by the need for twice-daily application, resulting in poor treatment compliance; loss of efficacy over time; risk for steroid-induced skin atrophy on special body sites; and patient concerns of potential systemic effects. The discovery of novel drug targets amenable to topical inhibition is needed.

Dysregulated aryl hydrocarbon receptor (AHR) levels have been reported in atopic dermatitis and psoriasis.⁸³ Aryl hydrocarbon receptors are ubiquitously expressed in many cell types and play an integral role in immune homeostasis within the skin, skin barrier function, protection against oxidative stressors, and regulation of proliferating melanocytes and keratinocytes.^84,85 They are widely expressed in multiple immune cell types (eg, antigen-presenting cells, T lymphocytes, fibroblasts) and modulate the differentiation of T17 and T22 cells as well as their balance with regulatory T-cell populations.⁸⁶ In keratinocytes, AHR helps to regulate terminal differentiation, enhance skin barrier integrity via AHR-dependent filaggrin (FLG) expression, and prevent transepidermal water loss.^87,88 The mechanisms by which AHR ligands lead to the upregulation or downregulation of specific genes is intricate and highly context dependent, such as the specific ligand and cell type involved. In preclinical studies, AHR-deficient mice develop psoriasiform skin inflammation, increased IL-17 and IL-22 expression, and abnormal skin barrier function.⁸⁹ Keratinocytes treated with AHR ligands in vitro modulated psoriasis-associated inflammatory cytokines, such as IL-6, IL-8, and type I and II IFNs.^89,90 The use of coal tar, one of the earliest historical treatments for psoriasis, is thought to activate AHRs in the skin via organic compound mixtures containing polyaromatic hydrocarbons that help normalize the proinflammatory environment in psoriatic skin.⁹¹

In June 2022, the FDA approved tapinarof as a first-in-class, topical, nonsteroidal AHR agonist for the treatment of plaque psoriasis in adults. Although the exact mechanism of action for tapinarof has not been fully elucidated, early studies suggest that its primary function is the activation of AHR, leading to reduced T-cell expansion and T17 cell differentiation. In the imiquimod mouse model, cytokine expression of IL-17A, IL-17F, IL-19, IL-22, IL-23A, and IL-lβ in psoriasiform skin lesions were downregulated following tapinarof treatment.⁹² In humans, tapinarof treatment is associated with a remittive effect, in which the average time for tapinarof-treated psoriasis lesions to remain clear was approximately 4 months.⁹³ Preliminary research investigating the mechanism by which tapinarof induces this remittive effect is ongoing and may involve the reduced activation and influx of T17 and Trm populations into the skin.⁹⁴ However, these preclinical studies were performed on healthy dermatome-derived skin tissue cultured in T17-skewing conditions and needs to be replicated in larger samples sizes using human-derived psoriatic tissue. Alternatively, a strong inhibitory effect on IL-23 cytokine signaling may, in part, explain the remittive effect of tapinarof, as an analogous response is observed in patients who start and discontinue treatment with selective IL-23 antagonists. Regardless, the once-daily dosing of tapinarof and sustained treatment response is appealing to psoriasis patients. Tapinarof generally is well tolerated with mild folliculitis (>20% of patients) and contact dermatitis (5% of patients) reported as the most common skin-related adverse events.

New Roles for Phosphodiesterase 4 Inhibition

Phosphodiesterases (PDEs) are enzymes that hydrolyze cyclic nucleotides (eg, cyclic adenosine monophosphate) to regulate intracellular secondary messengers involved in the inflammatory response. One of several enzymes in the PDE family, PDE4, has been shown to have greater activity in psoriatic skin compared to healthy skin.⁹⁵ Phosphodiesterase inhibitors decrease the degradation of cyclic adenosine monophosphate, which triggers protein kinase A to downregulate proinflammatory (eg, TNF-α, IL-6, IL-17, IL-12, IL-23) cytokines and increased expression of anti-inflammatory signals such as IL-10.^96,97 Apremilast, the first oral PDE4 inhibitor approved by the FDA for psoriasis, offered a safe alternative to traditional oral immunosuppressive agents that had extensive risks and potential end-organ adverse effects. Unfortunately, apremilast demonstrated modest efficacy for psoriatic disease (better efficacy in the skin vs joint manifestations) and was supplanted easily by next-generation targeted biologic agents that were more efficacious and lacked the troublesome gastrointestinal tract adverse effects of PDE4 inhibition.⁹⁸

Crisaborole became the first topical PDE4 inhibitor approved in the United States in December 2016 for twice-daily treatment of atopic dermatitis. Although phase 2 trial results were reported in psoriasis, this indication was never pursued, presumably due to similar improvements in primary outcome measures at week 12, compared to placebo (ClinicalTrials.gov Identifier NCT01300052).

