Psoriasis

To the Editor:

Psoriasis is a chronic inflammatory condition that affects individuals in various extracutaneous ways.¹ Prior studies have documented a decrease in exercise intensity among patients with psoriasis²; however, few studies have specifically investigated baseline mobility in this population. Baseline mobility denotes an individual’s fundamental ability to walk or move around without assistance of any kind. Impaired mobility—when baseline mobility is compromised—is an aspect of the wider diversity, equity, and inclusion framework that underscores the significance of recognizing challenges and promoting inclusive measures, both at the point of care and in research.³ study sought to analyze the relationship between psoriasis and baseline mobility among US adults (aged 45 to 80 years) utilizing the latest data from the National Health and Nutrition Examination Survey (NHANES) database for psoriasis.⁴ We used three 2-year cycles of NHANES data to create a 2009-2014 dataset.

The overall NHANES response rate among adults aged 45 to 80 years between 2009 and 2014 was 67.9%. Patients were categorized as having impaired mobility if they responded “yes” to the following question: “Because of a health problem, do you have difficulty walking without using any special equipment?” Psoriasis status was assessed by the following question: “Have you ever been told by a doctor or other health professional that you had psoriasis?” Multivariable logistic regression analyses were performed using Stata/SE 18.0 software (StataCorp LLC) to assess the relationship between psoriasis and impaired mobility. Age, income, education, sex, race, tobacco use, diabetes status, body mass index, and arthritis status were controlled for in our models.

Our analysis initially included 9982 participants; 14 did not respond to questions assessing psoriasis and impaired mobility and were excluded. The prevalence of impaired mobility in patients with psoriasis was 17.1% compared with 10.9% among those without psoriasis (Table 1). There was a significant association between psoriasis and impaired mobility among patients aged 45 to 80 years after adjusting for potential confounding variables (adjusted odds ratio [AOR], 1.54; 95% CI, 1.04- 2.29; P=.032)(Table 2). Analyses of subgroups yielded no statistically significant results.

Our study demonstrated a statistically significant difference in mobility between individuals with psoriasis compared with the general population, which remained significant when controlling for arthritis, obesity, and diabetes (P=.032). This may be the result of several influences. First, the location of the psoriasis may impact mobility. Plantar psoriasis—a manifestation on the soles of the feet—can cause discomfort and pain, which can hinder walking and standing.⁵ Second, a study by Lasselin et al⁶ found that systemic inflammation contributes to mobility impairment through alterations in gait and posture, which suggests that the inflammatory processes inherent in psoriasis could intrinsically modify walking speed and stride, potentially exacerbating mobility difficulties independent of other comorbid conditions. These findings suggest that psoriasis may disproportionately affect individuals with impaired mobility, independent of comorbid arthritis, obesity, and diabetes.

These findings have broad implications for diversity, equity, and inclusion. They should prompt us to consider the practical challenges faced by this patient population and the ways that we can address barriers to care. Offering telehealth appointments, making primary care referrals for impaired mobility workups, and advising patients of direct-to-home delivery of prescriptions are good places to start.

Limitations to our study include the lack of specificity in the survey question, self-reporting bias, and the inability to control for the psoriasis location. Further investigations are warranted in large, representative US adult populations to assess the implications of impaired mobility in patients with psoriasis.

To the Editor:

Psoriasis is a chronic inflammatory condition that affects individuals in various extracutaneous ways.¹ Prior studies have documented a decrease in exercise intensity among patients with psoriasis²; however, few studies have specifically investigated baseline mobility in this population. Baseline mobility denotes an individual’s fundamental ability to walk or move around without assistance of any kind. Impaired mobility—when baseline mobility is compromised—is an aspect of the wider diversity, equity, and inclusion framework that underscores the significance of recognizing challenges and promoting inclusive measures, both at the point of care and in research.³ study sought to analyze the relationship between psoriasis and baseline mobility among US adults (aged 45 to 80 years) utilizing the latest data from the National Health and Nutrition Examination Survey (NHANES) database for psoriasis.⁴ We used three 2-year cycles of NHANES data to create a 2009-2014 dataset.

The overall NHANES response rate among adults aged 45 to 80 years between 2009 and 2014 was 67.9%. Patients were categorized as having impaired mobility if they responded “yes” to the following question: “Because of a health problem, do you have difficulty walking without using any special equipment?” Psoriasis status was assessed by the following question: “Have you ever been told by a doctor or other health professional that you had psoriasis?” Multivariable logistic regression analyses were performed using Stata/SE 18.0 software (StataCorp LLC) to assess the relationship between psoriasis and impaired mobility. Age, income, education, sex, race, tobacco use, diabetes status, body mass index, and arthritis status were controlled for in our models.

Our analysis initially included 9982 participants; 14 did not respond to questions assessing psoriasis and impaired mobility and were excluded. The prevalence of impaired mobility in patients with psoriasis was 17.1% compared with 10.9% among those without psoriasis (Table 1). There was a significant association between psoriasis and impaired mobility among patients aged 45 to 80 years after adjusting for potential confounding variables (adjusted odds ratio [AOR], 1.54; 95% CI, 1.04- 2.29; P=.032)(Table 2). Analyses of subgroups yielded no statistically significant results.

Our study demonstrated a statistically significant difference in mobility between individuals with psoriasis compared with the general population, which remained significant when controlling for arthritis, obesity, and diabetes (P=.032). This may be the result of several influences. First, the location of the psoriasis may impact mobility. Plantar psoriasis—a manifestation on the soles of the feet—can cause discomfort and pain, which can hinder walking and standing.⁵ Second, a study by Lasselin et al⁶ found that systemic inflammation contributes to mobility impairment through alterations in gait and posture, which suggests that the inflammatory processes inherent in psoriasis could intrinsically modify walking speed and stride, potentially exacerbating mobility difficulties independent of other comorbid conditions. These findings suggest that psoriasis may disproportionately affect individuals with impaired mobility, independent of comorbid arthritis, obesity, and diabetes.

These findings have broad implications for diversity, equity, and inclusion. They should prompt us to consider the practical challenges faced by this patient population and the ways that we can address barriers to care. Offering telehealth appointments, making primary care referrals for impaired mobility workups, and advising patients of direct-to-home delivery of prescriptions are good places to start.

Limitations to our study include the lack of specificity in the survey question, self-reporting bias, and the inability to control for the psoriasis location. Further investigations are warranted in large, representative US adult populations to assess the implications of impaired mobility in patients with psoriasis.

To the Editor:

Psoriasis is a chronic inflammatory condition that affects individuals in various extracutaneous ways.¹ Prior studies have documented a decrease in exercise intensity among patients with psoriasis²; however, few studies have specifically investigated baseline mobility in this population. Baseline mobility denotes an individual’s fundamental ability to walk or move around without assistance of any kind. Impaired mobility—when baseline mobility is compromised—is an aspect of the wider diversity, equity, and inclusion framework that underscores the significance of recognizing challenges and promoting inclusive measures, both at the point of care and in research.³ study sought to analyze the relationship between psoriasis and baseline mobility among US adults (aged 45 to 80 years) utilizing the latest data from the National Health and Nutrition Examination Survey (NHANES) database for psoriasis.⁴ We used three 2-year cycles of NHANES data to create a 2009-2014 dataset.

The overall NHANES response rate among adults aged 45 to 80 years between 2009 and 2014 was 67.9%. Patients were categorized as having impaired mobility if they responded “yes” to the following question: “Because of a health problem, do you have difficulty walking without using any special equipment?” Psoriasis status was assessed by the following question: “Have you ever been told by a doctor or other health professional that you had psoriasis?” Multivariable logistic regression analyses were performed using Stata/SE 18.0 software (StataCorp LLC) to assess the relationship between psoriasis and impaired mobility. Age, income, education, sex, race, tobacco use, diabetes status, body mass index, and arthritis status were controlled for in our models.

Our analysis initially included 9982 participants; 14 did not respond to questions assessing psoriasis and impaired mobility and were excluded. The prevalence of impaired mobility in patients with psoriasis was 17.1% compared with 10.9% among those without psoriasis (Table 1). There was a significant association between psoriasis and impaired mobility among patients aged 45 to 80 years after adjusting for potential confounding variables (adjusted odds ratio [AOR], 1.54; 95% CI, 1.04- 2.29; P=.032)(Table 2). Analyses of subgroups yielded no statistically significant results.

Our study demonstrated a statistically significant difference in mobility between individuals with psoriasis compared with the general population, which remained significant when controlling for arthritis, obesity, and diabetes (P=.032). This may be the result of several influences. First, the location of the psoriasis may impact mobility. Plantar psoriasis—a manifestation on the soles of the feet—can cause discomfort and pain, which can hinder walking and standing.⁵ Second, a study by Lasselin et al⁶ found that systemic inflammation contributes to mobility impairment through alterations in gait and posture, which suggests that the inflammatory processes inherent in psoriasis could intrinsically modify walking speed and stride, potentially exacerbating mobility difficulties independent of other comorbid conditions. These findings suggest that psoriasis may disproportionately affect individuals with impaired mobility, independent of comorbid arthritis, obesity, and diabetes.

These findings have broad implications for diversity, equity, and inclusion. They should prompt us to consider the practical challenges faced by this patient population and the ways that we can address barriers to care. Offering telehealth appointments, making primary care referrals for impaired mobility workups, and advising patients of direct-to-home delivery of prescriptions are good places to start.

Limitations to our study include the lack of specificity in the survey question, self-reporting bias, and the inability to control for the psoriasis location. Further investigations are warranted in large, representative US adult populations to assess the implications of impaired mobility in patients with psoriasis.

THE DIAGNOSIS: Cutaneous Endometriosis

On histopathology, a biopsy specimen of an umbilical papule showed a dermal lymphohistiocyticrich infiltrate, hemorrhage, and ectopic endometrial glands consistent with cutaneous endometriosis (CE)(Figure). Cutaneous endometriosis is a rare condition that typically affects females of reproductive potential and is characterized by endometrial glands and stroma within the dermis and hypodermis. Cutaneous endometriosis is classified as primary or secondary. There is no surgical history of the abdomen or pelvis in primary CE. In contrast, a history of abdominopelvic surgery is the defining characteristic of secondary CE, which is more common than primary CE and typically manifests as painful red, brown, or purple papules along preexisting surgical scars of the umbilicus, lower abdomen, or pelvic region.¹ Our patient may have developed secondary CE related to the laparoscopic cholecystectomy performed 10 years prior. Surgical excision is considered the definitive treatment for CE, and hormonal therapy with danazol or leuprolide may help ameliorate symptoms.¹ Our patient deferred any hormonal or surgical interventions to undergo fertility treatments for pregnancy.

Cyclical bleeding and pain that coincides with menstruation is consistent with CE; however, cyclical symptoms are not always present, which can lead to delayed or incorrect diagnosis. Biopsy and histopathologic analysis are required for definitive diagnosis and are critical for distinguishing CE from other conditions. The differential diagnosis in our patient included pyogenic granuloma, dermatofibrosarcoma protuberans, keloid, and cutaneous metastasis of a primary malignancy. Vascular lesions such as pyogenic granuloma can manifest with bleeding but have a characteristic histopathologic lobular capillary arrangement that was not present in our patient.

Dermatofibrosarcoma protuberans is a rare, slow-growing, malignant soft-tissue sarcoma that most commonly manifests on the trunk, arms, and legs.² It is characterized by a slow-growing, indurated plaque that often is present for years and may suddenly progress into a smooth, red-brown, multinodular mass. Histopathology typically shows spindle cells infiltrating the dermis and subcutaneous tissue in storiform or whorled pattern with variations based on the tumor stage, as well as diffuse CD34 immunoreactivity.²

Keloids are dense, raised, hyperpigmented, fibrous nodules—sometimes with accompanying telangiectasias—that typically grow secondary to trauma and project past the boundaries of the initial trauma site.¹ Keloids are more commonly seen in individuals with darker skin types and tend to grow larger in this population. Histopathology reveals thickened hyalinized collagen bundles, which were not seen in our patient.¹

Metastatic skin lesions of the umbilicus are rare but can arise from internal malignancies including cancers of the lung, colon, and breast.³ We considered Sister Mary Joseph nodule, which is caused most commonly by metastasis of a primary gastrointestinal cancer and signifies poor prognosis. The histopathology of metastatic lesions would reveal the presence of atypical cells with cancer-specific markers. Histopathology along with the patient’s personal and family history, a comprehensive review of symptoms, and cancer screening may help with reaching the correct diagnosis.

The average duration between abdominopelvic surgery and onset of secondary CE symptoms is 3.7 to 5.3 years.⁴ Our patient presented 10 years post surgery and after cessation of oral contraception, which may suggest a potential role of hormonal contraception in delayed CE onset. Diagnosis of CE can be challenging due to atypical signs or symptoms, delayed onset, and lack of awareness among health care professionals. Patients with delayed diagnosis may endure multiple procedures, prolonged physical pain, and emotional distress. Furthermore, 30% to 50% of females with endometriosis experience infertility. Delayed diagnosis of CE compounded with associated age-related increase in oocyte atresia could potentially worsen fecundity as patients age.⁵ It is important to consider CE in the differential diagnosis of females of reproductive age who present with cyclical bleeding and abdominal or umbilical nodules.

THE DIAGNOSIS: Cutaneous Endometriosis

On histopathology, a biopsy specimen of an umbilical papule showed a dermal lymphohistiocyticrich infiltrate, hemorrhage, and ectopic endometrial glands consistent with cutaneous endometriosis (CE)(Figure). Cutaneous endometriosis is a rare condition that typically affects females of reproductive potential and is characterized by endometrial glands and stroma within the dermis and hypodermis. Cutaneous endometriosis is classified as primary or secondary. There is no surgical history of the abdomen or pelvis in primary CE. In contrast, a history of abdominopelvic surgery is the defining characteristic of secondary CE, which is more common than primary CE and typically manifests as painful red, brown, or purple papules along preexisting surgical scars of the umbilicus, lower abdomen, or pelvic region.¹ Our patient may have developed secondary CE related to the laparoscopic cholecystectomy performed 10 years prior. Surgical excision is considered the definitive treatment for CE, and hormonal therapy with danazol or leuprolide may help ameliorate symptoms.¹ Our patient deferred any hormonal or surgical interventions to undergo fertility treatments for pregnancy.

Cyclical bleeding and pain that coincides with menstruation is consistent with CE; however, cyclical symptoms are not always present, which can lead to delayed or incorrect diagnosis. Biopsy and histopathologic analysis are required for definitive diagnosis and are critical for distinguishing CE from other conditions. The differential diagnosis in our patient included pyogenic granuloma, dermatofibrosarcoma protuberans, keloid, and cutaneous metastasis of a primary malignancy. Vascular lesions such as pyogenic granuloma can manifest with bleeding but have a characteristic histopathologic lobular capillary arrangement that was not present in our patient.

Dermatofibrosarcoma protuberans is a rare, slow-growing, malignant soft-tissue sarcoma that most commonly manifests on the trunk, arms, and legs.² It is characterized by a slow-growing, indurated plaque that often is present for years and may suddenly progress into a smooth, red-brown, multinodular mass. Histopathology typically shows spindle cells infiltrating the dermis and subcutaneous tissue in storiform or whorled pattern with variations based on the tumor stage, as well as diffuse CD34 immunoreactivity.²

Keloids are dense, raised, hyperpigmented, fibrous nodules—sometimes with accompanying telangiectasias—that typically grow secondary to trauma and project past the boundaries of the initial trauma site.¹ Keloids are more commonly seen in individuals with darker skin types and tend to grow larger in this population. Histopathology reveals thickened hyalinized collagen bundles, which were not seen in our patient.¹

Metastatic skin lesions of the umbilicus are rare but can arise from internal malignancies including cancers of the lung, colon, and breast.³ We considered Sister Mary Joseph nodule, which is caused most commonly by metastasis of a primary gastrointestinal cancer and signifies poor prognosis. The histopathology of metastatic lesions would reveal the presence of atypical cells with cancer-specific markers. Histopathology along with the patient’s personal and family history, a comprehensive review of symptoms, and cancer screening may help with reaching the correct diagnosis.

The average duration between abdominopelvic surgery and onset of secondary CE symptoms is 3.7 to 5.3 years.⁴ Our patient presented 10 years post surgery and after cessation of oral contraception, which may suggest a potential role of hormonal contraception in delayed CE onset. Diagnosis of CE can be challenging due to atypical signs or symptoms, delayed onset, and lack of awareness among health care professionals. Patients with delayed diagnosis may endure multiple procedures, prolonged physical pain, and emotional distress. Furthermore, 30% to 50% of females with endometriosis experience infertility. Delayed diagnosis of CE compounded with associated age-related increase in oocyte atresia could potentially worsen fecundity as patients age.⁵ It is important to consider CE in the differential diagnosis of females of reproductive age who present with cyclical bleeding and abdominal or umbilical nodules.

THE DIAGNOSIS: Cutaneous Endometriosis

On histopathology, a biopsy specimen of an umbilical papule showed a dermal lymphohistiocyticrich infiltrate, hemorrhage, and ectopic endometrial glands consistent with cutaneous endometriosis (CE)(Figure). Cutaneous endometriosis is a rare condition that typically affects females of reproductive potential and is characterized by endometrial glands and stroma within the dermis and hypodermis. Cutaneous endometriosis is classified as primary or secondary. There is no surgical history of the abdomen or pelvis in primary CE. In contrast, a history of abdominopelvic surgery is the defining characteristic of secondary CE, which is more common than primary CE and typically manifests as painful red, brown, or purple papules along preexisting surgical scars of the umbilicus, lower abdomen, or pelvic region.¹ Our patient may have developed secondary CE related to the laparoscopic cholecystectomy performed 10 years prior. Surgical excision is considered the definitive treatment for CE, and hormonal therapy with danazol or leuprolide may help ameliorate symptoms.¹ Our patient deferred any hormonal or surgical interventions to undergo fertility treatments for pregnancy.

Cyclical bleeding and pain that coincides with menstruation is consistent with CE; however, cyclical symptoms are not always present, which can lead to delayed or incorrect diagnosis. Biopsy and histopathologic analysis are required for definitive diagnosis and are critical for distinguishing CE from other conditions. The differential diagnosis in our patient included pyogenic granuloma, dermatofibrosarcoma protuberans, keloid, and cutaneous metastasis of a primary malignancy. Vascular lesions such as pyogenic granuloma can manifest with bleeding but have a characteristic histopathologic lobular capillary arrangement that was not present in our patient.