In July 2022, the first topical PDE4 inhibitor indicated for plaque psoriasis was approved by the FDA—­roflumilast cream 0.3% for once-daily use in individuals 12 years and older. Roflumilast was found to be clinically efficacious as early as 2 weeks after its use in an early-phase clinical trial.⁹⁹ In 2 phase 3 clinical trials (DERMIS-1 and DERMIS-2), roflumilast significantly increased the proportion of patients achieving PASI75 at week 8 compared to vehicle (39%–41.6% vs 5.3%–7.6%, respectively)(P<.001).¹⁰⁰ Overall, this nonsteroidal topical therapy was found to be well tolerated, with infrequent reports of application site pain or irritation as adverse events. Similar to tapinarof, patients can apply roflumilast on all body surface areas including the face, external genitalia, and other intertriginous areas.¹⁰⁰ Importantly, the broad immune impact of PDE4 inhibition suggests that topical roflumilast likely will be an effective treatment for several additional inflammatory conditions, including seborrheic dermatitis and atopic dermatitis, which would expand the clinical utility of this specific medication.

Conclusion

In the last 2 decades, we have witnessed a translational revolution in our understanding of the underlying genetics and immunology of psoriatic disease. Psoriasis is widely considered one of the best-managed inflammatory conditions in all of medicine due to the development and availability of highly targeted, effective topical and systemic therapies that predominantly disrupt IL-23/IL-17 cytokine signaling in affected tissues. However, future clinical studies and laboratory research are necessary to elucidate the precise cause of psoriasis as well as the underlying genetic and immune signaling pathways driving less common clinical variants and recalcitrant disease.

Psoriasis is a chronic inflammatory disease that affects approximately 3% of the US population.¹ Plaque psoriasis comprises 80% to 90% of cases, while pustular, erythrodermic, guttate, inverse, and palmoplantar disease are less common variants (Figure 1). Psoriatic skin manifestations range from localized to widespread or generalized disease with recurrent flares. Body surface area or psoriasis area and severity index (PASI) measurements primarily focus on skin manifestations and are important for evaluating disease activity and response to treatment, but they have inherent limitations: they do not capture extracutaneous disease activity, systemic inflammation, comorbid conditions, quality of life impact, or the economic burden of psoriasis.

A common manifestation of psoriasis is psoriatic arthritis (PsA), which can involve the nails, joints, ligaments, or tendons in 30% to 41% of affected individuals (Figure 2).^2,3 A growing number of psoriasis-associated comorbidities also have been reported including metabolic syndrome⁴; hyperlipidemia⁵; cardiovascular disease⁶; stroke⁷; hypertension⁸; obesity⁹; sleep disorders¹⁰; malignancy¹¹; infections¹²; inflammatory bowel disease¹³; and mental health disorders such as depression,¹⁴ anxiety,¹⁵ and suicidal ideation.¹⁵ Psoriatic disease also interferes with daily life activities and a patient’s overall quality of life, including interpersonal relationships, intimacy, employment, and work productivity.¹⁶ Finally, the total estimated cost of psoriasis-related health care is more than $35 billion annually,¹⁷ representing a substantial economic burden to our health care system and individual patients.

The overall burden of psoriatic disease has declined markedly in the last 2 decades due to revolutionary advances in our understanding of the immunopathogenesis of psoriasis and the subsequent development of improved therapies that predominantly interrupt IL-23/IL-17 cytokine signaling; however, critical knowledge and treatment gaps persist, underscoring the importance of ongoing clinical and research efforts in psoriatic disease. We review the working immune model of psoriasis, summarize related immune discoveries, and highlight recent therapeutic innovations that are shaping psoriatic disease management.

Current Immune Model of Psoriatic Disease

Psoriasis is an autoinflammatory T cell–mediated disease with negligible contributions from the humoral immune response. Early clinical observations reported increased inflammatory infiltrates in psoriatic skin lesions primarily consisting of both CD4⁺ and CD8⁺ T-cell populations.^18,19 Additionally, patients treated with broad-acting, systemic immunosuppressive medications (eg, cyclosporine, oral corticosteroids) experienced improvement of psoriatic lesions and normalization of the immune infiltrates observed in skin biopsy specimens.^20,21 These early clinical findings led to more sophisticated experimentation in xenotransplant models of psoriasis,^22,23 which explored the clinical efficacy of several less immunosuppressive (eg, methotrexate, anti–tumor necrosis factor [TNF] biologics)²⁴ or T cell–specific agents (eg, alefacept, abatacept, efalizumab).^25-27 The results of these translational studies provided indisputable evidence for the role of the dysregulated immune response as the primary pathogenic process driving plaque formation; they also led to a paradigm shift in how the immunopathogenesis of psoriatic disease was viewed and paved the way for the identification and targeting of other specific proinflammatory signals produced by activated dendritic cell (DC) and T-lymphocyte populations. Among the psoriasis-associated cytokines subsequently identified and studied, elevated IL-23 and IL-17 cytokine levels in psoriatic skin were most closely associated with disease activity, and rapid normalization of IL-23/IL-17 signaling in response to effective oral or injectable antipsoriatic treatments was the hallmark of skin clearance.²⁸ The predominant role of IL-23/IL-17 signaling in the development and maintenance of psoriatic disease is the central feature of all working immune models for this disease (Figure 3).

Psoriasis-Associated Genetic and Environmental Risk Factors

The exact sequence of events that lead to the initiation and formation of plaque psoriasis in susceptible individuals is still poorly understood; however, several important risk factors and key immune events have been identified. First, decades of genetic research have reported more than 80 known psoriasis-associated susceptibility loci,²⁹ which explains approximately 50% of psoriasis heritability. The major genetic determinant of psoriasis, HLA-C*06:02 (formerly HLA-Cw6), resides in the major histocompatibility complex class I region on chromosome 6p21.3 (psoriasis susceptibility gene 1, PSORS1) and is most strongly associated with psoriatic disease.³⁰ Less common psoriasis-associated susceptibility genes also are known to directly or indirectly impact innate and adaptive immune functions that contribute to the pathogenesis of psoriasis.

Second, several nongenetic environmental risk factors for psoriasis have been reported across diverse patient populations, including skin trauma/injury, infections, alcohol/tobacco use, obesity, medication exposure (eg, lithium, antimalarials, beta-blockers), and stress.³¹ These genetic and/or environmental risk factors can trigger the onset of psoriatic disease at any stage of life, though most patients develop disease in early adulthood or later (age range, 50–60 years). Some patients never develop psoriasis despite exposure to environmental risk factors and/or a genetic makeup that is similar to affected first-degree relatives, which requires further study.

Prepsoriatic Skin and Initiation of Plaque Development

In response to environmental stimuli and/or other triggers of the immune system, DC and resident IL-17–producing T-cell (T17) populations become activated in predisposed individuals. Dendritic cell activation leads to the upregulation and increase of several proinflammatory cytokines, including TNF, interferon (IFN) α, IFN-γ, IL-12, and IL-23. Tumor necrosis factor and IL-23 play a vital role in psoriasis by helping to regulate the polarization and expansion of T22 and T17 cells in the skin, whereas IL-12 promotes a corresponding type 1 inflammatory response.³² Increased IL-17 and IL-22 result in alteration of the terminal differentiation and proliferative potential of epidermal keratinocytes, leading to the early clinical hallmarks of psoriatic plaques. The potential contribution of overexpressed psoriasis-related autoantigens, such as LL-37/cathelicidin, ADAMTSL5, and PLA2G4D,³³ in the initiation of psoriatic plaques has been suggested but is poorly characterized.³⁴ Whether these specific autoantigens or others presented by HLA-C variants found on antigen-presenting cells are required for the breakdown of immune tolerance and psoriatic disease initiation is highly relevant but requires further investigation and validation.

In response to the upstream production of IL-23 by dermal DCs, high levels of IL-17 cytokines can be found in mature psoriatic plaques. The IL-17 family consists of 6 dimeric cytokines (IL-17A through IL-17F) that provide innate cutaneous protection against bacterial, viral, and fungal infectious agents, such as Candida albicans. Unlike other IL-17 isoforms, IL-17A and IL-17F share the same receptor complex and have the highest structural homology of any pair (approximately 50% similar).³⁵ The relative expression of IL-17F is higher than IL-17A in psoriasis,³⁶ though IL-17A has been considered as the predominant IL-17 cytokine found in psoriatic skin lesions due to its higher potency.

Binding of IL-17A/F with the IL-17 receptor (IL-17R) on keratinocytes contributes to the development of psoriatic plaques by inducing epidermal hyperplasia via activation of CCAAT/enhancer-binding proteins β and δ, nuclear factor κB, and signal transducer and activator of transcription 1 gene (STAT1).^37,38 This also increases the expression of other keratinocyte-derived proteins (eg, human β-defensins, S-100 proteins, LL-37, other antimicrobial peptides, IL-19, IL-36, IL-17C) that act as reinforcing proinflammatory signals or chemotactic factors (eg, chemokine [C-C motif] ligand 20 [CCL20], chemokine [C-C motif] ligand 1/2/3/5 [CXCL1/2/3/5], CXCL8, IL-8) that facilitate the recruitment of additional immune cells to the skin including polymorphonuclear neutrophils (PMNs), macrophages, and DCs.^39-41 Routine immunohistochemical staining for these keratinocyte-derived proteins reveals a striking epidermal gene expression gradient wherein levels of IL-17–induced proteins are most highly expressed in the uppermost layers of keratinocytes and facilitate the recruitment of immune cells into the epidermis. Activated T17 cells also stimulate the production of keratinocyte-derived chemokines (eg, CXCL9/10/11), which recruit type 1 inflammatory T-cell populations into developing psoriatic plaques.^42,43 Finally, TNF, IL-36, and IL-17C cytokines act synergistically with IL-17A/F to amplify the proinflammatory effects of IL-17 signaling and further stimulate their production from T17 cell populations.⁴⁰ This inflammatory circuit in the skin creates and supports a self-amplifying or positive feedback loop between the skin and immune system that commonly is referred to as feed-forward inflammation (Figure 3).³⁴ The feed-forward inflammatory loop in psoriasis—predominantly driven by increased IL-23/IL-17 signaling—best characterizes the mature psoriatic plaque.