Dermatofibrosarcoma protuberans is a rare, slow-growing, malignant soft-tissue sarcoma that most commonly manifests on the trunk, arms, and legs.² It is characterized by a slow-growing, indurated plaque that often is present for years and may suddenly progress into a smooth, red-brown, multinodular mass. Histopathology typically shows spindle cells infiltrating the dermis and subcutaneous tissue in storiform or whorled pattern with variations based on the tumor stage, as well as diffuse CD34 immunoreactivity.²

Keloids are dense, raised, hyperpigmented, fibrous nodules—sometimes with accompanying telangiectasias—that typically grow secondary to trauma and project past the boundaries of the initial trauma site.¹ Keloids are more commonly seen in individuals with darker skin types and tend to grow larger in this population. Histopathology reveals thickened hyalinized collagen bundles, which were not seen in our patient.¹

Metastatic skin lesions of the umbilicus are rare but can arise from internal malignancies including cancers of the lung, colon, and breast.³ We considered Sister Mary Joseph nodule, which is caused most commonly by metastasis of a primary gastrointestinal cancer and signifies poor prognosis. The histopathology of metastatic lesions would reveal the presence of atypical cells with cancer-specific markers. Histopathology along with the patient’s personal and family history, a comprehensive review of symptoms, and cancer screening may help with reaching the correct diagnosis.

The average duration between abdominopelvic surgery and onset of secondary CE symptoms is 3.7 to 5.3 years.⁴ Our patient presented 10 years post surgery and after cessation of oral contraception, which may suggest a potential role of hormonal contraception in delayed CE onset. Diagnosis of CE can be challenging due to atypical signs or symptoms, delayed onset, and lack of awareness among health care professionals. Patients with delayed diagnosis may endure multiple procedures, prolonged physical pain, and emotional distress. Furthermore, 30% to 50% of females with endometriosis experience infertility. Delayed diagnosis of CE compounded with associated age-related increase in oocyte atresia could potentially worsen fecundity as patients age.⁵ It is important to consider CE in the differential diagnosis of females of reproductive age who present with cyclical bleeding and abdominal or umbilical nodules.

To the Editor:

Psoriasis is a chronic systemic inflammatory disease that affects 1% to 3% of the global population.^1,2 Due to dysregulation of the immune system, patients with HIV who have concurrent moderate to severe psoriasis present a clinical therapeutic challenge for dermatologists. Recent guidelines from the American Academy of Dermatology recommended avoiding certain systemic treatments (eg, methotrexate, cyclosporine) in patients who are HIV positive due to their immunosuppressive effects, as well as cautious use of certain biologics in populations with HIV.³ Traditional therapies for managing psoriasis in patients with HIV have included topical agents, antiretroviral therapy (ART), phototherapy, and acitretin; however, phototherapy can be logistically cumbersome for patients, and in the setting of ART, acitretin has the potential to exacerbate hypertriglyceridemia as well as other undesirable adverse effects.³

Apremilast is a phosphodiesterase 4 inhibitor that has emerged as a promising alternative in patients with HIV who require treatment for psoriasis. It has demonstrated clinical efficacy in psoriasis and has minimal immunosuppressive risk.⁴ Despite its potential in this population, reports of apremilast used in patients who are HIV positive are rare, and these patients often are excluded from larges studies. In this study, we reviewed the literature to evaluate outcomes and adverse events in patients with HIV who underwent psoriasis treatment with apremilast.

A search of PubMed articles indexed for MEDLINE from the inception of the database through January 2023 was conducted using the terms psoriasis, human immunodeficiency virus, acquired immunodeficiency syndrome, therapy, apremilast, and adverse events. The inclusion criteria were articles that reported patients with HIV and psoriasis undergoing treatment with apremilast with subsequent follow-up to delineate potential outcomes and adverse effects. Non–English language articles were excluded.

Our search of the literature yielded 7 patients with HIV and psoriasis who were treated with apremilast (eTable).^5-11 All of the patients were male and ranged in age from 31 to 55 years, and all had pretreatment CD4 cell counts greater than 450 cells/mm³. All but 1 patient were confirmed to have undergone ART prior to treatment with apremilast, and all were treated using the traditional apremilast titration from 10 mg to 30 mg orally twice daily.

The mean pretreatment Psoriasis Area and Severity Index (PASI) score in the patients we evaluated was 12.2, with an average reduction in PASI score of 9.3. This equated to achievement of PASI 75 or greater (ie, representing at least a 75% improvement in psoriasis) in 4 (57.1%) patients, with clinical improvement confirmed in all 7 patients (100.0%)(eTable). The average follow-up time was 9.7 months (range, 6 weeks to 24 months). Only 1 (14.3%) patient experienced any adverse effects, which included self-resolving diarrhea and respiratory infections (nonopportunistic) over a follow-up period of 2 years.⁶ Of note, gastrointestinal upset is common with apremilast and usually improves over time.¹²

Apremilast represents a safe and effective alternative systemic therapy for patients with HIV and psoriasis.⁴ As a phosphodiesterase 4 inhibitor, apremilast leads to increased levels of cyclic adenosine monophosphate, which restores an equilibrium between proinflammatory (eg, tumor necrosis factors, interferons, IL-2, IL-6, IL-12, IL-23) and anti-inflammatory (eg, IL-10) cytokines.¹³ Unlike most biologics that target and inhibit a specific proinflammatory cytokine, apremilast’s homeostatic mechanism may explain its minimal immunosuppressive adverse effects.

In the majority of patients we evaluated, initiation of apremilast led to documented clinical improvement. It is worth noting that some patients presented with a relevant medical history and/or comorbidities such as hepatitis and metabolic conditions (eg, obesity, type 2 diabetes mellitus, hypertriglyceridemia). Despite these comorbidities, initiation of apremilast therapy in these patients led to clinical improvement of psoriasis overall. Notable cases from our study included a 41-year-old man with concurrent hepatitis B and psoriatic arthritis who achieved PASI 90 after 24 weeks of apremilast therapy⁸; a 46-year-old man with concurrent hepatitis C who went from 8% to 1.5% body surface area affected after 5 months of treatment with apremilast⁵; and a 54-year-old man with concurrent obesity, type 2 diabetes mellitus, and hypertriglyceridemia who went from a PASI score of 10.2 to 4.1 after 3 months of apremilast treatment and maintained a PASI score of 2.7 at 2 years’ follow up (eTable).⁶

Limitations of this study included the small sample size and homogeneous demographic consisting only of adult males, which restrict the external validity of the findings. Despite limitations, apremilast was utilized effectively for patients with both psoriasis and psoriatic arthritis. The observed effectiveness of apremilast in multiple forms of psoriasis provides valuable insights into the drug’s versatility in this patient population.

The use of apremilast for treatment of psoriasis in patients with HIV represents an important therapeutic development. Its effectiveness in reducing psoriasis symptoms in these immunocompromised patients makes it a viable alternative to traditional systemic therapies that might be contraindicated in this population. While larger studies would be ideal, the exclusion of patients with HIV from clinical trials presents an obstacle and therefore makes case series and reviews helpful for clinicians in bridging the gap with respect to treatment options for these patients. Apremilast may be a safe and effective medication for patients with HIV and psoriasis who require systemic therapy to treat their skin disease.

To the Editor:

Psoriasis is a chronic systemic inflammatory disease that affects 1% to 3% of the global population.^1,2 Due to dysregulation of the immune system, patients with HIV who have concurrent moderate to severe psoriasis present a clinical therapeutic challenge for dermatologists. Recent guidelines from the American Academy of Dermatology recommended avoiding certain systemic treatments (eg, methotrexate, cyclosporine) in patients who are HIV positive due to their immunosuppressive effects, as well as cautious use of certain biologics in populations with HIV.³ Traditional therapies for managing psoriasis in patients with HIV have included topical agents, antiretroviral therapy (ART), phototherapy, and acitretin; however, phototherapy can be logistically cumbersome for patients, and in the setting of ART, acitretin has the potential to exacerbate hypertriglyceridemia as well as other undesirable adverse effects.³

Apremilast is a phosphodiesterase 4 inhibitor that has emerged as a promising alternative in patients with HIV who require treatment for psoriasis. It has demonstrated clinical efficacy in psoriasis and has minimal immunosuppressive risk.⁴ Despite its potential in this population, reports of apremilast used in patients who are HIV positive are rare, and these patients often are excluded from larges studies. In this study, we reviewed the literature to evaluate outcomes and adverse events in patients with HIV who underwent psoriasis treatment with apremilast.

A search of PubMed articles indexed for MEDLINE from the inception of the database through January 2023 was conducted using the terms psoriasis, human immunodeficiency virus, acquired immunodeficiency syndrome, therapy, apremilast, and adverse events. The inclusion criteria were articles that reported patients with HIV and psoriasis undergoing treatment with apremilast with subsequent follow-up to delineate potential outcomes and adverse effects. Non–English language articles were excluded.

Our search of the literature yielded 7 patients with HIV and psoriasis who were treated with apremilast (eTable).^5-11 All of the patients were male and ranged in age from 31 to 55 years, and all had pretreatment CD4 cell counts greater than 450 cells/mm³. All but 1 patient were confirmed to have undergone ART prior to treatment with apremilast, and all were treated using the traditional apremilast titration from 10 mg to 30 mg orally twice daily.

The mean pretreatment Psoriasis Area and Severity Index (PASI) score in the patients we evaluated was 12.2, with an average reduction in PASI score of 9.3. This equated to achievement of PASI 75 or greater (ie, representing at least a 75% improvement in psoriasis) in 4 (57.1%) patients, with clinical improvement confirmed in all 7 patients (100.0%)(eTable). The average follow-up time was 9.7 months (range, 6 weeks to 24 months). Only 1 (14.3%) patient experienced any adverse effects, which included self-resolving diarrhea and respiratory infections (nonopportunistic) over a follow-up period of 2 years.⁶ Of note, gastrointestinal upset is common with apremilast and usually improves over time.¹²

Apremilast represents a safe and effective alternative systemic therapy for patients with HIV and psoriasis.⁴ As a phosphodiesterase 4 inhibitor, apremilast leads to increased levels of cyclic adenosine monophosphate, which restores an equilibrium between proinflammatory (eg, tumor necrosis factors, interferons, IL-2, IL-6, IL-12, IL-23) and anti-inflammatory (eg, IL-10) cytokines.¹³ Unlike most biologics that target and inhibit a specific proinflammatory cytokine, apremilast’s homeostatic mechanism may explain its minimal immunosuppressive adverse effects.

In the majority of patients we evaluated, initiation of apremilast led to documented clinical improvement. It is worth noting that some patients presented with a relevant medical history and/or comorbidities such as hepatitis and metabolic conditions (eg, obesity, type 2 diabetes mellitus, hypertriglyceridemia). Despite these comorbidities, initiation of apremilast therapy in these patients led to clinical improvement of psoriasis overall. Notable cases from our study included a 41-year-old man with concurrent hepatitis B and psoriatic arthritis who achieved PASI 90 after 24 weeks of apremilast therapy⁸; a 46-year-old man with concurrent hepatitis C who went from 8% to 1.5% body surface area affected after 5 months of treatment with apremilast⁵; and a 54-year-old man with concurrent obesity, type 2 diabetes mellitus, and hypertriglyceridemia who went from a PASI score of 10.2 to 4.1 after 3 months of apremilast treatment and maintained a PASI score of 2.7 at 2 years’ follow up (eTable).⁶

Limitations of this study included the small sample size and homogeneous demographic consisting only of adult males, which restrict the external validity of the findings. Despite limitations, apremilast was utilized effectively for patients with both psoriasis and psoriatic arthritis. The observed effectiveness of apremilast in multiple forms of psoriasis provides valuable insights into the drug’s versatility in this patient population.

The use of apremilast for treatment of psoriasis in patients with HIV represents an important therapeutic development. Its effectiveness in reducing psoriasis symptoms in these immunocompromised patients makes it a viable alternative to traditional systemic therapies that might be contraindicated in this population. While larger studies would be ideal, the exclusion of patients with HIV from clinical trials presents an obstacle and therefore makes case series and reviews helpful for clinicians in bridging the gap with respect to treatment options for these patients. Apremilast may be a safe and effective medication for patients with HIV and psoriasis who require systemic therapy to treat their skin disease.

To the Editor:

Psoriasis is a chronic systemic inflammatory disease that affects 1% to 3% of the global population.^1,2 Due to dysregulation of the immune system, patients with HIV who have concurrent moderate to severe psoriasis present a clinical therapeutic challenge for dermatologists. Recent guidelines from the American Academy of Dermatology recommended avoiding certain systemic treatments (eg, methotrexate, cyclosporine) in patients who are HIV positive due to their immunosuppressive effects, as well as cautious use of certain biologics in populations with HIV.³ Traditional therapies for managing psoriasis in patients with HIV have included topical agents, antiretroviral therapy (ART), phototherapy, and acitretin; however, phototherapy can be logistically cumbersome for patients, and in the setting of ART, acitretin has the potential to exacerbate hypertriglyceridemia as well as other undesirable adverse effects.³

Apremilast is a phosphodiesterase 4 inhibitor that has emerged as a promising alternative in patients with HIV who require treatment for psoriasis. It has demonstrated clinical efficacy in psoriasis and has minimal immunosuppressive risk.⁴ Despite its potential in this population, reports of apremilast used in patients who are HIV positive are rare, and these patients often are excluded from larges studies. In this study, we reviewed the literature to evaluate outcomes and adverse events in patients with HIV who underwent psoriasis treatment with apremilast.

A search of PubMed articles indexed for MEDLINE from the inception of the database through January 2023 was conducted using the terms psoriasis, human immunodeficiency virus, acquired immunodeficiency syndrome, therapy, apremilast, and adverse events. The inclusion criteria were articles that reported patients with HIV and psoriasis undergoing treatment with apremilast with subsequent follow-up to delineate potential outcomes and adverse effects. Non–English language articles were excluded.

Our search of the literature yielded 7 patients with HIV and psoriasis who were treated with apremilast (eTable).^5-11 All of the patients were male and ranged in age from 31 to 55 years, and all had pretreatment CD4 cell counts greater than 450 cells/mm³. All but 1 patient were confirmed to have undergone ART prior to treatment with apremilast, and all were treated using the traditional apremilast titration from 10 mg to 30 mg orally twice daily.

The mean pretreatment Psoriasis Area and Severity Index (PASI) score in the patients we evaluated was 12.2, with an average reduction in PASI score of 9.3. This equated to achievement of PASI 75 or greater (ie, representing at least a 75% improvement in psoriasis) in 4 (57.1%) patients, with clinical improvement confirmed in all 7 patients (100.0%)(eTable). The average follow-up time was 9.7 months (range, 6 weeks to 24 months). Only 1 (14.3%) patient experienced any adverse effects, which included self-resolving diarrhea and respiratory infections (nonopportunistic) over a follow-up period of 2 years.⁶ Of note, gastrointestinal upset is common with apremilast and usually improves over time.¹²

Apremilast represents a safe and effective alternative systemic therapy for patients with HIV and psoriasis.⁴ As a phosphodiesterase 4 inhibitor, apremilast leads to increased levels of cyclic adenosine monophosphate, which restores an equilibrium between proinflammatory (eg, tumor necrosis factors, interferons, IL-2, IL-6, IL-12, IL-23) and anti-inflammatory (eg, IL-10) cytokines.¹³ Unlike most biologics that target and inhibit a specific proinflammatory cytokine, apremilast’s homeostatic mechanism may explain its minimal immunosuppressive adverse effects.

In the majority of patients we evaluated, initiation of apremilast led to documented clinical improvement. It is worth noting that some patients presented with a relevant medical history and/or comorbidities such as hepatitis and metabolic conditions (eg, obesity, type 2 diabetes mellitus, hypertriglyceridemia). Despite these comorbidities, initiation of apremilast therapy in these patients led to clinical improvement of psoriasis overall. Notable cases from our study included a 41-year-old man with concurrent hepatitis B and psoriatic arthritis who achieved PASI 90 after 24 weeks of apremilast therapy⁸; a 46-year-old man with concurrent hepatitis C who went from 8% to 1.5% body surface area affected after 5 months of treatment with apremilast⁵; and a 54-year-old man with concurrent obesity, type 2 diabetes mellitus, and hypertriglyceridemia who went from a PASI score of 10.2 to 4.1 after 3 months of apremilast treatment and maintained a PASI score of 2.7 at 2 years’ follow up (eTable).⁶

Limitations of this study included the small sample size and homogeneous demographic consisting only of adult males, which restrict the external validity of the findings. Despite limitations, apremilast was utilized effectively for patients with both psoriasis and psoriatic arthritis. The observed effectiveness of apremilast in multiple forms of psoriasis provides valuable insights into the drug’s versatility in this patient population.

The use of apremilast for treatment of psoriasis in patients with HIV represents an important therapeutic development. Its effectiveness in reducing psoriasis symptoms in these immunocompromised patients makes it a viable alternative to traditional systemic therapies that might be contraindicated in this population. While larger studies would be ideal, the exclusion of patients with HIV from clinical trials presents an obstacle and therefore makes case series and reviews helpful for clinicians in bridging the gap with respect to treatment options for these patients. Apremilast may be a safe and effective medication for patients with HIV and psoriasis who require systemic therapy to treat their skin disease.

Biologic therapies have transformed the treatment of psoriasis. Current biologics approved for psoriasis include monoclonal antibodies targeting various pathways: tumor necrosis factor α (TNF-α) inhibitors (infliximab, adalimumab, certolizumab, etanercept), the p40 subunit common to IL-12 and IL-23 (ustekinumab), the p19 subunit of IL-23 (guselkumab, tildrakizumab, risankizumab), IL-17A (secukinumab, ixekizumab), IL-17 receptor A (brodalumab), and dual IL-17A/IL-17F inhibition (bimekizumab). Recent research showed that risankizumab achieved the highest Psoriasis Area and Severity Index (PASI) 90 scores in short- and long-term treatment periods (4 and 16 weeks, respectively) compared to other biologics, and IL-23 inhibitors demonstrated the lowest short- and long-term adverse event rates and the most favorable long-term risk-benefit profile compared to IL-17, IL-12/23, and TNF-α inhibitors.¹

Although these monoclonal antibodies have revolutionized psoriasis treatment, they are large proteins that must be administered subcutaneously or via intravenous injection. Emerging biologics are smaller proteins administered orally via a tablet or pill. In clinical trials, oral biologics have demonstrated efficacy (eTable), suggesting that oral biologics may be the future for psoriasis treatment, as this noninvasive delivery method may help improve patient compliance with treatment.