Several findings suggest that the influx of persistent, long-lived resident memory T cells (Trms) may contribute to the mature psoriatic plaque. It is believed that CD8⁺CD103⁺CD49a⁻ Trm cell populations may be responsible for the sharply demarcated borders of untreated psoriasis plaques or their recurrence at specific body sites such as the scalp, buttocks, extremity extensor surfaces, umbilicus, or acral skin following specific stimuli or trauma (Koebner phenomenon or isomorphic response).^44,45 It is not known if repeated stimuli or trauma induce disease formation via the activation of Trm cell populations; further study in large patient cohorts is needed, but this remains an intriguing area of study for durable treatment responses and potential cures for psoriasis.

Recent Discoveries in Psoriatic Disease

Remarkable treatment outcomes for psoriasis have been achieved with multiple selective IL-17 and IL-23 inhibitors (eTable). As demonstrated in several pivotal phase 3 clinical trials for members of these classes of medications, the majority of treated psoriasis patients achieved PASI90 clearance.⁴⁶ Due to their more favorable dosing schedule (ie, fewer injections) and ability to induce a durable remissionlike treatment response, IL-23 inhibitors have become the preferred treatment class for cutaneous disease, while IL-17 inhibitors may be preferred when treating patients with both plaque psoriasis and PsA.^47,48 Nevertheless, the complexity of this disease is punctuated by treated patients who do not adequately respond to selective IL-23/IL-17 blockade.⁴⁹ Recent and emerging treatments may shed light on these recalcitrant cases and will add to the rapidly growing arsenal of available psoriasis therapies.

The Role of IL-17F in Psoriasis and Other Inflammatory Skin Diseases

Dysregulation of IL-17A and IL-17F is associated with several chronic inflammatory conditions, such as psoriasis and PsA.^35,50 Both cytokines, either as homodimers or heterodimers, can selectively bind to the heterodimeric IL-17R formed by the IL-17RA and IL-17RC subunits.³⁵ IL-17F and IL-17C also can synergize with TNF and other cytokines to promote and support the self-sustaining inflammatory circuits in mature psoriatic plaques, though their inflammatory effects in the skin are more limited than IL-17A.^51,52 Therefore, incomplete blockade of IL-17 signaling (ie, unopposed IL-17F and IL-17C) represents a potential mechanism to explain the persistence of psoriasis in patients treated with selective IL-17A inhibitors. This hypothesis is supported by reports of psoriasis patients who have inadequate clinical responses to selective IL-17A inhibition but subsequently improve with IL-17R blockade, which results in disruption of IL-17A as well as IL-17C/E/F cytokine signaling. This formed the basis for further study into the specific role of IL-17F in psoriatic disease and any potential therapeutic benefits associated with its inhibition.

Recently approved in the European Union, Canada, Australia, Japan, the United Kingdom, and the United States for moderate to severe psoriasis, bimekizumab is a novel humanized IgG antibody that selectively inhibits both IL-17A and IL-17F cytokines.⁵³ Specifically, bimekizumab simultaneously prevents binding of IL-17A/A, IL-17A/F, and IL-17F/F dimers with the IL-17R. Compared to other IL-17 and IL-23 biologic therapies, bimekizumab (320 mg) achieved relatively higher response rates for PASI75, PASI90, and PASI100.⁴⁹ Neutralization of IL-17A and IL-17F by bimekizumab also resulted in more complete suppression of cytokine responses and PMN chemotaxis than either cytokine alone in treated PsA patients,⁵⁴ which is notable because of the incremental benefits of recent IL-23 and IL-17 inhibitors on inflammatory arthritis symptoms in contrast to the substantial improvements observed for cutaneous disease with those same agents.

The primary disadvantage of bimekizumab and its more complete blockade of the IL-17 signaling pathway is that treated patients have a substantially increased risk for oral candidiasis (>10%).⁵⁵ However, the precise link between candidiasis and IL-17 blockade is not yet fully understood because other targeted agents that also broadly suppress IL-17 signaling (ie, IL-17R, IL-23 inhibitors) are associated with much lower rates of candidiasis.^56-58 Bimekizumab also is being investigated as a novel therapy for hidradenitis suppurativa and will provide important reference information regarding the role for bispecific biologic agents in the treatment of chronic inflammatory skin diseases.⁵⁹

Recent genetic and clinical studies have expanded our understanding of the role of IL-36 signaling in the immunopathogenesis of pustular psoriasis variants. Generalized pustular psoriasis (GPP) is a rare distinct psoriasis subtype characterized by the recurrent development of widespread erythema, superficial sterile pustules, and desquamation. Systemic symptoms such as fever, malaise, itching, and skin pain accompany acute GPP flares.⁶⁰ Generalized pustular psoriasis is more common in female patients (in contrast with plaque psoriasis), and acute flares may be caused by multiple stimuli including infections, hypocalcemia, initiation or discontinuation of medications (eg, oral corticosteroids), pregnancy, or stress.^61,62 Flares of GPP often require emergency or in-patient care, as untreated symptoms increase the risk for severe health complications such as secondary infections, sepsis, or multisystem organ failure.⁶³ The prevalence of GPP is estimated to be approximately 1 in 10,000 individuals in the United States,^64-67 with mortality rates ranging from 0 to 3.3 deaths per 100 patient-years.⁶⁷

In contrast to plaque psoriasis, aberrant IL-36 signaling is the predominant driver of GPP. IL-36 is a member of the IL-1 cytokine family that includes three IL-36 agonists (IL-36α, IL-36β, IL-36γ) and 1 endogenous antagonist (IL-36Ra, encoded by IL36RN).⁶⁸ The immunopathogenesis of GPP involves dysregulation of the IL-36–chemokine–PMN axis, resulting in unopposed IL-36 signaling and the subsequent recruitment and influx of PMNs into the epidermis. IL36RN mutations are strongly associated with GPP and result in impaired function of the IL-36Ra protein, leading to unopposed IL-36 signaling.⁶⁹ However, approximately two-thirds of GPP patients lack identifiable gene mutations, suggesting other immune mechanisms or triggers causing upregulated IL-36 signaling.⁷⁰ In response to these triggers, increased IL-36 cytokines released by keratinocytes bind to the IL-36R, resulting in substantial keratinocyte hyperproliferation, increased IL-36 levels, and the expression of hundreds of additional inflammatory signals (eg, IL-17C, antimicrobial peptides, TNF, IL-6).⁷¹ Increased IL-36 levels also drive the production of PMN chemotactic proteins (eg, CXCL1/2/3/5/6/8 and CXCR1/2) and act synergistically with IL-17 cytokines to create an autoamplifying circuit that is analogous to the feed-forward inflammatory loop in plaque psoriasis.⁷² Biopsies of involved GPP skin reveal increased expression of IL-36 in the uppermost layers of the epidermis, which creates a gene expression gradient that acts as a strong attractant for PMNs and forms the basis for the hallmark pustular lesions observed in GPP patients.

Until recently, treatment strategies for GPP involved the off-label use of topical, oral, or biologic therapies approved for plaque psoriasis, which often was associated with variable or incomplete disease control. In September 2022, the US Food and Drug Administration (FDA) approved intravenous spesolimab as a first-in-class humanized monoclonal IgG1 antibody for the treatment of GPP flares in adults. Spesolimab binds to IL-36R and prevents its activation by its endogenous agonists. A phase 2, randomized, 12-week clinical trial (Effisayil-1) evaluated the efficacy and safety of a single 900-mg intravenous dose of spesolimab followed by an optional second dose 1 week later for inadequate treatment responses in 53 enrolled GPP patients (2:1 treatment to placebo randomization).⁷³ Remarkably, more than half (19/35 [54%]) of GPP patients experienced complete resolution of pustules (GPP physician global assessment subscore of 0 [range, 0–4]) and showed sustained efficacy out to week 12 after just 1 or 2 doses of spesolimab. Overall, the safety profile of spesolimab was good; asthenia, fatigue, nausea, vomiting, headache, pruritus, infusion-related reaction and symptoms, and mild infections (eg, urinary tract infection) were the most common adverse events reported.⁷³

Imsidolimab, a high-affinity humanized IgG4 monoclonal antibody that binds and blocks activation of IL-36R, also has completed phase 2 testing,⁷⁴ with phase 3 study results expected in early 2024. The rapid onset of action and overall safety of imsidolimab was in line with and similar to spesolimab. Future approval of imsidolimab would add to the limited treatment options available for GPP and has the additional convenience of being administered to patients subcutaneously. Overall, the development of selective IL-36R inhibitors offers a much-needed therapeutic option for GPP and illustrates the importance of translational research.

Role of Tyrosine Kinase in Psoriatic Disease

The Janus kinase (JAK) enzyme family consists of 4 enzymes—tyrosine kinase 2 (TYK2), JAK1, JAK2, and JAK3—that function as intracellular transduction signals that mediate the biologic response of most extracellular cytokines and growth factors.⁷⁵ Critical psoriasis-related cytokines are dependent on intact JAK-STAT signaling, including IL-23, IL-12, and type I IFNs. In 2010, a genome-wide association identified TYK2 as a psoriasis susceptibility locus,⁷⁶ and loss-of-function TYK2 mutations confer a reduced risk for psoriasis.⁷⁷ Unlike other JAK isoforms, TYK2 mediates biologic functions that are highly restricted to the immune responses associated with IL-23, IL-12, and type I IFN signaling.^78,79 For these reasons, blockade of TYK2 signaling is an attractive therapeutic target for the potential treatment of psoriatic disease.

In September 2022, the FDA approved deucravacitinib as a first-in-class, oral, selective TYK2 inhibitor for the treatment of adult patients with moderate to severe plaque psoriasis. It was the first FDA approval of an oral small-molecule treatment for plaque psoriasis in nearly a decade. Deucravacitinib inhibits TYK2 signaling via selective binding of its unique regulatory domain, resulting in a conformational (allosteric) change that interferes with its active domain.⁸⁰ This novel mechanism of action limits the unwanted blockade of other broad biologic processes mediated by JAK1/2/3. Of note, the FDA did not issue any boxed warnings for deucravacitinib as it did for other FDA-approved JAK inhibitors.