A major inflammatory pathway in psoriasis, IL-23 has been an effective and safe drug target. The novel oral IL-23 inhibitor, JNJ-2113, was discovered in 2017 and currently is being compared to deucravacitinib in the phase III ICONIC-LEAD trial (ClinicalTrials. gov Identifier NCT06095115) in patients with moderate to severe plaque psoriasis.^2,3 In the phase IIb FRONTIER 1 trial, treatment with either 3 once-daily (25 mg, 50 mg, 100 mg) and 2 twice-daily (25 mg, 100 mg) doses of JNJ-2113 led to significant improvements in PASI 75 response at 16 weeks compared to placebo (P<.001).⁴ In the phase IIb long-term extension FRONTIER 2 trial, JNJ-2113 maintained high rates of skin clearance through 52 weeks in adults with moderate to severe plaque psoriasis, with the highest PASI 75 response observed in the 100-mg twice-daily group (32/42 [76.2%]).⁵ Responses were maintained through week 52 for all JNJ-2113 treatment groups for PASI 90 and PASI 100 endpoints. In addition to ICONIC-LEAD, JNJ-2113 is being evaluated in the phase III multicenter, randomized, double-blind, placebo-controlled trial ICONIC-TOTAL (NCT06095102) in patients with special area psoriasis and ANTHEM-UC (NCT06049017) in patients with ulcerative colitis to evaluate its efficacy and safety. The most common adverse events associated with JNJ-77242113 were mild to moderate and included COVID-19 infection and nasopharyngitis.⁶ Higher rates of COVID-19 infection likely were due to immune compromise in the setting of the recent pandemic. Similar percentages of at least 1 adverse event were found in JNJ-77242113 and placebo groups (52%-58.6% and 51%-65.7%, respectively).^4,5,7

An orally administered small-molecule inhibitor of IL-17A, LY3509754, may represent a convenient alternative to IL-17A–targeting monoclonal antibodies. In a study of 91 participants,⁸ LY3509754 showed strong target engagement indicated by elevated plasma IL-17A levels within 12 hours of dosing. Despite strong target engagement and a pharmacokinetics profile that supports once-daily administration, this study showed that oral dosing with LY3509754 was poorly tolerated, as 4.4% (4/91) of participants (3 receiving 1000 mg once daily and 1 receiving 400 mg once daily) had increased liver transaminases or acute hepatitis (onset, ≥12 days following the last dose), which was consistent with drug-induced liver injury.⁸

The small potent molecule SAR441566 inhibits TNF-α by stabilizing an asymmetrical form of the soluble TNF trimer. As the asymmetrical trimer is the biologically active form of TNF-α, stabilization of the trimer compromises downstream signaling and inhibits the functions of TNF-α in vitro and in vivo. Recently, SAR441566 was found to be safe and well tolerated in healthy participants, showing efficacy in mild to moderate psoriasis in a phase Ib trial.⁹ A phase II trial of SAR441566 (NCT06073119) is being developed to create a more convenient orally bioavailable treatment option for patients with psoriasis compared to established biologic drugs targeting TNF-α.¹⁰

Few trials have focused on investigating the antipsoriatic effects of orally administered small molecules. Some of these small molecules can enter cells and inhibit the activation of T lymphocytes, leukocyte trafficking, leukotriene activity/production and angiogenesis, and promote apoptosis. Oral administration of small molecules is the future of effective and affordable psoriasis treatment, but safety and efficacy must first be assessed in clinical trials. JNJ-77242113 has shown a more promising safety profile, has recently undergone phase III trials, and may represent the newest wave for psoriasis treatment. While LY3509754 had a strong pharmacokinetics profile, it was poorly tolerated, and study participants' laboratory results suggested the drug to be hepatotoxic.⁸ SAR441566 has been shown to be safe and well tolerated in treating psoriasis, and phase II readouts are expected later in 2025. We can expect a new wave of psoriasis treatments with emerging oral therapies.

Biologic therapies have transformed the treatment of psoriasis. Current biologics approved for psoriasis include monoclonal antibodies targeting various pathways: tumor necrosis factor α (TNF-α) inhibitors (infliximab, adalimumab, certolizumab, etanercept), the p40 subunit common to IL-12 and IL-23 (ustekinumab), the p19 subunit of IL-23 (guselkumab, tildrakizumab, risankizumab), IL-17A (secukinumab, ixekizumab), IL-17 receptor A (brodalumab), and dual IL-17A/IL-17F inhibition (bimekizumab). Recent research showed that risankizumab achieved the highest Psoriasis Area and Severity Index (PASI) 90 scores in short- and long-term treatment periods (4 and 16 weeks, respectively) compared to other biologics, and IL-23 inhibitors demonstrated the lowest short- and long-term adverse event rates and the most favorable long-term risk-benefit profile compared to IL-17, IL-12/23, and TNF-α inhibitors.¹

Although these monoclonal antibodies have revolutionized psoriasis treatment, they are large proteins that must be administered subcutaneously or via intravenous injection. Emerging biologics are smaller proteins administered orally via a tablet or pill. In clinical trials, oral biologics have demonstrated efficacy (eTable), suggesting that oral biologics may be the future for psoriasis treatment, as this noninvasive delivery method may help improve patient compliance with treatment.

A major inflammatory pathway in psoriasis, IL-23 has been an effective and safe drug target. The novel oral IL-23 inhibitor, JNJ-2113, was discovered in 2017 and currently is being compared to deucravacitinib in the phase III ICONIC-LEAD trial (ClinicalTrials. gov Identifier NCT06095115) in patients with moderate to severe plaque psoriasis.^2,3 In the phase IIb FRONTIER 1 trial, treatment with either 3 once-daily (25 mg, 50 mg, 100 mg) and 2 twice-daily (25 mg, 100 mg) doses of JNJ-2113 led to significant improvements in PASI 75 response at 16 weeks compared to placebo (P<.001).⁴ In the phase IIb long-term extension FRONTIER 2 trial, JNJ-2113 maintained high rates of skin clearance through 52 weeks in adults with moderate to severe plaque psoriasis, with the highest PASI 75 response observed in the 100-mg twice-daily group (32/42 [76.2%]).⁵ Responses were maintained through week 52 for all JNJ-2113 treatment groups for PASI 90 and PASI 100 endpoints. In addition to ICONIC-LEAD, JNJ-2113 is being evaluated in the phase III multicenter, randomized, double-blind, placebo-controlled trial ICONIC-TOTAL (NCT06095102) in patients with special area psoriasis and ANTHEM-UC (NCT06049017) in patients with ulcerative colitis to evaluate its efficacy and safety. The most common adverse events associated with JNJ-77242113 were mild to moderate and included COVID-19 infection and nasopharyngitis.⁶ Higher rates of COVID-19 infection likely were due to immune compromise in the setting of the recent pandemic. Similar percentages of at least 1 adverse event were found in JNJ-77242113 and placebo groups (52%-58.6% and 51%-65.7%, respectively).^4,5,7

An orally administered small-molecule inhibitor of IL-17A, LY3509754, may represent a convenient alternative to IL-17A–targeting monoclonal antibodies. In a study of 91 participants,⁸ LY3509754 showed strong target engagement indicated by elevated plasma IL-17A levels within 12 hours of dosing. Despite strong target engagement and a pharmacokinetics profile that supports once-daily administration, this study showed that oral dosing with LY3509754 was poorly tolerated, as 4.4% (4/91) of participants (3 receiving 1000 mg once daily and 1 receiving 400 mg once daily) had increased liver transaminases or acute hepatitis (onset, ≥12 days following the last dose), which was consistent with drug-induced liver injury.⁸

The small potent molecule SAR441566 inhibits TNF-α by stabilizing an asymmetrical form of the soluble TNF trimer. As the asymmetrical trimer is the biologically active form of TNF-α, stabilization of the trimer compromises downstream signaling and inhibits the functions of TNF-α in vitro and in vivo. Recently, SAR441566 was found to be safe and well tolerated in healthy participants, showing efficacy in mild to moderate psoriasis in a phase Ib trial.⁹ A phase II trial of SAR441566 (NCT06073119) is being developed to create a more convenient orally bioavailable treatment option for patients with psoriasis compared to established biologic drugs targeting TNF-α.¹⁰

Few trials have focused on investigating the antipsoriatic effects of orally administered small molecules. Some of these small molecules can enter cells and inhibit the activation of T lymphocytes, leukocyte trafficking, leukotriene activity/production and angiogenesis, and promote apoptosis. Oral administration of small molecules is the future of effective and affordable psoriasis treatment, but safety and efficacy must first be assessed in clinical trials. JNJ-77242113 has shown a more promising safety profile, has recently undergone phase III trials, and may represent the newest wave for psoriasis treatment. While LY3509754 had a strong pharmacokinetics profile, it was poorly tolerated, and study participants' laboratory results suggested the drug to be hepatotoxic.⁸ SAR441566 has been shown to be safe and well tolerated in treating psoriasis, and phase II readouts are expected later in 2025. We can expect a new wave of psoriasis treatments with emerging oral therapies.

Biologic therapies have transformed the treatment of psoriasis. Current biologics approved for psoriasis include monoclonal antibodies targeting various pathways: tumor necrosis factor α (TNF-α) inhibitors (infliximab, adalimumab, certolizumab, etanercept), the p40 subunit common to IL-12 and IL-23 (ustekinumab), the p19 subunit of IL-23 (guselkumab, tildrakizumab, risankizumab), IL-17A (secukinumab, ixekizumab), IL-17 receptor A (brodalumab), and dual IL-17A/IL-17F inhibition (bimekizumab). Recent research showed that risankizumab achieved the highest Psoriasis Area and Severity Index (PASI) 90 scores in short- and long-term treatment periods (4 and 16 weeks, respectively) compared to other biologics, and IL-23 inhibitors demonstrated the lowest short- and long-term adverse event rates and the most favorable long-term risk-benefit profile compared to IL-17, IL-12/23, and TNF-α inhibitors.¹

Although these monoclonal antibodies have revolutionized psoriasis treatment, they are large proteins that must be administered subcutaneously or via intravenous injection. Emerging biologics are smaller proteins administered orally via a tablet or pill. In clinical trials, oral biologics have demonstrated efficacy (eTable), suggesting that oral biologics may be the future for psoriasis treatment, as this noninvasive delivery method may help improve patient compliance with treatment.

A major inflammatory pathway in psoriasis, IL-23 has been an effective and safe drug target. The novel oral IL-23 inhibitor, JNJ-2113, was discovered in 2017 and currently is being compared to deucravacitinib in the phase III ICONIC-LEAD trial (ClinicalTrials. gov Identifier NCT06095115) in patients with moderate to severe plaque psoriasis.^2,3 In the phase IIb FRONTIER 1 trial, treatment with either 3 once-daily (25 mg, 50 mg, 100 mg) and 2 twice-daily (25 mg, 100 mg) doses of JNJ-2113 led to significant improvements in PASI 75 response at 16 weeks compared to placebo (P<.001).⁴ In the phase IIb long-term extension FRONTIER 2 trial, JNJ-2113 maintained high rates of skin clearance through 52 weeks in adults with moderate to severe plaque psoriasis, with the highest PASI 75 response observed in the 100-mg twice-daily group (32/42 [76.2%]).⁵ Responses were maintained through week 52 for all JNJ-2113 treatment groups for PASI 90 and PASI 100 endpoints. In addition to ICONIC-LEAD, JNJ-2113 is being evaluated in the phase III multicenter, randomized, double-blind, placebo-controlled trial ICONIC-TOTAL (NCT06095102) in patients with special area psoriasis and ANTHEM-UC (NCT06049017) in patients with ulcerative colitis to evaluate its efficacy and safety. The most common adverse events associated with JNJ-77242113 were mild to moderate and included COVID-19 infection and nasopharyngitis.⁶ Higher rates of COVID-19 infection likely were due to immune compromise in the setting of the recent pandemic. Similar percentages of at least 1 adverse event were found in JNJ-77242113 and placebo groups (52%-58.6% and 51%-65.7%, respectively).^4,5,7

An orally administered small-molecule inhibitor of IL-17A, LY3509754, may represent a convenient alternative to IL-17A–targeting monoclonal antibodies. In a study of 91 participants,⁸ LY3509754 showed strong target engagement indicated by elevated plasma IL-17A levels within 12 hours of dosing. Despite strong target engagement and a pharmacokinetics profile that supports once-daily administration, this study showed that oral dosing with LY3509754 was poorly tolerated, as 4.4% (4/91) of participants (3 receiving 1000 mg once daily and 1 receiving 400 mg once daily) had increased liver transaminases or acute hepatitis (onset, ≥12 days following the last dose), which was consistent with drug-induced liver injury.⁸

The small potent molecule SAR441566 inhibits TNF-α by stabilizing an asymmetrical form of the soluble TNF trimer. As the asymmetrical trimer is the biologically active form of TNF-α, stabilization of the trimer compromises downstream signaling and inhibits the functions of TNF-α in vitro and in vivo. Recently, SAR441566 was found to be safe and well tolerated in healthy participants, showing efficacy in mild to moderate psoriasis in a phase Ib trial.⁹ A phase II trial of SAR441566 (NCT06073119) is being developed to create a more convenient orally bioavailable treatment option for patients with psoriasis compared to established biologic drugs targeting TNF-α.¹⁰

Few trials have focused on investigating the antipsoriatic effects of orally administered small molecules. Some of these small molecules can enter cells and inhibit the activation of T lymphocytes, leukocyte trafficking, leukotriene activity/production and angiogenesis, and promote apoptosis. Oral administration of small molecules is the future of effective and affordable psoriasis treatment, but safety and efficacy must first be assessed in clinical trials. JNJ-77242113 has shown a more promising safety profile, has recently undergone phase III trials, and may represent the newest wave for psoriasis treatment. While LY3509754 had a strong pharmacokinetics profile, it was poorly tolerated, and study participants' laboratory results suggested the drug to be hepatotoxic.⁸ SAR441566 has been shown to be safe and well tolerated in treating psoriasis, and phase II readouts are expected later in 2025. We can expect a new wave of psoriasis treatments with emerging oral therapies.

To the Editor:

UV light plays an essential role in various environmental and biological processes.¹ Excessive exposure to UV radiation can lead to sunburn, which is marked by skin erythema and pain.² A study of more than 31,000 individuals found that 34.2% of adults aged 18 years and older reported at least 1 sunburn during the survey year.³ A lack of research regarding the incidence of sunburns in patients with psoriasis is particularly important considering the heightened incidence of skin cancer observed in this population.⁴ Thus, the aim of our study was to analyze the prevalence of sunburns among US adults with psoriasis utilizing data from the National Health and Nutrition Examination Survey (NHANES) database.⁵

Our analysis initially included 11,842 participants ranging in age from 20 to 59 years; 35 did not respond to questions assessing psoriasis and sunburn prevalence and thus were excluded. Multivariable logistic regression analyses were performed using Stata/SE 18 (StataCorp LLC) to assess the relationship between psoriasis and sunburns. Our models controlled for patient age, sex, income, race, education, diabetes status, tobacco use, and body mass index. A P value <.05 was considered statistically significant. The study period from January 2009 to December 2014 was chosen based on the availability of the most recent and comprehensive psoriasis data within the NHANES database.

In the NHANES data we evaluated, psoriasis status was assessed by asking, “Have you ever been told by a doctor or other health professional that you had psoriasis?” History of sunburns in the survey year was assessed by the question, “How many times in the past year have you had sunburn?” Patients who reported 1 or more sunburns were included in the sunburn cohort, while those who did not report a sunburn were included in the no sunburn cohort.

In our analysis, the prevalence of at least 1 sunburn in the survey year in patients with psoriasis was 55.4% (weighted), compared to 45.6% (weighted) among those without psoriasis (eTable 1). Although there was no statistically significant relationship between psoriasis and history of sunburn in patients aged 20 to 59 years, a subgroup analysis revealed a significant association between psoriasis and sunburn in adults aged 20 to 39 years after adjusting for potential confounding variables (adjusted OR, 1.57 [95% CI, 1.00-2.45]; P=.049)(eTable 2). Further analysis of subgroups showed no statistically significant results with adjustment of the logistic regression model. Characterizing response rates is important for assessing the validity of survey studies. The NHANES response rate from 2009 to 2014 was 72.9%, enhancing the reliability of our findings.

Our study revealed an increased prevalence of sunburn in US adults with psoriasis. A trend of increased sunburn prevalence among younger adults regardless of psoriasis status is corroborated by the literature. Surveys conducted in the United States in 2005, 2010, and 2015 showed that 43% to 50% of adults aged 18 to 39 years and 28% to 42% of those aged 40 to 59 years reported experiencing at least 1 sunburn within the respective survey year.⁶ Furthermore, in our study, patients with psoriasis reported higher rates of sunburn than their counterparts without psoriasis, both in those aged 20 to 39 years (psoriasis, 62.8% [73/136]; no psoriasis, 51.1% [2425/5840]) and those aged 40 to 59 years (psoriasis, 50.5% [n=75/179]; no psoriasis, 40.2% [1613/5652]), though it was only statistically significant in the 20-to-39 age group. This discrepancy may be attributed to differences in sun-protective behaviors in younger vs older adults. A study from the NHANES database found that, among individuals aged 20 to 39 years, 75.9% [4225/5493] reported staying in the shade, 50.0% [2346/5493] reported using sunscreen, and 31.2% [1874/5493] reported wearing sun-protective clothing.⁷ Interestingly, the likelihood of engaging in all 3 behaviors was 28% lower in the 20-to-39 age group vs the 40-to-59 age group (adjusted OR, 0.72; 95% CI, 0.62-0.83).⁷

While our analysis adjusted for age, race/ethnicity, and tobacco use to mitigate potential confounding, we acknowledge the statistically significant differences observed in these variables between study groups as presented in eTable 2. These differences may reflect inherent disparities in the study population. We employed multivariable regression analysis to control for these covariates in our primary analyses. Of note, there was a statistically significant difference associated with race/ethnicity when comparing non-Hispanic White individuals with psoriasis (77.0% [n=182/315]) and those without psoriasis (62.5% [n=4516/11,492])(P<.0001)(eTable 1). The higher proportion of non-Hispanic White patients in the psoriasis group may reflect an increased susceptibility to sunburn given their typically lighter skin pigmentation; however, our analysis controlled for race/ethnicity (eTable 2), thereby allowing us to isolate the effect of psoriasis on sunburn prevalence independent of racial/ethnic differences. There also were statistically significant differences in tobacco use (P=.0026) and age (P=.002) in our unadjusted findings (eTable 1). Again, our analysis controlled for these factors (eTable 2), thereby allowing us to isolate the effect of psoriasis on sunburn prevalence independent of tobacco use and age differences. This approach enhanced the reliability of our findings.