In a head-to-head, 52-week, double-blind, prospective, randomized, phase 3 study, deucravacitinib showed clear superiority over apremilast for PASI75 at week 16 (53.0% [271/511] vs 39.8% [101/254]) and week 24 (58.7% [296/504] vs 37.8% [96/254]).⁸¹ Clinical responses were sustained through week 52 and showed efficacy for difficult-to-treat areas such as the scalp, acral sites, and nails. Other advantages of deucravacitinib include once-daily dosing with no need for dose titration or adjustments for renal insufficiency as well as the absence of statistically significant differences in gastrointestinal tract symptoms compared to placebo. The most common adverse effects included nasopharyngitis, upper respiratory tract infections, headache, diarrhea, and herpes infections.⁸¹ The potential benefit of deucravacitinib for PsA and psoriasis comorbidities remains to be seen, but it is promising due to its simultaneous disruption of multiple psoriasis-related cytokine networks. Several other TYK2 inhibitors are being developed for psoriatic disease and related inflammatory conditions, underscoring the promise of targeting this intracellular pathway.

Topical steroids are the mainstay treatment option for localized or limited plaque psoriasis due to their potent immunosuppressive effect on the skin and relatively low cost. Combined with vitamin D analogs, topical steroids result in marked improvements in disease severity and improved tolerability.⁸² However, chronic use of topical steroids is limited by the need for twice-daily application, resulting in poor treatment compliance; loss of efficacy over time; risk for steroid-induced skin atrophy on special body sites; and patient concerns of potential systemic effects. The discovery of novel drug targets amenable to topical inhibition is needed.

Dysregulated aryl hydrocarbon receptor (AHR) levels have been reported in atopic dermatitis and psoriasis.⁸³ Aryl hydrocarbon receptors are ubiquitously expressed in many cell types and play an integral role in immune homeostasis within the skin, skin barrier function, protection against oxidative stressors, and regulation of proliferating melanocytes and keratinocytes.^84,85 They are widely expressed in multiple immune cell types (eg, antigen-presenting cells, T lymphocytes, fibroblasts) and modulate the differentiation of T17 and T22 cells as well as their balance with regulatory T-cell populations.⁸⁶ In keratinocytes, AHR helps to regulate terminal differentiation, enhance skin barrier integrity via AHR-dependent filaggrin (FLG) expression, and prevent transepidermal water loss.^87,88 The mechanisms by which AHR ligands lead to the upregulation or downregulation of specific genes is intricate and highly context dependent, such as the specific ligand and cell type involved. In preclinical studies, AHR-deficient mice develop psoriasiform skin inflammation, increased IL-17 and IL-22 expression, and abnormal skin barrier function.⁸⁹ Keratinocytes treated with AHR ligands in vitro modulated psoriasis-associated inflammatory cytokines, such as IL-6, IL-8, and type I and II IFNs.^89,90 The use of coal tar, one of the earliest historical treatments for psoriasis, is thought to activate AHRs in the skin via organic compound mixtures containing polyaromatic hydrocarbons that help normalize the proinflammatory environment in psoriatic skin.⁹¹

In June 2022, the FDA approved tapinarof as a first-in-class, topical, nonsteroidal AHR agonist for the treatment of plaque psoriasis in adults. Although the exact mechanism of action for tapinarof has not been fully elucidated, early studies suggest that its primary function is the activation of AHR, leading to reduced T-cell expansion and T17 cell differentiation. In the imiquimod mouse model, cytokine expression of IL-17A, IL-17F, IL-19, IL-22, IL-23A, and IL-lβ in psoriasiform skin lesions were downregulated following tapinarof treatment.⁹² In humans, tapinarof treatment is associated with a remittive effect, in which the average time for tapinarof-treated psoriasis lesions to remain clear was approximately 4 months.⁹³ Preliminary research investigating the mechanism by which tapinarof induces this remittive effect is ongoing and may involve the reduced activation and influx of T17 and Trm populations into the skin.⁹⁴ However, these preclinical studies were performed on healthy dermatome-derived skin tissue cultured in T17-skewing conditions and needs to be replicated in larger samples sizes using human-derived psoriatic tissue. Alternatively, a strong inhibitory effect on IL-23 cytokine signaling may, in part, explain the remittive effect of tapinarof, as an analogous response is observed in patients who start and discontinue treatment with selective IL-23 antagonists. Regardless, the once-daily dosing of tapinarof and sustained treatment response is appealing to psoriasis patients. Tapinarof generally is well tolerated with mild folliculitis (>20% of patients) and contact dermatitis (5% of patients) reported as the most common skin-related adverse events.