The association between psoriasis and skin cancer has previously been evaluated using the NHANES database—one study found that patients with psoriasis had a significantly higher prevalence of nonmelanoma skin cancer compared with those without psoriasis (3.0% vs 1.3%; relative risk, 2.29; P<.001).⁸ This difference remained significant after adjusting for confounding variables, as it was found that psoriasis was independently associated with a 1.5-fold increased risk for nonmelanoma skin cancer (adjusted relative risk, 2.06; P=.004).⁸

The relationship between psoriasis and sunburn may be due to behavioral choices, such as the use of phototherapy for managing psoriasis due to its recognized advantages.⁹ Patients may seek out both artificial and natural light sources more frequently, potentially increasing the risk for sunburn.¹⁰ Psoriasis-related sunburn susceptibility may stem from biological factors, including vitamin D insufficiency, as vitamin D is crucial for keratinocyte differentiation, immune function, and UV protection and repair.¹¹ One study examined the effects of high-dose vitamin D3 on sunburn-induced inflammation.¹² Patients who received high-dose vitamin D3 exhibited reduced skin inflammation, enhanced skin barrier repair, and increased anti-inflammatory response compared with those who did not receive the supplement. This improvement was associated with upregulation of arginase 1, an anti-inflammatory enzyme, leading to decreased levels of pro-inflammatory mediators such as tumor necrosis factor α and inducible nitric oxide synthase, thereby promoting tissue repair and reducing prolonged inflammation.¹² These findings suggest that vitamin D insufficiency coupled with dysregulated immune responses may contribute to the heightened susceptibility of individuals with psoriasis to sunburn.

The established correlation between sunburn and skin cancer^4,8 coupled with our findings of increased prevalence of sunburn in individuals with psoriasis underscores the need for additional research to clarify the underlying biological and behavioral factors that may contribute to a higher prevalence of sunburn in these patients, along with the implications for skin cancer development. Limitations of our study included potential recall bias, as individuals self-reported their clinical conditions and the inability to incorporate psoriasis severity into our analysis, as this was not consistently captured in the NHANES questionnaire during the study period.

To the Editor:

UV light plays an essential role in various environmental and biological processes.¹ Excessive exposure to UV radiation can lead to sunburn, which is marked by skin erythema and pain.² A study of more than 31,000 individuals found that 34.2% of adults aged 18 years and older reported at least 1 sunburn during the survey year.³ A lack of research regarding the incidence of sunburns in patients with psoriasis is particularly important considering the heightened incidence of skin cancer observed in this population.⁴ Thus, the aim of our study was to analyze the prevalence of sunburns among US adults with psoriasis utilizing data from the National Health and Nutrition Examination Survey (NHANES) database.⁵

Our analysis initially included 11,842 participants ranging in age from 20 to 59 years; 35 did not respond to questions assessing psoriasis and sunburn prevalence and thus were excluded. Multivariable logistic regression analyses were performed using Stata/SE 18 (StataCorp LLC) to assess the relationship between psoriasis and sunburns. Our models controlled for patient age, sex, income, race, education, diabetes status, tobacco use, and body mass index. A P value <.05 was considered statistically significant. The study period from January 2009 to December 2014 was chosen based on the availability of the most recent and comprehensive psoriasis data within the NHANES database.

In the NHANES data we evaluated, psoriasis status was assessed by asking, “Have you ever been told by a doctor or other health professional that you had psoriasis?” History of sunburns in the survey year was assessed by the question, “How many times in the past year have you had sunburn?” Patients who reported 1 or more sunburns were included in the sunburn cohort, while those who did not report a sunburn were included in the no sunburn cohort.

In our analysis, the prevalence of at least 1 sunburn in the survey year in patients with psoriasis was 55.4% (weighted), compared to 45.6% (weighted) among those without psoriasis (eTable 1). Although there was no statistically significant relationship between psoriasis and history of sunburn in patients aged 20 to 59 years, a subgroup analysis revealed a significant association between psoriasis and sunburn in adults aged 20 to 39 years after adjusting for potential confounding variables (adjusted OR, 1.57 [95% CI, 1.00-2.45]; P=.049)(eTable 2). Further analysis of subgroups showed no statistically significant results with adjustment of the logistic regression model. Characterizing response rates is important for assessing the validity of survey studies. The NHANES response rate from 2009 to 2014 was 72.9%, enhancing the reliability of our findings.

Our study revealed an increased prevalence of sunburn in US adults with psoriasis. A trend of increased sunburn prevalence among younger adults regardless of psoriasis status is corroborated by the literature. Surveys conducted in the United States in 2005, 2010, and 2015 showed that 43% to 50% of adults aged 18 to 39 years and 28% to 42% of those aged 40 to 59 years reported experiencing at least 1 sunburn within the respective survey year.⁶ Furthermore, in our study, patients with psoriasis reported higher rates of sunburn than their counterparts without psoriasis, both in those aged 20 to 39 years (psoriasis, 62.8% [73/136]; no psoriasis, 51.1% [2425/5840]) and those aged 40 to 59 years (psoriasis, 50.5% [n=75/179]; no psoriasis, 40.2% [1613/5652]), though it was only statistically significant in the 20-to-39 age group. This discrepancy may be attributed to differences in sun-protective behaviors in younger vs older adults. A study from the NHANES database found that, among individuals aged 20 to 39 years, 75.9% [4225/5493] reported staying in the shade, 50.0% [2346/5493] reported using sunscreen, and 31.2% [1874/5493] reported wearing sun-protective clothing.⁷ Interestingly, the likelihood of engaging in all 3 behaviors was 28% lower in the 20-to-39 age group vs the 40-to-59 age group (adjusted OR, 0.72; 95% CI, 0.62-0.83).⁷

While our analysis adjusted for age, race/ethnicity, and tobacco use to mitigate potential confounding, we acknowledge the statistically significant differences observed in these variables between study groups as presented in eTable 2. These differences may reflect inherent disparities in the study population. We employed multivariable regression analysis to control for these covariates in our primary analyses. Of note, there was a statistically significant difference associated with race/ethnicity when comparing non-Hispanic White individuals with psoriasis (77.0% [n=182/315]) and those without psoriasis (62.5% [n=4516/11,492])(P<.0001)(eTable 1). The higher proportion of non-Hispanic White patients in the psoriasis group may reflect an increased susceptibility to sunburn given their typically lighter skin pigmentation; however, our analysis controlled for race/ethnicity (eTable 2), thereby allowing us to isolate the effect of psoriasis on sunburn prevalence independent of racial/ethnic differences. There also were statistically significant differences in tobacco use (P=.0026) and age (P=.002) in our unadjusted findings (eTable 1). Again, our analysis controlled for these factors (eTable 2), thereby allowing us to isolate the effect of psoriasis on sunburn prevalence independent of tobacco use and age differences. This approach enhanced the reliability of our findings.

The association between psoriasis and skin cancer has previously been evaluated using the NHANES database—one study found that patients with psoriasis had a significantly higher prevalence of nonmelanoma skin cancer compared with those without psoriasis (3.0% vs 1.3%; relative risk, 2.29; P<.001).⁸ This difference remained significant after adjusting for confounding variables, as it was found that psoriasis was independently associated with a 1.5-fold increased risk for nonmelanoma skin cancer (adjusted relative risk, 2.06; P=.004).⁸

The relationship between psoriasis and sunburn may be due to behavioral choices, such as the use of phototherapy for managing psoriasis due to its recognized advantages.⁹ Patients may seek out both artificial and natural light sources more frequently, potentially increasing the risk for sunburn.¹⁰ Psoriasis-related sunburn susceptibility may stem from biological factors, including vitamin D insufficiency, as vitamin D is crucial for keratinocyte differentiation, immune function, and UV protection and repair.¹¹ One study examined the effects of high-dose vitamin D3 on sunburn-induced inflammation.¹² Patients who received high-dose vitamin D3 exhibited reduced skin inflammation, enhanced skin barrier repair, and increased anti-inflammatory response compared with those who did not receive the supplement. This improvement was associated with upregulation of arginase 1, an anti-inflammatory enzyme, leading to decreased levels of pro-inflammatory mediators such as tumor necrosis factor α and inducible nitric oxide synthase, thereby promoting tissue repair and reducing prolonged inflammation.¹² These findings suggest that vitamin D insufficiency coupled with dysregulated immune responses may contribute to the heightened susceptibility of individuals with psoriasis to sunburn.

The established correlation between sunburn and skin cancer^4,8 coupled with our findings of increased prevalence of sunburn in individuals with psoriasis underscores the need for additional research to clarify the underlying biological and behavioral factors that may contribute to a higher prevalence of sunburn in these patients, along with the implications for skin cancer development. Limitations of our study included potential recall bias, as individuals self-reported their clinical conditions and the inability to incorporate psoriasis severity into our analysis, as this was not consistently captured in the NHANES questionnaire during the study period.

To the Editor:

UV light plays an essential role in various environmental and biological processes.¹ Excessive exposure to UV radiation can lead to sunburn, which is marked by skin erythema and pain.² A study of more than 31,000 individuals found that 34.2% of adults aged 18 years and older reported at least 1 sunburn during the survey year.³ A lack of research regarding the incidence of sunburns in patients with psoriasis is particularly important considering the heightened incidence of skin cancer observed in this population.⁴ Thus, the aim of our study was to analyze the prevalence of sunburns among US adults with psoriasis utilizing data from the National Health and Nutrition Examination Survey (NHANES) database.⁵

Our analysis initially included 11,842 participants ranging in age from 20 to 59 years; 35 did not respond to questions assessing psoriasis and sunburn prevalence and thus were excluded. Multivariable logistic regression analyses were performed using Stata/SE 18 (StataCorp LLC) to assess the relationship between psoriasis and sunburns. Our models controlled for patient age, sex, income, race, education, diabetes status, tobacco use, and body mass index. A P value <.05 was considered statistically significant. The study period from January 2009 to December 2014 was chosen based on the availability of the most recent and comprehensive psoriasis data within the NHANES database.

In the NHANES data we evaluated, psoriasis status was assessed by asking, “Have you ever been told by a doctor or other health professional that you had psoriasis?” History of sunburns in the survey year was assessed by the question, “How many times in the past year have you had sunburn?” Patients who reported 1 or more sunburns were included in the sunburn cohort, while those who did not report a sunburn were included in the no sunburn cohort.

In our analysis, the prevalence of at least 1 sunburn in the survey year in patients with psoriasis was 55.4% (weighted), compared to 45.6% (weighted) among those without psoriasis (eTable 1). Although there was no statistically significant relationship between psoriasis and history of sunburn in patients aged 20 to 59 years, a subgroup analysis revealed a significant association between psoriasis and sunburn in adults aged 20 to 39 years after adjusting for potential confounding variables (adjusted OR, 1.57 [95% CI, 1.00-2.45]; P=.049)(eTable 2). Further analysis of subgroups showed no statistically significant results with adjustment of the logistic regression model. Characterizing response rates is important for assessing the validity of survey studies. The NHANES response rate from 2009 to 2014 was 72.9%, enhancing the reliability of our findings.

Our study revealed an increased prevalence of sunburn in US adults with psoriasis. A trend of increased sunburn prevalence among younger adults regardless of psoriasis status is corroborated by the literature. Surveys conducted in the United States in 2005, 2010, and 2015 showed that 43% to 50% of adults aged 18 to 39 years and 28% to 42% of those aged 40 to 59 years reported experiencing at least 1 sunburn within the respective survey year.⁶ Furthermore, in our study, patients with psoriasis reported higher rates of sunburn than their counterparts without psoriasis, both in those aged 20 to 39 years (psoriasis, 62.8% [73/136]; no psoriasis, 51.1% [2425/5840]) and those aged 40 to 59 years (psoriasis, 50.5% [n=75/179]; no psoriasis, 40.2% [1613/5652]), though it was only statistically significant in the 20-to-39 age group. This discrepancy may be attributed to differences in sun-protective behaviors in younger vs older adults. A study from the NHANES database found that, among individuals aged 20 to 39 years, 75.9% [4225/5493] reported staying in the shade, 50.0% [2346/5493] reported using sunscreen, and 31.2% [1874/5493] reported wearing sun-protective clothing.⁷ Interestingly, the likelihood of engaging in all 3 behaviors was 28% lower in the 20-to-39 age group vs the 40-to-59 age group (adjusted OR, 0.72; 95% CI, 0.62-0.83).⁷

While our analysis adjusted for age, race/ethnicity, and tobacco use to mitigate potential confounding, we acknowledge the statistically significant differences observed in these variables between study groups as presented in eTable 2. These differences may reflect inherent disparities in the study population. We employed multivariable regression analysis to control for these covariates in our primary analyses. Of note, there was a statistically significant difference associated with race/ethnicity when comparing non-Hispanic White individuals with psoriasis (77.0% [n=182/315]) and those without psoriasis (62.5% [n=4516/11,492])(P<.0001)(eTable 1). The higher proportion of non-Hispanic White patients in the psoriasis group may reflect an increased susceptibility to sunburn given their typically lighter skin pigmentation; however, our analysis controlled for race/ethnicity (eTable 2), thereby allowing us to isolate the effect of psoriasis on sunburn prevalence independent of racial/ethnic differences. There also were statistically significant differences in tobacco use (P=.0026) and age (P=.002) in our unadjusted findings (eTable 1). Again, our analysis controlled for these factors (eTable 2), thereby allowing us to isolate the effect of psoriasis on sunburn prevalence independent of tobacco use and age differences. This approach enhanced the reliability of our findings.

The association between psoriasis and skin cancer has previously been evaluated using the NHANES database—one study found that patients with psoriasis had a significantly higher prevalence of nonmelanoma skin cancer compared with those without psoriasis (3.0% vs 1.3%; relative risk, 2.29; P<.001).⁸ This difference remained significant after adjusting for confounding variables, as it was found that psoriasis was independently associated with a 1.5-fold increased risk for nonmelanoma skin cancer (adjusted relative risk, 2.06; P=.004).⁸

The relationship between psoriasis and sunburn may be due to behavioral choices, such as the use of phototherapy for managing psoriasis due to its recognized advantages.⁹ Patients may seek out both artificial and natural light sources more frequently, potentially increasing the risk for sunburn.¹⁰ Psoriasis-related sunburn susceptibility may stem from biological factors, including vitamin D insufficiency, as vitamin D is crucial for keratinocyte differentiation, immune function, and UV protection and repair.¹¹ One study examined the effects of high-dose vitamin D3 on sunburn-induced inflammation.¹² Patients who received high-dose vitamin D3 exhibited reduced skin inflammation, enhanced skin barrier repair, and increased anti-inflammatory response compared with those who did not receive the supplement. This improvement was associated with upregulation of arginase 1, an anti-inflammatory enzyme, leading to decreased levels of pro-inflammatory mediators such as tumor necrosis factor α and inducible nitric oxide synthase, thereby promoting tissue repair and reducing prolonged inflammation.¹² These findings suggest that vitamin D insufficiency coupled with dysregulated immune responses may contribute to the heightened susceptibility of individuals with psoriasis to sunburn.

The established correlation between sunburn and skin cancer^4,8 coupled with our findings of increased prevalence of sunburn in individuals with psoriasis underscores the need for additional research to clarify the underlying biological and behavioral factors that may contribute to a higher prevalence of sunburn in these patients, along with the implications for skin cancer development. Limitations of our study included potential recall bias, as individuals self-reported their clinical conditions and the inability to incorporate psoriasis severity into our analysis, as this was not consistently captured in the NHANES questionnaire during the study period.

Psoriasis treatments have come a long way in the past 20 years. We now have more than a dozen systemic targeted treatments for psoriatic disease, with more on the way; however, with each successive class of medications introduced, the gap has narrowed in terms of increasing efficacy. In an era of medications reporting complete clearance rates in the 70% range, the average improvement in Psoriasis Area and Severity Index (PASI) for most biologics has remained at 90% to 95% in the past half-decade. While this is a far cry from the mean PASI improvements of 70% seen with the first biologics,¹ it is becoming more challenging to base our treatment decisions solely on PASI outcome measures.

How, then, do we approach rational selection of a systemic psoriasis treatment? We could try to delineate based on mechanism of action, but it may be disingenuous to dissect minor differences in pathways (eg, IL-17 vs IL-23) that are fundamentally related and on the same continuum in psoriasis pathophysiology. Therefore, the most meaningful way to select an appropriate therapeutic may be to adopt a patient-centered approach that accounts for both individual preferences and specific medical needs by evaluating for other comorbidities² to exclude or select certain medicines or types of treatments. We have long known to avoid tumor necrosis factor (TNF) α inhibitors in patients with congestive heart failure or a history of demyelinating disorders while regularly considering the presence of psoriatic arthritis and family planning when making treatment decisions. Now, we can be more nuanced in our approaches to psoriasis biologics. Specifically, the most important comorbidities to consider broadly encompass cardiometabolic disorders, gastrointestinal conditions, and psychiatric conditions.

Cardiometabolic Disorders

Possibly the hottest topic in psoriasis for some years now, the relationship between cardiometabolic disorders and psoriasis is of great interest to clinicians, scientists, and patients alike. There is a clear link between development of atherosclerosis and Th17-related immune mechanisms that also are implicated in the pathogenesis of psoriasis.³ Furthermore, the incidence of cardiovascular disease is markedly increased in patients with psoriasis, which is an independent risk factor for myocardial infarction, particularly among younger patients.^4,5 Although several retrospective studies^6-8 have shown that TNF-α inhibitors are associated with a reduction in cardiovascular outcomes, it is yet to be seen whether biologic treatment actually has a direct impact on cardiovascular outcomes, multiple studies investigating the effect of biologics on arterial inflammation markers notwithstanding.⁹

There are some direct factors to keep in mind when considering cardiometabolic comorbidities in patients with psoriasis. Obesity is common in the psoriasis population and can have a direct negative effect on cardiovascular health.¹⁰ However, the data on obesity and psoriasis are somewhat mixed with regard to treatment outcomes. In general, with increased volumes of distribution for biologics in patients with obesity, it has been shown that treatment success is more difficult to achieve in those with a body mass index greater than 30.¹¹ Rather surprisingly, a separate nationwide study in South Korea found that patients on biologics for psoriasis were more likely to experience weight gain, even after controlling for factors such as exercise, smoking, and drinking,¹² but it is unclear whether this is driven mostly by a known connection between weight gain and TNF-α inhibitors.¹³ These contrasting results point to the need for further studies in this area, as our intuitive approach would involve promoting weight loss while starting on a systemic treatment for psoriasis—but perhaps it is important not to assume that one will come with the other in tow, reinforcing the need to discuss a healthy diet with our patients with psoriasis regardless of treatment decisions.

The data that we have do not directly answer the big questions about biologic treatment and cardiovascular health, but we are starting to see interesting signals. For example, in a report of tildrakizumab treatment in patients with and without metabolic syndrome, the rates of major adverse cardiovascular events as well as cardiac disorders were essentially the same in both groups after receiving treatment for up to 244 weeks.¹⁴ This is interesting, more because of the lack of an increase in cardiovascular adverse events in the metabolic syndrome group, who entered the trial on average 25 kg to 30 kg heavier than those without metabolic syndrome. There is an increased risk for adverse cardiovascular events among patients with metabolic syndrome, a roughly 2-fold relative risk in as few as 5 to 6 years of follow-up.¹⁵ While the cohorts in the tildrakizumab study¹⁴ were too small to draw firm conclusions, the data are interesting and a step in the right direction; we need much larger data sets for analysis. Among other agents, similar efficacy and safety have been reported for guselkumab in a long-term psoriasis study; as a class, IL-23 inhibitors also tend to perform well from an efficacy standpoint in patients with obesity.¹⁶

Overall, when assessing the evidence for cardiometabolic disorders, it is reasonable to consider starting a biologic from the IL-17 or IL-23 inhibitor classes— thus avoiding both the potential downside of weight gain and contraindication in patients with congestive heart failure associated with TNF-α inhibitors. It is important to counsel patients about weight loss in conjunction with these treatments, both to improve efficacy and reduce cardiovascular risk factors. There may be a preference for IL-23 inhibitors in patients with obesity, as this class of medications maintains efficacy particularly well in these patients. Patients with psoriasis should be counseled to follow up with a primary care physician given their higher risk for metabolic syndrome and adverse cardiovascular outcomes.

Gastrointestinal Conditions

Psoriasis and inflammatory bowel disease (IBD) have a bidirectional association, and patients with psoriasis are about 1.7 times more likely to have either Crohn disease or ulcerative colitis.^17,18 This association may be related to a shared pathogenesis with regard to immune dysregulation and overactivated inflammatory pathways, but there are some important differences to consider from a therapeutic standpoint. Given the increased expression of IL-17 in patients with IBD,¹⁹ a phase II trial of secukinumab yielded surprising results—not only was secukinumab ineffective in treating Crohn disease, but there also were higher rates of adverse events²⁰ (as noted on the product label for all IL-17 inhibitors). We have come to understand that there are regulatory subsets of IL-17 cells that are important in mucosal homeostasis and also regulate IL-10, which generally is considered an anti-inflammatory cytokine.²¹ Thus, while IL-17 inhibition can reduce some component of inflammatory signaling, it also can increase inflammatory signaling through indirect pathways while increasing intestinal permeability to microbes. Importantly, this process seems to occur via IL-23–independent pathways; as such, while direct inhibition of IL-17 can be deleterious, IL-23 inhibitors have become important therapeutics for IBD.²²

IL-17 family, IL-17A clearly is the culprit for worsening colitis as evidenced by both human and animal models. On the contrary, IL-17F blockade has been shown to ameliorate colitis in a murine model, whereas IL-17A inhibition worsens it.²³ Furthermore, dual blockade of IL-17A and IL-17F has a protective effect against colitis, suggesting that the IL-17F inhibition is dominant. This interesting finding has some mechanistic backing, since blockade of IL-17F induces Treg cells that serve to maintain gut epithelium homeostasis and integrity.²⁴

Overall, IL-17A inhibitors should be avoided in patients with a history of IBD—namely, secukinumab and ixekizumab. While there may be theoretical reasons that brodalumab or bimekizumab may confer a somewhat different risk for IBD exacerbation, there may be better choices that would be expected to effectively treat both the psoriasis and IBD manifestations. Given the US Food and Drug Administration approval of IL-23 inhibitors for IBD and their high levels of efficacy in treating psoriasis, these likely will be the best choice for most patients. Another mainstay of IBD treatment is TNF-α inhibitors, but they come with other risks such as increased immunosuppression and increased risk for nonmelanoma skin cancer.

An important question remains: What about patients who do not have known IBD? Do we proactively change our treatment choice due to fear of IBD development given the higher incidence of both Crohn disease and ulcerative colitis in patients with psoriasis? What about patients with a family history of IBD? First-degree relatives of patients with Crohn disease and ulcerative colitis have an 8- and 4-fold higher risk for those same conditions, respectively.²⁵ Postmarketing surveillance and database findings of low rates of IBD development with IL-17 inhibitors gives only modest reassurance, as dermatologists generally know to avoid these medications for patients with even questionable IBD symptoms. It is important to emphasize to our patients that in no case do we believe that a psoriasis medication actually will cause IBD—rather, someone with subclinical IBD could experience a flare and a first manifestation of colitis. The drug is not the culprit in inducing IBD but rather may serve to unmask existing disease.

One study suggested that for patients who move on to the IL-17 inhibitor secukinumab after being treated with TNF-α inhibitors for psoriasis, the rates of IBD development are higher (4.8%) than in those who start IL-17A inhibition without prior treatment (1%)(OR, 8.38; P=.018).²⁶ This begs the question of whether subclinical IBD in many patients with psoriasis who are treated with TNF-α inhibitors can be unmasked later when they are transitioned to a treatment that either does not treat the IBD or could worsen it. There may be a mechanistic drive behind this sequencing of treatments that predisposes patients to colitis, which would suggest selecting an IL-23 inhibitor after failing/trying a TNF-α inhibitor. However, the data are very preliminary, and in real practice, other concerns such as severe psoriatic arthritis may outweigh these considerations, as the IL-17 inhibitor class still is considered to be more effective than IL-23 inhibition at treating psoriatic arthritis overall. For most patients with no personal history of IBD and no strong family history of IBD (ie, first-degree relatives), the choice of biologic should not be affected by concern over gastrointestinal issues.

Psychiatric Conditions

It has been well established that psoriasis is linked to higher rates of depression, anxiety, and suicidality.²⁷ How do we take this into account when treating patients with psoriasis, especially when we have biologics with a warning label for suicidality and a Risk Evaluation and Mitigation Strategies program (brodalumab) and language around suicidal ideation in the label (bimekizumab)? While it is challenging to discuss mental health, it is not a conversation that we as dermatologists should shy away from. Appropriate treatment of psoriasis is an important tool to get our patients on the path to better mental health. A recent database study of more than 4000 patients showed that patients with psoriasis treated with biologics had a 17% lower risk for depression than those treated with conventional disease-modifying drugs such as methotrexate.²⁸ The comparator of the conventional disease-modifying drug class is important as it serves as a control for disease severity. Too often, a higher rate of depression, anxiety, or suicidality can be attributed to a medication when we in fact may just be capturing the background of higher incidence of all 3 in patients with severe psoriasis.

Indeed, even with the medication that many worry about on this front (brodalumab), multiple studies have confirmed that the effect on mental health generally is a positive one, with decreases in depressive symptoms.²⁹ In a cohort switched from TNF-α inhibitors to brodalumab, symptoms of depression actually improved,³⁰ so attributing a direct treatment effect to negative mental health outcomes does not seem to be justified, especially in light of the low number of suicide events in global postmarketing surveillance for brodalumab, comparable to or lower than other biologics for psoriasis.³¹ Similarly, bimekizumab has language in the label about discussing suicidality with patients, although the rates of suicidal ideation and behavior are no different from other biologics and rates of depression improved with its use.³²

Heightened awareness of our patients’ mental health is something that we as providers should embrace, even when it seems that we do not have much time to see each patient. The priority when a patient comes in with mental health symptoms should be to treat what is within our scope (ie, psoriasis) as quickly and effectively as possible— with a newer-generation biologic such as an IL-17 or IL-23 inhibitor—while encouraging the patient to seek care from a mental health professional. In these cases, one might even argue that the rapidity of action of IL-17 inhibitors may be of additional benefit.

Final Thoughts

We as dermatologists generally are tasked with seeing high volumes of patients, and an initial psoriasis consultation can be a lengthy visit; however, it is rewarding to establish this relationship with patients and a reminder of why we practice medicine to begin with. Psoriasis can be satisfying to treat, and we have so many highly effective medicines that can completely transform our patients’ lives. Applying an understanding of the interplay between psoriasis, its related comorbidities, and treatment choices can be a fulfilling exercise that captures the essence of shared decision-making, which can lead to better outcomes and satisfaction for both providers and patients.

Psoriasis treatments have come a long way in the past 20 years. We now have more than a dozen systemic targeted treatments for psoriatic disease, with more on the way; however, with each successive class of medications introduced, the gap has narrowed in terms of increasing efficacy. In an era of medications reporting complete clearance rates in the 70% range, the average improvement in Psoriasis Area and Severity Index (PASI) for most biologics has remained at 90% to 95% in the past half-decade. While this is a far cry from the mean PASI improvements of 70% seen with the first biologics,¹ it is becoming more challenging to base our treatment decisions solely on PASI outcome measures.

How, then, do we approach rational selection of a systemic psoriasis treatment? We could try to delineate based on mechanism of action, but it may be disingenuous to dissect minor differences in pathways (eg, IL-17 vs IL-23) that are fundamentally related and on the same continuum in psoriasis pathophysiology. Therefore, the most meaningful way to select an appropriate therapeutic may be to adopt a patient-centered approach that accounts for both individual preferences and specific medical needs by evaluating for other comorbidities² to exclude or select certain medicines or types of treatments. We have long known to avoid tumor necrosis factor (TNF) α inhibitors in patients with congestive heart failure or a history of demyelinating disorders while regularly considering the presence of psoriatic arthritis and family planning when making treatment decisions. Now, we can be more nuanced in our approaches to psoriasis biologics. Specifically, the most important comorbidities to consider broadly encompass cardiometabolic disorders, gastrointestinal conditions, and psychiatric conditions.

Cardiometabolic Disorders

Possibly the hottest topic in psoriasis for some years now, the relationship between cardiometabolic disorders and psoriasis is of great interest to clinicians, scientists, and patients alike. There is a clear link between development of atherosclerosis and Th17-related immune mechanisms that also are implicated in the pathogenesis of psoriasis.³ Furthermore, the incidence of cardiovascular disease is markedly increased in patients with psoriasis, which is an independent risk factor for myocardial infarction, particularly among younger patients.^4,5 Although several retrospective studies^6-8 have shown that TNF-α inhibitors are associated with a reduction in cardiovascular outcomes, it is yet to be seen whether biologic treatment actually has a direct impact on cardiovascular outcomes, multiple studies investigating the effect of biologics on arterial inflammation markers notwithstanding.⁹

There are some direct factors to keep in mind when considering cardiometabolic comorbidities in patients with psoriasis. Obesity is common in the psoriasis population and can have a direct negative effect on cardiovascular health.¹⁰ However, the data on obesity and psoriasis are somewhat mixed with regard to treatment outcomes. In general, with increased volumes of distribution for biologics in patients with obesity, it has been shown that treatment success is more difficult to achieve in those with a body mass index greater than 30.¹¹ Rather surprisingly, a separate nationwide study in South Korea found that patients on biologics for psoriasis were more likely to experience weight gain, even after controlling for factors such as exercise, smoking, and drinking,¹² but it is unclear whether this is driven mostly by a known connection between weight gain and TNF-α inhibitors.¹³ These contrasting results point to the need for further studies in this area, as our intuitive approach would involve promoting weight loss while starting on a systemic treatment for psoriasis—but perhaps it is important not to assume that one will come with the other in tow, reinforcing the need to discuss a healthy diet with our patients with psoriasis regardless of treatment decisions.

The data that we have do not directly answer the big questions about biologic treatment and cardiovascular health, but we are starting to see interesting signals. For example, in a report of tildrakizumab treatment in patients with and without metabolic syndrome, the rates of major adverse cardiovascular events as well as cardiac disorders were essentially the same in both groups after receiving treatment for up to 244 weeks.¹⁴ This is interesting, more because of the lack of an increase in cardiovascular adverse events in the metabolic syndrome group, who entered the trial on average 25 kg to 30 kg heavier than those without metabolic syndrome. There is an increased risk for adverse cardiovascular events among patients with metabolic syndrome, a roughly 2-fold relative risk in as few as 5 to 6 years of follow-up.¹⁵ While the cohorts in the tildrakizumab study¹⁴ were too small to draw firm conclusions, the data are interesting and a step in the right direction; we need much larger data sets for analysis. Among other agents, similar efficacy and safety have been reported for guselkumab in a long-term psoriasis study; as a class, IL-23 inhibitors also tend to perform well from an efficacy standpoint in patients with obesity.¹⁶

Overall, when assessing the evidence for cardiometabolic disorders, it is reasonable to consider starting a biologic from the IL-17 or IL-23 inhibitor classes— thus avoiding both the potential downside of weight gain and contraindication in patients with congestive heart failure associated with TNF-α inhibitors. It is important to counsel patients about weight loss in conjunction with these treatments, both to improve efficacy and reduce cardiovascular risk factors. There may be a preference for IL-23 inhibitors in patients with obesity, as this class of medications maintains efficacy particularly well in these patients. Patients with psoriasis should be counseled to follow up with a primary care physician given their higher risk for metabolic syndrome and adverse cardiovascular outcomes.

Gastrointestinal Conditions

Psoriasis and inflammatory bowel disease (IBD) have a bidirectional association, and patients with psoriasis are about 1.7 times more likely to have either Crohn disease or ulcerative colitis.^17,18 This association may be related to a shared pathogenesis with regard to immune dysregulation and overactivated inflammatory pathways, but there are some important differences to consider from a therapeutic standpoint. Given the increased expression of IL-17 in patients with IBD,¹⁹ a phase II trial of secukinumab yielded surprising results—not only was secukinumab ineffective in treating Crohn disease, but there also were higher rates of adverse events²⁰ (as noted on the product label for all IL-17 inhibitors). We have come to understand that there are regulatory subsets of IL-17 cells that are important in mucosal homeostasis and also regulate IL-10, which generally is considered an anti-inflammatory cytokine.²¹ Thus, while IL-17 inhibition can reduce some component of inflammatory signaling, it also can increase inflammatory signaling through indirect pathways while increasing intestinal permeability to microbes. Importantly, this process seems to occur via IL-23–independent pathways; as such, while direct inhibition of IL-17 can be deleterious, IL-23 inhibitors have become important therapeutics for IBD.²²

IL-17 family, IL-17A clearly is the culprit for worsening colitis as evidenced by both human and animal models. On the contrary, IL-17F blockade has been shown to ameliorate colitis in a murine model, whereas IL-17A inhibition worsens it.²³ Furthermore, dual blockade of IL-17A and IL-17F has a protective effect against colitis, suggesting that the IL-17F inhibition is dominant. This interesting finding has some mechanistic backing, since blockade of IL-17F induces Treg cells that serve to maintain gut epithelium homeostasis and integrity.²⁴

Overall, IL-17A inhibitors should be avoided in patients with a history of IBD—namely, secukinumab and ixekizumab. While there may be theoretical reasons that brodalumab or bimekizumab may confer a somewhat different risk for IBD exacerbation, there may be better choices that would be expected to effectively treat both the psoriasis and IBD manifestations. Given the US Food and Drug Administration approval of IL-23 inhibitors for IBD and their high levels of efficacy in treating psoriasis, these likely will be the best choice for most patients. Another mainstay of IBD treatment is TNF-α inhibitors, but they come with other risks such as increased immunosuppression and increased risk for nonmelanoma skin cancer.

An important question remains: What about patients who do not have known IBD? Do we proactively change our treatment choice due to fear of IBD development given the higher incidence of both Crohn disease and ulcerative colitis in patients with psoriasis? What about patients with a family history of IBD? First-degree relatives of patients with Crohn disease and ulcerative colitis have an 8- and 4-fold higher risk for those same conditions, respectively.²⁵ Postmarketing surveillance and database findings of low rates of IBD development with IL-17 inhibitors gives only modest reassurance, as dermatologists generally know to avoid these medications for patients with even questionable IBD symptoms. It is important to emphasize to our patients that in no case do we believe that a psoriasis medication actually will cause IBD—rather, someone with subclinical IBD could experience a flare and a first manifestation of colitis. The drug is not the culprit in inducing IBD but rather may serve to unmask existing disease.

One study suggested that for patients who move on to the IL-17 inhibitor secukinumab after being treated with TNF-α inhibitors for psoriasis, the rates of IBD development are higher (4.8%) than in those who start IL-17A inhibition without prior treatment (1%)(OR, 8.38; P=.018).²⁶ This begs the question of whether subclinical IBD in many patients with psoriasis who are treated with TNF-α inhibitors can be unmasked later when they are transitioned to a treatment that either does not treat the IBD or could worsen it. There may be a mechanistic drive behind this sequencing of treatments that predisposes patients to colitis, which would suggest selecting an IL-23 inhibitor after failing/trying a TNF-α inhibitor. However, the data are very preliminary, and in real practice, other concerns such as severe psoriatic arthritis may outweigh these considerations, as the IL-17 inhibitor class still is considered to be more effective than IL-23 inhibition at treating psoriatic arthritis overall. For most patients with no personal history of IBD and no strong family history of IBD (ie, first-degree relatives), the choice of biologic should not be affected by concern over gastrointestinal issues.

Psychiatric Conditions

It has been well established that psoriasis is linked to higher rates of depression, anxiety, and suicidality.²⁷ How do we take this into account when treating patients with psoriasis, especially when we have biologics with a warning label for suicidality and a Risk Evaluation and Mitigation Strategies program (brodalumab) and language around suicidal ideation in the label (bimekizumab)? While it is challenging to discuss mental health, it is not a conversation that we as dermatologists should shy away from. Appropriate treatment of psoriasis is an important tool to get our patients on the path to better mental health. A recent database study of more than 4000 patients showed that patients with psoriasis treated with biologics had a 17% lower risk for depression than those treated with conventional disease-modifying drugs such as methotrexate.²⁸ The comparator of the conventional disease-modifying drug class is important as it serves as a control for disease severity. Too often, a higher rate of depression, anxiety, or suicidality can be attributed to a medication when we in fact may just be capturing the background of higher incidence of all 3 in patients with severe psoriasis.

Indeed, even with the medication that many worry about on this front (brodalumab), multiple studies have confirmed that the effect on mental health generally is a positive one, with decreases in depressive symptoms.²⁹ In a cohort switched from TNF-α inhibitors to brodalumab, symptoms of depression actually improved,³⁰ so attributing a direct treatment effect to negative mental health outcomes does not seem to be justified, especially in light of the low number of suicide events in global postmarketing surveillance for brodalumab, comparable to or lower than other biologics for psoriasis.³¹ Similarly, bimekizumab has language in the label about discussing suicidality with patients, although the rates of suicidal ideation and behavior are no different from other biologics and rates of depression improved with its use.³²

Heightened awareness of our patients’ mental health is something that we as providers should embrace, even when it seems that we do not have much time to see each patient. The priority when a patient comes in with mental health symptoms should be to treat what is within our scope (ie, psoriasis) as quickly and effectively as possible— with a newer-generation biologic such as an IL-17 or IL-23 inhibitor—while encouraging the patient to seek care from a mental health professional. In these cases, one might even argue that the rapidity of action of IL-17 inhibitors may be of additional benefit.