New Roles for Phosphodiesterase 4 Inhibition

Phosphodiesterases (PDEs) are enzymes that hydrolyze cyclic nucleotides (eg, cyclic adenosine monophosphate) to regulate intracellular secondary messengers involved in the inflammatory response. One of several enzymes in the PDE family, PDE4, has been shown to have greater activity in psoriatic skin compared to healthy skin.⁹⁵ Phosphodiesterase inhibitors decrease the degradation of cyclic adenosine monophosphate, which triggers protein kinase A to downregulate proinflammatory (eg, TNF-α, IL-6, IL-17, IL-12, IL-23) cytokines and increased expression of anti-inflammatory signals such as IL-10.^96,97 Apremilast, the first oral PDE4 inhibitor approved by the FDA for psoriasis, offered a safe alternative to traditional oral immunosuppressive agents that had extensive risks and potential end-organ adverse effects. Unfortunately, apremilast demonstrated modest efficacy for psoriatic disease (better efficacy in the skin vs joint manifestations) and was supplanted easily by next-generation targeted biologic agents that were more efficacious and lacked the troublesome gastrointestinal tract adverse effects of PDE4 inhibition.⁹⁸

Crisaborole became the first topical PDE4 inhibitor approved in the United States in December 2016 for twice-daily treatment of atopic dermatitis. Although phase 2 trial results were reported in psoriasis, this indication was never pursued, presumably due to similar improvements in primary outcome measures at week 12, compared to placebo (ClinicalTrials.gov Identifier NCT01300052).

In July 2022, the first topical PDE4 inhibitor indicated for plaque psoriasis was approved by the FDA—­roflumilast cream 0.3% for once-daily use in individuals 12 years and older. Roflumilast was found to be clinically efficacious as early as 2 weeks after its use in an early-phase clinical trial.⁹⁹ In 2 phase 3 clinical trials (DERMIS-1 and DERMIS-2), roflumilast significantly increased the proportion of patients achieving PASI75 at week 8 compared to vehicle (39%–41.6% vs 5.3%–7.6%, respectively)(P<.001).¹⁰⁰ Overall, this nonsteroidal topical therapy was found to be well tolerated, with infrequent reports of application site pain or irritation as adverse events. Similar to tapinarof, patients can apply roflumilast on all body surface areas including the face, external genitalia, and other intertriginous areas.¹⁰⁰ Importantly, the broad immune impact of PDE4 inhibition suggests that topical roflumilast likely will be an effective treatment for several additional inflammatory conditions, including seborrheic dermatitis and atopic dermatitis, which would expand the clinical utility of this specific medication.

Conclusion

In the last 2 decades, we have witnessed a translational revolution in our understanding of the underlying genetics and immunology of psoriatic disease. Psoriasis is widely considered one of the best-managed inflammatory conditions in all of medicine due to the development and availability of highly targeted, effective topical and systemic therapies that predominantly disrupt IL-23/IL-17 cytokine signaling in affected tissues. However, future clinical studies and laboratory research are necessary to elucidate the precise cause of psoriasis as well as the underlying genetic and immune signaling pathways driving less common clinical variants and recalcitrant disease.

TOPLINE:

A daily low dose of colchicine significantly reduces ischemic cardiovascular events in patients with type 2 diabetes (T2D) and a recent myocardial infarction (MI). 

METHODOLOGY:

• After an MI, patients with vs without T2D have a higher risk for another cardiovascular event.
• The Colchicine Cardiovascular Outcomes Trial (COLCOT), a randomized, double-blinded trial, found a lower risk for ischemic cardiovascular events with 0.5 mg colchicine taken daily vs placebo, initiated within 30 days of an MI.
• Researchers conducted a prespecified subgroup analysis of 959 adult patients with T2D (mean age, 62.4 years; 22.2% women) in COLCOT (462 patients in colchicine and 497 patients in placebo groups).
• The primary efficacy endpoint was a composite of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring coronary revascularization within a median 23 months.
• The patients were taking a variety of appropriate medications, including aspirin and another antiplatelet agent and a statin (98%-99%) and metformin (75%-76%).

TAKEAWAY:

• The risk for the primary endpoint was reduced by 35% in patients with T2D who received colchicine than in those who received placebo (hazard ratio, 0.65; P = .03).
• The primary endpoint event rate per 100 patient-months was significantly lower in the colchicine group than in the placebo group (rate ratio, 0.53; P = .01).
• The frequencies of adverse events were similar in both the treatment and placebo groups (14.6% and 12.8%, respectively; P = .41), with gastrointestinal adverse events being the most common.
• In COLCOT, patients with T2D had a 1.86-fold higher risk for a primary endpoint cardiovascular event, but there was no significant difference in the primary endpoint between those with and without T2D on colchicine.

IN PRACTICE:

“Patients with both T2D and a recent MI derive a large benefit from inflammation-reducing therapy with colchicine,” the authors noted.

SOURCE:

This study, led by François Roubille, University Hospital of Montpellier, France, was published online on January 5, 2024, in Diabetes Care. 

LIMITATIONS:

Patients were not stratified at inclusion for the presence of diabetes. Also, the study did not evaluate the role of glycated hemoglobin and low-density lipoprotein cholesterol, as well as the effects of different glucose-lowering medications or possible hypoglycemic episodes.

DISCLOSURES:

The COLCOT study was funded by the Government of Quebec, the Canadian Institutes of Health Research, and philanthropic foundations. Coauthors Jean-Claude Tardif and Wolfgang Koenig declared receiving research grants, honoraria, advisory board fees, and lecture fees from pharmaceutical companies, as well as having other ties with various sources.
 

A version of this article appeared on Medscape.com.