Final Thoughts

We as dermatologists generally are tasked with seeing high volumes of patients, and an initial psoriasis consultation can be a lengthy visit; however, it is rewarding to establish this relationship with patients and a reminder of why we practice medicine to begin with. Psoriasis can be satisfying to treat, and we have so many highly effective medicines that can completely transform our patients’ lives. Applying an understanding of the interplay between psoriasis, its related comorbidities, and treatment choices can be a fulfilling exercise that captures the essence of shared decision-making, which can lead to better outcomes and satisfaction for both providers and patients.

Psoriasis treatments have come a long way in the past 20 years. We now have more than a dozen systemic targeted treatments for psoriatic disease, with more on the way; however, with each successive class of medications introduced, the gap has narrowed in terms of increasing efficacy. In an era of medications reporting complete clearance rates in the 70% range, the average improvement in Psoriasis Area and Severity Index (PASI) for most biologics has remained at 90% to 95% in the past half-decade. While this is a far cry from the mean PASI improvements of 70% seen with the first biologics,¹ it is becoming more challenging to base our treatment decisions solely on PASI outcome measures.

How, then, do we approach rational selection of a systemic psoriasis treatment? We could try to delineate based on mechanism of action, but it may be disingenuous to dissect minor differences in pathways (eg, IL-17 vs IL-23) that are fundamentally related and on the same continuum in psoriasis pathophysiology. Therefore, the most meaningful way to select an appropriate therapeutic may be to adopt a patient-centered approach that accounts for both individual preferences and specific medical needs by evaluating for other comorbidities² to exclude or select certain medicines or types of treatments. We have long known to avoid tumor necrosis factor (TNF) α inhibitors in patients with congestive heart failure or a history of demyelinating disorders while regularly considering the presence of psoriatic arthritis and family planning when making treatment decisions. Now, we can be more nuanced in our approaches to psoriasis biologics. Specifically, the most important comorbidities to consider broadly encompass cardiometabolic disorders, gastrointestinal conditions, and psychiatric conditions.

Cardiometabolic Disorders

Possibly the hottest topic in psoriasis for some years now, the relationship between cardiometabolic disorders and psoriasis is of great interest to clinicians, scientists, and patients alike. There is a clear link between development of atherosclerosis and Th17-related immune mechanisms that also are implicated in the pathogenesis of psoriasis.³ Furthermore, the incidence of cardiovascular disease is markedly increased in patients with psoriasis, which is an independent risk factor for myocardial infarction, particularly among younger patients.^4,5 Although several retrospective studies^6-8 have shown that TNF-α inhibitors are associated with a reduction in cardiovascular outcomes, it is yet to be seen whether biologic treatment actually has a direct impact on cardiovascular outcomes, multiple studies investigating the effect of biologics on arterial inflammation markers notwithstanding.⁹

There are some direct factors to keep in mind when considering cardiometabolic comorbidities in patients with psoriasis. Obesity is common in the psoriasis population and can have a direct negative effect on cardiovascular health.¹⁰ However, the data on obesity and psoriasis are somewhat mixed with regard to treatment outcomes. In general, with increased volumes of distribution for biologics in patients with obesity, it has been shown that treatment success is more difficult to achieve in those with a body mass index greater than 30.¹¹ Rather surprisingly, a separate nationwide study in South Korea found that patients on biologics for psoriasis were more likely to experience weight gain, even after controlling for factors such as exercise, smoking, and drinking,¹² but it is unclear whether this is driven mostly by a known connection between weight gain and TNF-α inhibitors.¹³ These contrasting results point to the need for further studies in this area, as our intuitive approach would involve promoting weight loss while starting on a systemic treatment for psoriasis—but perhaps it is important not to assume that one will come with the other in tow, reinforcing the need to discuss a healthy diet with our patients with psoriasis regardless of treatment decisions.

The data that we have do not directly answer the big questions about biologic treatment and cardiovascular health, but we are starting to see interesting signals. For example, in a report of tildrakizumab treatment in patients with and without metabolic syndrome, the rates of major adverse cardiovascular events as well as cardiac disorders were essentially the same in both groups after receiving treatment for up to 244 weeks.¹⁴ This is interesting, more because of the lack of an increase in cardiovascular adverse events in the metabolic syndrome group, who entered the trial on average 25 kg to 30 kg heavier than those without metabolic syndrome. There is an increased risk for adverse cardiovascular events among patients with metabolic syndrome, a roughly 2-fold relative risk in as few as 5 to 6 years of follow-up.¹⁵ While the cohorts in the tildrakizumab study¹⁴ were too small to draw firm conclusions, the data are interesting and a step in the right direction; we need much larger data sets for analysis. Among other agents, similar efficacy and safety have been reported for guselkumab in a long-term psoriasis study; as a class, IL-23 inhibitors also tend to perform well from an efficacy standpoint in patients with obesity.¹⁶

Overall, when assessing the evidence for cardiometabolic disorders, it is reasonable to consider starting a biologic from the IL-17 or IL-23 inhibitor classes— thus avoiding both the potential downside of weight gain and contraindication in patients with congestive heart failure associated with TNF-α inhibitors. It is important to counsel patients about weight loss in conjunction with these treatments, both to improve efficacy and reduce cardiovascular risk factors. There may be a preference for IL-23 inhibitors in patients with obesity, as this class of medications maintains efficacy particularly well in these patients. Patients with psoriasis should be counseled to follow up with a primary care physician given their higher risk for metabolic syndrome and adverse cardiovascular outcomes.

Gastrointestinal Conditions

Psoriasis and inflammatory bowel disease (IBD) have a bidirectional association, and patients with psoriasis are about 1.7 times more likely to have either Crohn disease or ulcerative colitis.^17,18 This association may be related to a shared pathogenesis with regard to immune dysregulation and overactivated inflammatory pathways, but there are some important differences to consider from a therapeutic standpoint. Given the increased expression of IL-17 in patients with IBD,¹⁹ a phase II trial of secukinumab yielded surprising results—not only was secukinumab ineffective in treating Crohn disease, but there also were higher rates of adverse events²⁰ (as noted on the product label for all IL-17 inhibitors). We have come to understand that there are regulatory subsets of IL-17 cells that are important in mucosal homeostasis and also regulate IL-10, which generally is considered an anti-inflammatory cytokine.²¹ Thus, while IL-17 inhibition can reduce some component of inflammatory signaling, it also can increase inflammatory signaling through indirect pathways while increasing intestinal permeability to microbes. Importantly, this process seems to occur via IL-23–independent pathways; as such, while direct inhibition of IL-17 can be deleterious, IL-23 inhibitors have become important therapeutics for IBD.²²

IL-17 family, IL-17A clearly is the culprit for worsening colitis as evidenced by both human and animal models. On the contrary, IL-17F blockade has been shown to ameliorate colitis in a murine model, whereas IL-17A inhibition worsens it.²³ Furthermore, dual blockade of IL-17A and IL-17F has a protective effect against colitis, suggesting that the IL-17F inhibition is dominant. This interesting finding has some mechanistic backing, since blockade of IL-17F induces Treg cells that serve to maintain gut epithelium homeostasis and integrity.²⁴

Overall, IL-17A inhibitors should be avoided in patients with a history of IBD—namely, secukinumab and ixekizumab. While there may be theoretical reasons that brodalumab or bimekizumab may confer a somewhat different risk for IBD exacerbation, there may be better choices that would be expected to effectively treat both the psoriasis and IBD manifestations. Given the US Food and Drug Administration approval of IL-23 inhibitors for IBD and their high levels of efficacy in treating psoriasis, these likely will be the best choice for most patients. Another mainstay of IBD treatment is TNF-α inhibitors, but they come with other risks such as increased immunosuppression and increased risk for nonmelanoma skin cancer.

An important question remains: What about patients who do not have known IBD? Do we proactively change our treatment choice due to fear of IBD development given the higher incidence of both Crohn disease and ulcerative colitis in patients with psoriasis? What about patients with a family history of IBD? First-degree relatives of patients with Crohn disease and ulcerative colitis have an 8- and 4-fold higher risk for those same conditions, respectively.²⁵ Postmarketing surveillance and database findings of low rates of IBD development with IL-17 inhibitors gives only modest reassurance, as dermatologists generally know to avoid these medications for patients with even questionable IBD symptoms. It is important to emphasize to our patients that in no case do we believe that a psoriasis medication actually will cause IBD—rather, someone with subclinical IBD could experience a flare and a first manifestation of colitis. The drug is not the culprit in inducing IBD but rather may serve to unmask existing disease.

One study suggested that for patients who move on to the IL-17 inhibitor secukinumab after being treated with TNF-α inhibitors for psoriasis, the rates of IBD development are higher (4.8%) than in those who start IL-17A inhibition without prior treatment (1%)(OR, 8.38; P=.018).²⁶ This begs the question of whether subclinical IBD in many patients with psoriasis who are treated with TNF-α inhibitors can be unmasked later when they are transitioned to a treatment that either does not treat the IBD or could worsen it. There may be a mechanistic drive behind this sequencing of treatments that predisposes patients to colitis, which would suggest selecting an IL-23 inhibitor after failing/trying a TNF-α inhibitor. However, the data are very preliminary, and in real practice, other concerns such as severe psoriatic arthritis may outweigh these considerations, as the IL-17 inhibitor class still is considered to be more effective than IL-23 inhibition at treating psoriatic arthritis overall. For most patients with no personal history of IBD and no strong family history of IBD (ie, first-degree relatives), the choice of biologic should not be affected by concern over gastrointestinal issues.

Psychiatric Conditions

It has been well established that psoriasis is linked to higher rates of depression, anxiety, and suicidality.²⁷ How do we take this into account when treating patients with psoriasis, especially when we have biologics with a warning label for suicidality and a Risk Evaluation and Mitigation Strategies program (brodalumab) and language around suicidal ideation in the label (bimekizumab)? While it is challenging to discuss mental health, it is not a conversation that we as dermatologists should shy away from. Appropriate treatment of psoriasis is an important tool to get our patients on the path to better mental health. A recent database study of more than 4000 patients showed that patients with psoriasis treated with biologics had a 17% lower risk for depression than those treated with conventional disease-modifying drugs such as methotrexate.²⁸ The comparator of the conventional disease-modifying drug class is important as it serves as a control for disease severity. Too often, a higher rate of depression, anxiety, or suicidality can be attributed to a medication when we in fact may just be capturing the background of higher incidence of all 3 in patients with severe psoriasis.

Indeed, even with the medication that many worry about on this front (brodalumab), multiple studies have confirmed that the effect on mental health generally is a positive one, with decreases in depressive symptoms.²⁹ In a cohort switched from TNF-α inhibitors to brodalumab, symptoms of depression actually improved,³⁰ so attributing a direct treatment effect to negative mental health outcomes does not seem to be justified, especially in light of the low number of suicide events in global postmarketing surveillance for brodalumab, comparable to or lower than other biologics for psoriasis.³¹ Similarly, bimekizumab has language in the label about discussing suicidality with patients, although the rates of suicidal ideation and behavior are no different from other biologics and rates of depression improved with its use.³²

Heightened awareness of our patients’ mental health is something that we as providers should embrace, even when it seems that we do not have much time to see each patient. The priority when a patient comes in with mental health symptoms should be to treat what is within our scope (ie, psoriasis) as quickly and effectively as possible— with a newer-generation biologic such as an IL-17 or IL-23 inhibitor—while encouraging the patient to seek care from a mental health professional. In these cases, one might even argue that the rapidity of action of IL-17 inhibitors may be of additional benefit.

Final Thoughts

We as dermatologists generally are tasked with seeing high volumes of patients, and an initial psoriasis consultation can be a lengthy visit; however, it is rewarding to establish this relationship with patients and a reminder of why we practice medicine to begin with. Psoriasis can be satisfying to treat, and we have so many highly effective medicines that can completely transform our patients’ lives. Applying an understanding of the interplay between psoriasis, its related comorbidities, and treatment choices can be a fulfilling exercise that captures the essence of shared decision-making, which can lead to better outcomes and satisfaction for both providers and patients.

TOPLINE:

Tildrakizumab was well tolerated and achieved sustained response in patients with moderate to severe plaque psoriasis of the scalp in a phase 3 study.

METHODOLOGY:

• A 72-week, multicenter, randomized, double-blind, placebo-controlled phase 3b trial enrolled 231 patients with moderate to severe plaque psoriasis of the scalp.
• Patients were randomly assigned to receive placebo (n = 114) or tildrakizumab (n = 117) until week 16, when patients in the placebo group switched to receive tildrakizumab.
• The primary endpoint, Investigator Global Assessment modified 2011 (IGA) scalp response, was defined as a score of 0 (clear) or 1 (almost clear) or an improvement of at least two points at week 16.
• The treatment was stopped at week 52, and participants were observed for another 20 weeks for safety and tolerability.

TAKEAWAY:

• At week 16, the response rate was higher in the tildrakizumab group than in the placebo group (49.4% vs 7.3%; P < .00001), and it increased to 62.9% and 56.1% (after crossover), respectively, at week 52.
• Psoriasis Scalp Severity Index 90 (PSSI 90) response rates were 60.7% and 4.9% at week 16 in the tildrakizumab and placebo groups, rising to 65.2% and 57.3%, respectively, at week 52.
• More than 80% of the week 16 responders maintained IGA and PSSI 90 responses at week 52.
• More than 50% of patients in both groups experienced adverse events, with no treatment-related serious toxicity.

IN PRACTICE:

“Tildrakizumab maintains improvements in scalp psoriasis for up to 52 weeks,” the authors wrote.

SOURCE:

Howard L. Sofen, MD, University of California, Los Angeles, led the study, which was published online on December 22, 2024, in the Journal of the American Academy of Dermatology.

LIMITATIONS:

This study excluded patients with predominantly scalp involvement and minimal whole body psoriasis, who might respond differently to the treatment. Results were obtained under controlled clinical conditions and may not be generalizable to clinical practice.

DISCLOSURES:

This study and analyses were funded by Sun Pharma. Sofen reported serving as a clinical investigator for various pharmaceutical companies, including Sun Pharma. Five authors were current or former employees of Sun Pharma and associated companies. Others also disclosed financial ties outside this work.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Tildrakizumab was well tolerated and achieved sustained response in patients with moderate to severe plaque psoriasis of the scalp in a phase 3 study.

METHODOLOGY:

• A 72-week, multicenter, randomized, double-blind, placebo-controlled phase 3b trial enrolled 231 patients with moderate to severe plaque psoriasis of the scalp.
• Patients were randomly assigned to receive placebo (n = 114) or tildrakizumab (n = 117) until week 16, when patients in the placebo group switched to receive tildrakizumab.
• The primary endpoint, Investigator Global Assessment modified 2011 (IGA) scalp response, was defined as a score of 0 (clear) or 1 (almost clear) or an improvement of at least two points at week 16.
• The treatment was stopped at week 52, and participants were observed for another 20 weeks for safety and tolerability.

TAKEAWAY:

• At week 16, the response rate was higher in the tildrakizumab group than in the placebo group (49.4% vs 7.3%; P < .00001), and it increased to 62.9% and 56.1% (after crossover), respectively, at week 52.
• Psoriasis Scalp Severity Index 90 (PSSI 90) response rates were 60.7% and 4.9% at week 16 in the tildrakizumab and placebo groups, rising to 65.2% and 57.3%, respectively, at week 52.
• More than 80% of the week 16 responders maintained IGA and PSSI 90 responses at week 52.
• More than 50% of patients in both groups experienced adverse events, with no treatment-related serious toxicity.

IN PRACTICE:

“Tildrakizumab maintains improvements in scalp psoriasis for up to 52 weeks,” the authors wrote.

SOURCE:

Howard L. Sofen, MD, University of California, Los Angeles, led the study, which was published online on December 22, 2024, in the Journal of the American Academy of Dermatology.

LIMITATIONS:

This study excluded patients with predominantly scalp involvement and minimal whole body psoriasis, who might respond differently to the treatment. Results were obtained under controlled clinical conditions and may not be generalizable to clinical practice.

DISCLOSURES:

This study and analyses were funded by Sun Pharma. Sofen reported serving as a clinical investigator for various pharmaceutical companies, including Sun Pharma. Five authors were current or former employees of Sun Pharma and associated companies. Others also disclosed financial ties outside this work.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Tildrakizumab was well tolerated and achieved sustained response in patients with moderate to severe plaque psoriasis of the scalp in a phase 3 study.

METHODOLOGY:

• A 72-week, multicenter, randomized, double-blind, placebo-controlled phase 3b trial enrolled 231 patients with moderate to severe plaque psoriasis of the scalp.
• Patients were randomly assigned to receive placebo (n = 114) or tildrakizumab (n = 117) until week 16, when patients in the placebo group switched to receive tildrakizumab.
• The primary endpoint, Investigator Global Assessment modified 2011 (IGA) scalp response, was defined as a score of 0 (clear) or 1 (almost clear) or an improvement of at least two points at week 16.
• The treatment was stopped at week 52, and participants were observed for another 20 weeks for safety and tolerability.

TAKEAWAY:

• At week 16, the response rate was higher in the tildrakizumab group than in the placebo group (49.4% vs 7.3%; P < .00001), and it increased to 62.9% and 56.1% (after crossover), respectively, at week 52.
• Psoriasis Scalp Severity Index 90 (PSSI 90) response rates were 60.7% and 4.9% at week 16 in the tildrakizumab and placebo groups, rising to 65.2% and 57.3%, respectively, at week 52.
• More than 80% of the week 16 responders maintained IGA and PSSI 90 responses at week 52.
• More than 50% of patients in both groups experienced adverse events, with no treatment-related serious toxicity.

IN PRACTICE:

“Tildrakizumab maintains improvements in scalp psoriasis for up to 52 weeks,” the authors wrote.

SOURCE:

Howard L. Sofen, MD, University of California, Los Angeles, led the study, which was published online on December 22, 2024, in the Journal of the American Academy of Dermatology.

LIMITATIONS:

This study excluded patients with predominantly scalp involvement and minimal whole body psoriasis, who might respond differently to the treatment. Results were obtained under controlled clinical conditions and may not be generalizable to clinical practice.

DISCLOSURES:

This study and analyses were funded by Sun Pharma. Sofen reported serving as a clinical investigator for various pharmaceutical companies, including Sun Pharma. Five authors were current or former employees of Sun Pharma and associated companies. Others also disclosed financial ties outside this work.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

The newer biologics — interleukin (IL)–17, IL-12/23, and IL-23 inhibitors — demonstrate comparable cardiovascular safety profiles to tumor necrosis factor (TNF) inhibitors in biologic-naive patients with psoriasis or psoriatic arthritis (PsA).

METHODOLOGY:

• In a retrospective cohort study, researchers conducted an emulated target trial analysis using data of 32,098 biologic-naive patients with psoriasis or PsA who were treated with one of the newer biologics (infliximab, adalimumab, etanercept, certolizumab pegol, secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, and tildrakizumab) from the TriNetX Research Network between 2014 and 2022.
• Patients received TNF inhibitors (n = 20,314), IL-17 inhibitors (n = 5073), IL-12/23 inhibitors (n = 3573), or IL-23 inhibitors (n = 3138).
• A propensity-matched analysis compared each class of newer biologics with TNF inhibitors, adjusting for demographics, comorbidities, and medication use.
• The primary outcomes were major adverse cardiovascular events (MACE; myocardial infarction and stroke) or venous thromboembolic events (VTE).

TAKEAWAY:

• Compared with patients who received TNF inhibitors, the risk for MACE was not significantly different between patients who received IL-17 inhibitors (incidence rate ratio [IRR], 1.14; 95% CI, 0.86-1.52), IL-12/23 inhibitors (IRR, 1.24; 95% CI, 0.84-1.78), or IL-23 inhibitors (IRR, 0.93; 95% CI, 0.61-1.38)
• The VTE risk was also not significantly different between patients who received IL-17 inhibitors (IRR, 1.12; 95% CI, 0.63-2.08), IL-12/23 inhibitors (IRR, 1.51; 95% CI, 0.73-3.19), or IL-23 inhibitors (IRR, 1.42; 95% CI, 0.64-3.25) compared with those who received TNF inhibitors.
• Subgroup analyses for psoriasis or psoriatic arthritis alone confirmed consistent findings.
• Patients with preexisting hyperlipidemia and diabetes mellitus showed lower risks for MACE and VTE with newer biologics compared with TNF inhibitors. 

IN PRACTICE:

“No significant MACE and VTE risk differences were detected in patients with psoriasis or PsA between those receiving IL-17, IL-12/23, and IL-23 inhibitors and those with TNF inhibitors,” the authors concluded. These findings, they added “can be considered by physicians and patients when making treatment decisions” and also provide “evidence for future pharmacovigilance studies.”

SOURCE:

The study was led by Tai-Li Chen, MD, of the Department of Dermatology, Taipei Veterans General Hospital in Taipei, Taiwan. It was published online on December 27, 2024, in the Journal of the American Academy of Dermatology.

LIMITATIONS:

Study limitations included potential residual confounding factors, lack of information on disease severity, and inclusion of predominantly White individuals.

DISCLOSURES:

The study received support from Taipei Veterans General Hospital and Ministry of Science and Technology, Taiwan. The authors reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The newer biologics — interleukin (IL)–17, IL-12/23, and IL-23 inhibitors — demonstrate comparable cardiovascular safety profiles to tumor necrosis factor (TNF) inhibitors in biologic-naive patients with psoriasis or psoriatic arthritis (PsA).

METHODOLOGY:

• In a retrospective cohort study, researchers conducted an emulated target trial analysis using data of 32,098 biologic-naive patients with psoriasis or PsA who were treated with one of the newer biologics (infliximab, adalimumab, etanercept, certolizumab pegol, secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, and tildrakizumab) from the TriNetX Research Network between 2014 and 2022.
• Patients received TNF inhibitors (n = 20,314), IL-17 inhibitors (n = 5073), IL-12/23 inhibitors (n = 3573), or IL-23 inhibitors (n = 3138).
• A propensity-matched analysis compared each class of newer biologics with TNF inhibitors, adjusting for demographics, comorbidities, and medication use.
• The primary outcomes were major adverse cardiovascular events (MACE; myocardial infarction and stroke) or venous thromboembolic events (VTE).

TAKEAWAY:

• Compared with patients who received TNF inhibitors, the risk for MACE was not significantly different between patients who received IL-17 inhibitors (incidence rate ratio [IRR], 1.14; 95% CI, 0.86-1.52), IL-12/23 inhibitors (IRR, 1.24; 95% CI, 0.84-1.78), or IL-23 inhibitors (IRR, 0.93; 95% CI, 0.61-1.38)
• The VTE risk was also not significantly different between patients who received IL-17 inhibitors (IRR, 1.12; 95% CI, 0.63-2.08), IL-12/23 inhibitors (IRR, 1.51; 95% CI, 0.73-3.19), or IL-23 inhibitors (IRR, 1.42; 95% CI, 0.64-3.25) compared with those who received TNF inhibitors.
• Subgroup analyses for psoriasis or psoriatic arthritis alone confirmed consistent findings.
• Patients with preexisting hyperlipidemia and diabetes mellitus showed lower risks for MACE and VTE with newer biologics compared with TNF inhibitors. 

IN PRACTICE:

“No significant MACE and VTE risk differences were detected in patients with psoriasis or PsA between those receiving IL-17, IL-12/23, and IL-23 inhibitors and those with TNF inhibitors,” the authors concluded. These findings, they added “can be considered by physicians and patients when making treatment decisions” and also provide “evidence for future pharmacovigilance studies.”

SOURCE:

The study was led by Tai-Li Chen, MD, of the Department of Dermatology, Taipei Veterans General Hospital in Taipei, Taiwan. It was published online on December 27, 2024, in the Journal of the American Academy of Dermatology.

LIMITATIONS:

Study limitations included potential residual confounding factors, lack of information on disease severity, and inclusion of predominantly White individuals.

DISCLOSURES:

The study received support from Taipei Veterans General Hospital and Ministry of Science and Technology, Taiwan. The authors reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The newer biologics — interleukin (IL)–17, IL-12/23, and IL-23 inhibitors — demonstrate comparable cardiovascular safety profiles to tumor necrosis factor (TNF) inhibitors in biologic-naive patients with psoriasis or psoriatic arthritis (PsA).

METHODOLOGY:

• In a retrospective cohort study, researchers conducted an emulated target trial analysis using data of 32,098 biologic-naive patients with psoriasis or PsA who were treated with one of the newer biologics (infliximab, adalimumab, etanercept, certolizumab pegol, secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, and tildrakizumab) from the TriNetX Research Network between 2014 and 2022.
• Patients received TNF inhibitors (n = 20,314), IL-17 inhibitors (n = 5073), IL-12/23 inhibitors (n = 3573), or IL-23 inhibitors (n = 3138).
• A propensity-matched analysis compared each class of newer biologics with TNF inhibitors, adjusting for demographics, comorbidities, and medication use.
• The primary outcomes were major adverse cardiovascular events (MACE; myocardial infarction and stroke) or venous thromboembolic events (VTE).

TAKEAWAY:

• Compared with patients who received TNF inhibitors, the risk for MACE was not significantly different between patients who received IL-17 inhibitors (incidence rate ratio [IRR], 1.14; 95% CI, 0.86-1.52), IL-12/23 inhibitors (IRR, 1.24; 95% CI, 0.84-1.78), or IL-23 inhibitors (IRR, 0.93; 95% CI, 0.61-1.38)
• The VTE risk was also not significantly different between patients who received IL-17 inhibitors (IRR, 1.12; 95% CI, 0.63-2.08), IL-12/23 inhibitors (IRR, 1.51; 95% CI, 0.73-3.19), or IL-23 inhibitors (IRR, 1.42; 95% CI, 0.64-3.25) compared with those who received TNF inhibitors.
• Subgroup analyses for psoriasis or psoriatic arthritis alone confirmed consistent findings.
• Patients with preexisting hyperlipidemia and diabetes mellitus showed lower risks for MACE and VTE with newer biologics compared with TNF inhibitors. 

IN PRACTICE:

“No significant MACE and VTE risk differences were detected in patients with psoriasis or PsA between those receiving IL-17, IL-12/23, and IL-23 inhibitors and those with TNF inhibitors,” the authors concluded. These findings, they added “can be considered by physicians and patients when making treatment decisions” and also provide “evidence for future pharmacovigilance studies.”

SOURCE:

The study was led by Tai-Li Chen, MD, of the Department of Dermatology, Taipei Veterans General Hospital in Taipei, Taiwan. It was published online on December 27, 2024, in the Journal of the American Academy of Dermatology.

LIMITATIONS:

Study limitations included potential residual confounding factors, lack of information on disease severity, and inclusion of predominantly White individuals.

DISCLOSURES:

The study received support from Taipei Veterans General Hospital and Ministry of Science and Technology, Taiwan. The authors reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by uncontrolled hyperglycemia. Over the past few decades, its prevalence has steadily increased, now affecting approximately 10% of adults worldwide and ranking among the top 10 leading causes of death globally.¹ The pathophysiology of T2DM involves persistent hyperglycemia that drives insulin resistance and a progressive decline in insulin production from the pancreas.² Medical management of this condition aims to reduce blood glucose levels or enhance insulin production and sensitivity. Aside from lifestyle modifications, metformin is considered the first-line treatment for glycemic control according to the 2023 American Association of Clinical Endocrinology’s T2DM management algorithm.³ These updated guidelines stratify adjunct treatments by individualized glycemic targets and patient needs. For patients who are overweight or obese, glucagonlike peptide 1 (GLP-1) and dual GLP-1/ gastric inhibitory polypeptide (GIP) agonists are the preferred adjunct or second-line treatments.³

In this review, we highlight the dermatologic adverse effects and potential therapeutic benefits of metformin as well as GLP-1 and GLP-1/GIP agonists.

METFORMIN

Metformin is a biguanide agent used as a first-line treatment for T2DM because of its ability to reduce hepatic glucose production and increase peripheral tissue glucose uptake.⁴ In addition to its effects on glucose, metformin has been shown to have anti-inflammatory properties via inhibition of the nuclear factor κB and mammalian target of rapamycin (mTOR) pathways, leading to decreased production of cytokines associated with T helper (Th) 1 and Th17 cell responses, such as IL-17, interferon gamma (IFN-γ), and tumor necrosis factor α (TNF-α).^5-7 These findings have spurred interest among clinicians in the potential use of metformin for inflammatory conditions, including dermatologic diseases such as psoriasis and hidradenitis suppurativa (HS).⁸

Adverse Effects

Metformin is administered orally and generally is well tolerated. The most common adverse effects include gastrointestinal symptoms such as diarrhea, nausea, vomiting, and abdominal pain.⁹ While cutaneous adverse effects are rare, multiple dermatologic adverse reactions to metformin have been reported,^10,11 including leukocytoclastic vasculitis,^11-13 fixed drug eruptions,^14-17 drug rash with eosinophilia and systemic symptoms (DRESS) syndrome,¹⁸ and photosensitivity reactions.¹⁹ Leukocytoclastic vasculitis and DRESS syndrome typically develop within the first month following metformin initiation, while fixed drug eruption and photosensitivity reactions have more variable timing, occurring weeks to years after treatment initiation.^12-19

Dermatologic Implications

Acanthosis Nigricans—Acanthosis nigricans (AN) is characterized by hyperpigmentation and velvety skin thickening, typically in intertriginous areas such as the back of the neck, axillae, and groin.²⁰ It commonly is associated with insulin resistance and obesity.^21-23 Treatments for AN primarily center around insulin sensitivity and weight loss,^24,25 with some benefit observed from the use of keratolytic agents.^26,27 Metformin may have utility in treating AN through its effects on insulin sensitivity and glycemic control. Multiple case reports have noted marked improvements in AN in patients with and without obesity with the addition of metformin to their existing treatment regimens in doses ranging from 500 mg to 1700 mg daily.^28-30 However, an unblinded randomized controlled trial (RCT) comparing the efficacy of metformin (500 mg 3 times daily) with rosiglitazone (4 mg/d), another T2DM medication, on AN neck lesions in patients who were overweight and obese found no significant effects in lesion severity and only modest improvements in skin texture in both groups at 12 weeks following treatment initiation.³¹ Another RCT comparing metformin (500 mg twice daily) with a twice-daily capsule containing α-lipoic acid, biotin, chromium polynicotinate, and zinc sulfate, showed significant (P<.001) improvements in AN neck lesions in both groups after 12 weeks.³² According to Sung et al,⁸ longer duration of therapy (>6 months), higher doses (1700–2000 mg), and lower baseline weight were associated with higher efficacy of metformin for treatment of AN. Overall, the use of metformin as an adjunct treatment for AN, particularly in patients with underlying hyperglycemia, is supported in the literature, but further studies are needed to clarify dosing, duration of therapy, and patient populations that will benefit most from adding metformin to their treatment regimens.

Hirsutism—Hirsutism, which is characterized by excessive hair growth in androgen-dependent areas, can be challenging to treat. Metformin has been shown to reduce circulating insulin, luteinizing hormone, androstenedione, and testosterone, thus improving underlying hyperandrogenism, particularly in patients with polycystic ovary syndrome (PCOS).^33-35 Although single studies evaluating the efficacy of metformin for treatment of hirsutism in patients with PCOS have shown potential benefits,^36-38 meta-analyses showed no significant effects of metformin compared to placebo or oral contraceptives and decreased benefits compared to spironolactone and flutamide.³⁹ Given these findings showing that metformin was no more effective than placebo or other treatments, the current Endocrine Society guidelines recommend against the use of metformin for hirsutism.^39,40 There may be a role for metformin as an adjuvant therapy in certain populations (eg, patients with comorbid T2DM), although further studies stratifying risk factors such as body mass index and age are needed.⁴¹

Hidradenitis Suppurativa—Hidradenitis suppurativa is a follicular occlusive disease characterized by recurrent inflamed nodules leading to chronic dermal abscesses, fibrosis, and sinus tract formation primarily in intertriginous areas such as the axillae and groin.⁴² Medical management depends on disease severity but usually involves antibiotic treatment with adjunct therapies such as oral contraceptives, antiandrogenic medications (eg, spironolactone), biologic medications, and metformin.⁴² Preclinical and clinical data suggest that metformin can impact HS through metabolic and immunomodulatory mechanisms.^5,42 Like many chronic inflammatory disorders, HS is associated with metabolic syndrome.^43,44 A study evaluating insulin secretion after oral glucose tolerance testing showed increased insulin levels in patients with HS compared to controls (P=.02), with 60% (6/10) of patients with HS meeting criteria for insulin resistance. In addition, serum insulin levels in insulin-resistant patients with HS correlated with increased lesional skin mTOR gene expression at 30 (r=.80) and 60 (r=1.00) minutes, and mTOR was found to be upregulated in lesional and extralesional skin in patients with HS compared to healthy controls (P<.01).45 Insulin activates mTOR signaling, which mediates cell growth and survival, among other processes.⁴⁶ Thus, metformin’s ability to increase insulin sensitivity and inhibit mTOR signaling could be beneficial in the setting of HS. Additionally, insulin and insulinlike growth factor 1 (IGF-1) increase androgen signaling, a process that has been implicated in HS.⁴⁷

Metformin also may impact HS through its effects on testosterone and other hormones.⁴⁸ A study evaluating peripheral blood mononuclear cells in patients with HS showed reduced IL-17, IFN-γ, TNF-α, and IL-6 levels in patients who were taking metformin (dose not reported) for longer than 6 months compared to patients who were not on metformin. Further analysis of ex vivo HS lesions cultured with metformin showed decreased IL-17, IFN-γ, TNF-α, and IL-8 expression in tissue, suggesting an antiinflammatory role of metformin in HS.⁵

Although there are no known RCTs assessing the efficacy of metformin in HS, existing clinical data are supportive of the use of metformin for refractory HS.⁴⁹ Following a case report describing a patient with T2DM and stable HS while on metformin,⁵⁰ several cohort studies have assessed the efficacy of metformin for the treatment of HS. A prospective study evaluating the efficacy of metformin monotherapy (starting dose of 500 mg/d, titrated to 500 mg 3 times daily) in patients with and without T2DM with HS refractory to other therapies found clinical improvement in 72% (18/25) of patients using the Sartorius Hidradenitis Suppurativa Score, improving from a mean (SD) score of 34.40 (12.46) to 26.76 (11.22) at 12 weeks (P=.0055,) and 22.39 (11.30) at 24 weeks (P=.0001). Additionally, 64% (16/25) of patients showed improved quality of life as evaluated by the Dermatology Life Quality Index (DLQI), which decreased from a mean (SD) score of 15.00 (4.96) to 10.08 (5.96)(P=.0017) at 12 weeks and 7.65 (7.12)(P=.000009) at 24 weeks on treatment.⁴⁸ In a retrospective study of 53 patients with HS taking metformin started at 500 mg daily and increased to 500 mg twice daily after 2 weeks (when tolerated), 68% (36/53) showed some clinical response, with 19% (7/36) of those patients having achieved complete response to metformin monotherapy (defined as no active HS).⁵¹ Similarly, a retrospective study of pediatric patients with HS evaluating metformin (doses ranging from 500-2000 mg daily) as an adjunct therapy described a subset of patients with decreased frequency of HS flares with metformin.⁵² These studies emphasize the safety profile of metformin and support its current use as an adjunctive therapy for HS.

Acne Vulgaris—Acne vulgaris (AV) is a chronic inflammatory disorder affecting the pilosebaceous follicles.¹¹ Similar to HS, AV has metabolic and hormonal influences that can be targeted by metformin.⁵³ In AV, androgens lead to increased sebum production by binding to androgen receptors on sebocytes, which in turn attracts Cutibacterium acnes and promotes hyperkeratinization, inducing inflammation.⁵⁴ Thus, the antiandrogenic effects of metformin may be beneficial for treatment of AV. Additionally, sebocytes express receptors for insulin and IGF-1, which can increase the size and number of sebocytes, as well as promote lipogenesis and inflammatory response, influencing sebum production.⁵⁴ Serum levels for IGF-1 have been observed to be increased in patients with AV⁵⁵ and reduced by metformin.⁵⁶ A recent meta-analysis assessing the efficacy of metformin on AV indicated that 87% (13/15) of studies noted disease improvement on metformin, with 47% (7/15) of studies showing statistically significant (P<0.05) decreases in acne severity.57 Although most studies showed improvement, 47% (7/15) did not find significant differences between metformin and other interventions, indicating the availability of comparable treatment options. Overall, there has been a positive association between metformin use and acne improvement.⁵⁷ However, it is important to note that most studies have focused on females with PCOS,⁵⁷ and the main benefits of metformin in acne might be seen when managing comorbid conditions, particularly those associated with metabolic dysregulation and insulin resistance. Further studies are needed to determine the generalizability of prior results.