TOPLINE:

A daily low dose of colchicine significantly reduces ischemic cardiovascular events in patients with type 2 diabetes (T2D) and a recent myocardial infarction (MI). 

METHODOLOGY:

• After an MI, patients with vs without T2D have a higher risk for another cardiovascular event.
• The Colchicine Cardiovascular Outcomes Trial (COLCOT), a randomized, double-blinded trial, found a lower risk for ischemic cardiovascular events with 0.5 mg colchicine taken daily vs placebo, initiated within 30 days of an MI.
• Researchers conducted a prespecified subgroup analysis of 959 adult patients with T2D (mean age, 62.4 years; 22.2% women) in COLCOT (462 patients in colchicine and 497 patients in placebo groups).
• The primary efficacy endpoint was a composite of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring coronary revascularization within a median 23 months.
• The patients were taking a variety of appropriate medications, including aspirin and another antiplatelet agent and a statin (98%-99%) and metformin (75%-76%).

TAKEAWAY:

• The risk for the primary endpoint was reduced by 35% in patients with T2D who received colchicine than in those who received placebo (hazard ratio, 0.65; P = .03).
• The primary endpoint event rate per 100 patient-months was significantly lower in the colchicine group than in the placebo group (rate ratio, 0.53; P = .01).
• The frequencies of adverse events were similar in both the treatment and placebo groups (14.6% and 12.8%, respectively; P = .41), with gastrointestinal adverse events being the most common.
• In COLCOT, patients with T2D had a 1.86-fold higher risk for a primary endpoint cardiovascular event, but there was no significant difference in the primary endpoint between those with and without T2D on colchicine.

IN PRACTICE:

“Patients with both T2D and a recent MI derive a large benefit from inflammation-reducing therapy with colchicine,” the authors noted.

SOURCE:

This study, led by François Roubille, University Hospital of Montpellier, France, was published online on January 5, 2024, in Diabetes Care. 

LIMITATIONS:

Patients were not stratified at inclusion for the presence of diabetes. Also, the study did not evaluate the role of glycated hemoglobin and low-density lipoprotein cholesterol, as well as the effects of different glucose-lowering medications or possible hypoglycemic episodes.

DISCLOSURES:

The COLCOT study was funded by the Government of Quebec, the Canadian Institutes of Health Research, and philanthropic foundations. Coauthors Jean-Claude Tardif and Wolfgang Koenig declared receiving research grants, honoraria, advisory board fees, and lecture fees from pharmaceutical companies, as well as having other ties with various sources.
 

A version of this article appeared on Medscape.com.

TOPLINE:

A daily low dose of colchicine significantly reduces ischemic cardiovascular events in patients with type 2 diabetes (T2D) and a recent myocardial infarction (MI). 

METHODOLOGY:

• After an MI, patients with vs without T2D have a higher risk for another cardiovascular event.
• The Colchicine Cardiovascular Outcomes Trial (COLCOT), a randomized, double-blinded trial, found a lower risk for ischemic cardiovascular events with 0.5 mg colchicine taken daily vs placebo, initiated within 30 days of an MI.
• Researchers conducted a prespecified subgroup analysis of 959 adult patients with T2D (mean age, 62.4 years; 22.2% women) in COLCOT (462 patients in colchicine and 497 patients in placebo groups).
• The primary efficacy endpoint was a composite of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring coronary revascularization within a median 23 months.
• The patients were taking a variety of appropriate medications, including aspirin and another antiplatelet agent and a statin (98%-99%) and metformin (75%-76%).

TAKEAWAY:

• The risk for the primary endpoint was reduced by 35% in patients with T2D who received colchicine than in those who received placebo (hazard ratio, 0.65; P = .03).
• The primary endpoint event rate per 100 patient-months was significantly lower in the colchicine group than in the placebo group (rate ratio, 0.53; P = .01).
• The frequencies of adverse events were similar in both the treatment and placebo groups (14.6% and 12.8%, respectively; P = .41), with gastrointestinal adverse events being the most common.
• In COLCOT, patients with T2D had a 1.86-fold higher risk for a primary endpoint cardiovascular event, but there was no significant difference in the primary endpoint between those with and without T2D on colchicine.

IN PRACTICE:

“Patients with both T2D and a recent MI derive a large benefit from inflammation-reducing therapy with colchicine,” the authors noted.

SOURCE:

This study, led by François Roubille, University Hospital of Montpellier, France, was published online on January 5, 2024, in Diabetes Care. 

LIMITATIONS:

Patients were not stratified at inclusion for the presence of diabetes. Also, the study did not evaluate the role of glycated hemoglobin and low-density lipoprotein cholesterol, as well as the effects of different glucose-lowering medications or possible hypoglycemic episodes.

DISCLOSURES:

The COLCOT study was funded by the Government of Quebec, the Canadian Institutes of Health Research, and philanthropic foundations. Coauthors Jean-Claude Tardif and Wolfgang Koenig declared receiving research grants, honoraria, advisory board fees, and lecture fees from pharmaceutical companies, as well as having other ties with various sources.
 

A version of this article appeared on Medscape.com.