Psoriasis—Psoriasis is a chronic autoinflammatory disease characterized by epidermal hyperplasia with multiple cutaneous manifestations and potential for multiorgan involvement. Comorbid conditions include psoriatic arthritis, metabolic syndrome, and cardiovascular disease.⁵⁸ Current treatment options depend on several factors (eg, disease severity, location of cutaneous lesions, comorbidities) and include topical, systemic, and phototherapy options, many of which target the immune system.^58,59 A meta-analysis of 3 RCTs showed that metformin (500 mg/d or 1000 mg/d) was associated with significantly improved Psoriasis Area and Severity Index (PASI) 75% reductions (odds ratio [OR], 22.02; 95% CI, 2.12-228.49; P=.01) and 75% reductions in erythema, scaling, and induration (OR, 9.12; 95% CI, 2.13-39.02; P=.003) compared to placebo.⁶⁰ In addition, an RCT evaluating the efficacy of metformin (1000 mg/d) or pioglitazone (30 mg/d) for 12 weeks in patients with psoriasis with metabolic syndrome found significant improvements in PASI75 (P=.001) and erythema, scaling, and induration (P=.016) scores as well as in Physician Global Assessment scores (P=.012) compared to placebo and no differences compared to pioglitazone.⁶¹ While current psoriasis management guidelines do not include metformin, its use may be worth consideration as an adjunct therapy in patients with psoriasis and comorbidities such as T2DM and metabolic syndrome.⁵⁹ Metformin’s potential benefits in psoriasis may lie outside its metabolic influences and occur secondary to its immunomodulatory effects, including targeting of the Th17 axis or cytokine-specific pathways such as TNF-α, which are known to be involved in psoriasis pathogenesis.⁵⁸

Central Centrifugal Cicatricial Alopecia—Central centrifugal cicatricial alopecia (CCCA) is a form of scarring alopecia characterized by chronic inflammation leading to permanent loss of hair follicles on the crown of the scalp.⁶² Current treatments include topical and intralesional corticosteroids, as well as oral antibiotics. In addition, therapies including the antimalarial hydroxychloroquine and immunosuppressants mycophenolate and cyclosporine are used in refractory disease.^63,64 A case report described 2 patients with hair regrowth after 4 and 6 months of treatment with topical metformin 10% compounded in a proprietary transdermal vehicle.⁶⁵ The authors speculated that metformin’s effects on CCCA could be attributed to its known agonistic effects on the adenosine monophosphate-activated protein kinase (AMPK) pathway with subsequent reduction in inflammation-induced fibrosis.^65,66 Microarray⁶⁷ and proteomic⁶⁸ analysis have shown that AMPK is known to be downregulated in CCCA , making it an interesting therapeutic target in this disease. A recent retrospective case series demonstrated that 67% (8/12) of patients with refractory CCCA had symptomatic improvement, and 50% (6/12) showed hair regrowth after 6 months of low-dose (500 mg/d) oral metformin treatment.⁶² In addition, metformin therapy showed antifibrotic and anti-inflammatory effects when comparing scalp biopsies before and after treatment. Results showed decreased expression of fibrosisrelated genes (matrix metalloproteinase 7, collagen type IV á 1 chain), and gene set variation analysis showing reduced Th17 (P=.04) and increased AMPK signaling (P=.02) gene set expression.⁶² These findings are consistent with previous studies describing the upregulation of AMPK66 and downregulation of Th176 following metformin treatment. The immunomodulatory effects of metformin could be attributed to AMPK-mediated mTOR and NF-κB downregulation,⁶² although more studies are needed to understand these mechanisms and further explore the use of metformin in CCCA.

Skin Cancer—Metformin also has been evaluated in the setting of skin malignancies, including melanoma, squamous cell carcinoma, and basal cell carcinoma. Preclinical data suggest that metformin decreases cell viability in tumors through interactions with pathways involved in proinflammatory and prosurvival mechanisms such as NF-κB and mTOR.^69,70 Additionally, given metformin’s inhibitory effects on oxidative phosphorylation, it has been postulated that it could be used to overcome treatment resistance driven by metabolic reprogramming.^71,72 Most studies related to metformin and skin malignancies are still in preclinical stages; however, a meta-analysis of RCTs and cohort studies did not find significant associations between metformin use and skin cancer risk, although data trended toward a modest reduction in skin cancer among metformin users.⁷³ A retrospective cohort study of melanoma in patients with T2DM taking metformin (250-2000 mg/d) found that the 5-year incidence of recurrence was lower in the metformin cohort compared to nonusers (43.8% vs 58.2%, respectively)(P=.002), and overall survival rates trended upward in the higher body mass index (>30) and melanoma stages 1 and 2 groups but did not reach statistical significance.⁷⁴ In addition, a whole population casecontrol study in Iceland reported that metformin use at least 2 years before first-time basal cell carcinoma diagnosis was associated with a lower risk for disease (adjusted OR, 0.71; 95% CI, 0.61-0.83) with no significant dose-dependent differences; there were no notable effects on squamous cell carcinoma risk.⁷⁵ Further preclinical and clinical data are needed to elucidate metformin’s effects on skin malignancies.

GLP-1 AND DUAL GLP-1/GIP AGONISTS

Glucagonlike peptide 1 and dual GLP-1/GIP agonists are emerging classes of medications currently approved as adjunct and second-line therapies for T2DM, particularly in patients who are overweight or obese as well as in those who are at risk for hypoglycemia.³ Currently approved GLP-1 agonists for T2DM include semaglutide, dulaglutide, exenatide, liraglutide, and lixisenatide, while tirzepatide is the only approved dual GLP-1/GIP agonist. Activating GLP-1 and GIP receptors stimulates insulin secretion and decreases glucagon production by the pancreas, thereby reducing blood glucose levels. Additionally, some of these medications are approved for obesity given their effects in delayed gastric emptying and increased satiety, among other factors.

Over the past few years, multiple case reports have described the associations between GLP-1 agonist use and improvement of dermatologic conditions, particularly those associated with T2DM and obesity, including HS and psoriasis.^76,77 The mechanisms through which this occurs are not fully elucidated, although basic science and clinical studies have shown that GLP-1 agonists have immunomodulatory effects by reducing proinflammatory cytokines and altering immune cell populations.^77-80 The numerous ongoing clinical trials and research studies will help further elucidate their benefits in other disease settings.⁸¹

Adverse Reactions

Most GLP-1 and GLP-1/GIP agonists are administered subcutaneously, and the most commonly reported cutaneous adverse effects are injection site reactions.⁸² Anaphylactic reactions to these medications also have been reported, although it is unclear if these were specific to the active ingredients or to injection excipients.^83,84 A review of 33 cases of cutaneous reactions to GLP-1 agonists reported 11 (33%) dermal hypersensitivity reactions occurring as early as 4 weeks and as late as 3 years after treatment initiation. It also described 10 (30%) cases of eosinophilic panniculitis that developed within 3 weeks to 5 months of GLP-1 treatment, 3 (9%) cases of bullous pemphigoid that occurred within the first 2 months, 2 (6%) morbilliform drug eruptions that occurred within 5 weeks, 2 (6%) cases of angioedema that occurred 15 minutes to 2 weeks after treatment initiation, and 7 (21%) other isolated cutaneous reactions. Extended-release exenatide had the most reported reactions followed by liraglutide and subcutaneous semaglutide.⁸⁵

In a different study, semaglutide use was most commonly associated with injection site reactions followed by alopecia, especially with oral administration. Unique cases of angioedema (2 days after injection), cutaneous hypersensitivity (within 10 months on treatment), bullous pemphigoid (within 2 months on treatment), eosinophilic fasciitis (within 2 weeks on treatment), and leukocytoclastic vasculitis (unclear timing), most of which resolved after discontinuation, also were reported.⁸⁶ A recent case report linked semaglutide (0.5 mg/wk) to a case of drug-induced systemic lupus erythematosus that developed within 3 months of treatment initiation and described systemic lupus erythematosus–like symptoms in a subset of patients using this medication, namely females older than 60 years, within the first month of treatment.⁸⁷ Hyperhidrosis was listed as a common adverse event in exenatide clinical trials, and various cases of panniculitis with exenatide use have been reported.^82,88 Alopecia, mainly attributed to accelerated telogen effluvium secondary to rapid weight loss, also has been reported, although hair loss is not officially listed as an adverse effect of GLP-1 agonists, and reports are highly variable.⁸⁹ Also secondary to weight loss, facial changes including sunken eyes, development of wrinkles, sagging jowls around the neck and jaw, and a hollowed appearance, among others, are recognized as undesirable adverse effects.⁹⁰ Mansour et al⁹⁰ described the potential challenges and considerations to these rising concerns associated with GLP1-agonist use.

Dermatologic Implications

Hidradenitis Suppurativa—Weight loss commonly is recommended as a lifestyle modification in the management of HS. Multiple reports have described clinical improvement of HS following weight loss with other medical interventions, such as dietary measures and bariatric surgery.^91-94 Thus, it has been postulated that medically supported weight loss with GLP-1 agonists can help improve HS⁹⁵; however, the data on the effectiveness of GLP-1 agonists on HS are still scarce and mostly have been reported in individual patients. One case report described a patient with improvements in their recalcitrant HS and DLQI score following weight loss on liraglutide (initial dose of 0.6 mg/d, titrated to 1.8 mg/d).⁷⁶ In addition, a recent case report described improvements in HS and DLQI score following concomitant tirzepatide (initial dose of 2.5 mg/0.5 mL weekly, titrated to 7.5 mg/0.5 mL weekly) and infliximab treatment.⁹⁶ The off-label use of these medications for HS is debated, and further studies regarding the benefits of GLP-1 agonists on HS still are needed.

Psoriasis—Similarly, several case reports have commented on the effects of GLP-1 agonists on psoriasis.^97,98 An early study found GLP-1 receptors were expressed in psoriasis plaques but not in healthy skin and discussed that this could be due to immune infiltration in the plaques, providing a potential rationale for using anti-inflammatory GLP-1 agonists for psoriasis.⁹⁹ Two prospective cohort studies observed improvements in PASI and DLQI scores in patients with psoriasis and T2DM after liraglutide treatment and noted important changes in immune cell populations.^80,100 A recent RCT also found improvements in DLQI and PASI scores (P<.05) in patients with T2DM following liraglutide (1.8 mg/d) treatment, along with overall decreases in inflammatory cytokines, such as IL-23, IL-17, and TNF-α.⁷⁷ However, another RCT in patients with obesity did not observe significant improvements in PASI and DLQI scores compared to placebo after 8 weeks of liraglutide (initial dose of 0.6 mg/d, titrated to 1.8 mg/d) treatment. ⁹⁹ Although these results could have been influenced by the short length of treatment compared to other studies, which observed participants for more than 10 weeks, they highlight the need for tailored studies considering the different comorbidities to identify patients who could benefit the most from these therapies.

Alopecia—Although some studies have reported increased rates of alopecia following GLP-1 agonist treatment, others have speculated about the potential role of these medications in treating hair loss through improved insulin sensitivity and scalp blood flow.^86,89 For example, a case report described a patient with improvement in androgenetic alopecia within 6 months of tirzepatide monotherapy at 2.5 mg weekly for the first 3 months followed by an increased dose of 5 mg weekly.¹⁰¹ The authors described the role of insulin in increasing dihydrotestosterone levels, which leads to miniaturization of the dermal papilla of hair follicles and argued that improvement of insulin resistance could benefit hair loss. Further studies can help elucidate the role of these medications on alopecia.

FINAL THOUGHTS

Standard T2DM treatments including metformin and GLP-1 and GLP-1/GIP agonists exhibit metabolic, immunologic, and hormonal effects that should be explored in other disease contexts. We reviewed the current data on T2DM medications in dermatologic conditions to highlight the need for additional studies to better understand the role that these medications play across diverse patient populations. Type 2 diabetes mellitus is a common comorbidity in dermatology patients, and understanding the multifactorial effects of these medications can help optimize treatment strategies, especially in patients with coexisting dermatologic and metabolic diseases.

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by uncontrolled hyperglycemia. Over the past few decades, its prevalence has steadily increased, now affecting approximately 10% of adults worldwide and ranking among the top 10 leading causes of death globally.¹ The pathophysiology of T2DM involves persistent hyperglycemia that drives insulin resistance and a progressive decline in insulin production from the pancreas.² Medical management of this condition aims to reduce blood glucose levels or enhance insulin production and sensitivity. Aside from lifestyle modifications, metformin is considered the first-line treatment for glycemic control according to the 2023 American Association of Clinical Endocrinology’s T2DM management algorithm.³ These updated guidelines stratify adjunct treatments by individualized glycemic targets and patient needs. For patients who are overweight or obese, glucagonlike peptide 1 (GLP-1) and dual GLP-1/ gastric inhibitory polypeptide (GIP) agonists are the preferred adjunct or second-line treatments.³

In this review, we highlight the dermatologic adverse effects and potential therapeutic benefits of metformin as well as GLP-1 and GLP-1/GIP agonists.

METFORMIN

Metformin is a biguanide agent used as a first-line treatment for T2DM because of its ability to reduce hepatic glucose production and increase peripheral tissue glucose uptake.⁴ In addition to its effects on glucose, metformin has been shown to have anti-inflammatory properties via inhibition of the nuclear factor κB and mammalian target of rapamycin (mTOR) pathways, leading to decreased production of cytokines associated with T helper (Th) 1 and Th17 cell responses, such as IL-17, interferon gamma (IFN-γ), and tumor necrosis factor α (TNF-α).^5-7 These findings have spurred interest among clinicians in the potential use of metformin for inflammatory conditions, including dermatologic diseases such as psoriasis and hidradenitis suppurativa (HS).⁸

Adverse Effects

Metformin is administered orally and generally is well tolerated. The most common adverse effects include gastrointestinal symptoms such as diarrhea, nausea, vomiting, and abdominal pain.⁹ While cutaneous adverse effects are rare, multiple dermatologic adverse reactions to metformin have been reported,^10,11 including leukocytoclastic vasculitis,^11-13 fixed drug eruptions,^14-17 drug rash with eosinophilia and systemic symptoms (DRESS) syndrome,¹⁸ and photosensitivity reactions.¹⁹ Leukocytoclastic vasculitis and DRESS syndrome typically develop within the first month following metformin initiation, while fixed drug eruption and photosensitivity reactions have more variable timing, occurring weeks to years after treatment initiation.^12-19

Dermatologic Implications

Acanthosis Nigricans—Acanthosis nigricans (AN) is characterized by hyperpigmentation and velvety skin thickening, typically in intertriginous areas such as the back of the neck, axillae, and groin.²⁰ It commonly is associated with insulin resistance and obesity.^21-23 Treatments for AN primarily center around insulin sensitivity and weight loss,^24,25 with some benefit observed from the use of keratolytic agents.^26,27 Metformin may have utility in treating AN through its effects on insulin sensitivity and glycemic control. Multiple case reports have noted marked improvements in AN in patients with and without obesity with the addition of metformin to their existing treatment regimens in doses ranging from 500 mg to 1700 mg daily.^28-30 However, an unblinded randomized controlled trial (RCT) comparing the efficacy of metformin (500 mg 3 times daily) with rosiglitazone (4 mg/d), another T2DM medication, on AN neck lesions in patients who were overweight and obese found no significant effects in lesion severity and only modest improvements in skin texture in both groups at 12 weeks following treatment initiation.³¹ Another RCT comparing metformin (500 mg twice daily) with a twice-daily capsule containing α-lipoic acid, biotin, chromium polynicotinate, and zinc sulfate, showed significant (P<.001) improvements in AN neck lesions in both groups after 12 weeks.³² According to Sung et al,⁸ longer duration of therapy (>6 months), higher doses (1700–2000 mg), and lower baseline weight were associated with higher efficacy of metformin for treatment of AN. Overall, the use of metformin as an adjunct treatment for AN, particularly in patients with underlying hyperglycemia, is supported in the literature, but further studies are needed to clarify dosing, duration of therapy, and patient populations that will benefit most from adding metformin to their treatment regimens.

Hirsutism—Hirsutism, which is characterized by excessive hair growth in androgen-dependent areas, can be challenging to treat. Metformin has been shown to reduce circulating insulin, luteinizing hormone, androstenedione, and testosterone, thus improving underlying hyperandrogenism, particularly in patients with polycystic ovary syndrome (PCOS).^33-35 Although single studies evaluating the efficacy of metformin for treatment of hirsutism in patients with PCOS have shown potential benefits,^36-38 meta-analyses showed no significant effects of metformin compared to placebo or oral contraceptives and decreased benefits compared to spironolactone and flutamide.³⁹ Given these findings showing that metformin was no more effective than placebo or other treatments, the current Endocrine Society guidelines recommend against the use of metformin for hirsutism.^39,40 There may be a role for metformin as an adjuvant therapy in certain populations (eg, patients with comorbid T2DM), although further studies stratifying risk factors such as body mass index and age are needed.⁴¹

Hidradenitis Suppurativa—Hidradenitis suppurativa is a follicular occlusive disease characterized by recurrent inflamed nodules leading to chronic dermal abscesses, fibrosis, and sinus tract formation primarily in intertriginous areas such as the axillae and groin.⁴² Medical management depends on disease severity but usually involves antibiotic treatment with adjunct therapies such as oral contraceptives, antiandrogenic medications (eg, spironolactone), biologic medications, and metformin.⁴² Preclinical and clinical data suggest that metformin can impact HS through metabolic and immunomodulatory mechanisms.^5,42 Like many chronic inflammatory disorders, HS is associated with metabolic syndrome.^43,44 A study evaluating insulin secretion after oral glucose tolerance testing showed increased insulin levels in patients with HS compared to controls (P=.02), with 60% (6/10) of patients with HS meeting criteria for insulin resistance. In addition, serum insulin levels in insulin-resistant patients with HS correlated with increased lesional skin mTOR gene expression at 30 (r=.80) and 60 (r=1.00) minutes, and mTOR was found to be upregulated in lesional and extralesional skin in patients with HS compared to healthy controls (P<.01).45 Insulin activates mTOR signaling, which mediates cell growth and survival, among other processes.⁴⁶ Thus, metformin’s ability to increase insulin sensitivity and inhibit mTOR signaling could be beneficial in the setting of HS. Additionally, insulin and insulinlike growth factor 1 (IGF-1) increase androgen signaling, a process that has been implicated in HS.⁴⁷

Metformin also may impact HS through its effects on testosterone and other hormones.⁴⁸ A study evaluating peripheral blood mononuclear cells in patients with HS showed reduced IL-17, IFN-γ, TNF-α, and IL-6 levels in patients who were taking metformin (dose not reported) for longer than 6 months compared to patients who were not on metformin. Further analysis of ex vivo HS lesions cultured with metformin showed decreased IL-17, IFN-γ, TNF-α, and IL-8 expression in tissue, suggesting an antiinflammatory role of metformin in HS.⁵

Although there are no known RCTs assessing the efficacy of metformin in HS, existing clinical data are supportive of the use of metformin for refractory HS.⁴⁹ Following a case report describing a patient with T2DM and stable HS while on metformin,⁵⁰ several cohort studies have assessed the efficacy of metformin for the treatment of HS. A prospective study evaluating the efficacy of metformin monotherapy (starting dose of 500 mg/d, titrated to 500 mg 3 times daily) in patients with and without T2DM with HS refractory to other therapies found clinical improvement in 72% (18/25) of patients using the Sartorius Hidradenitis Suppurativa Score, improving from a mean (SD) score of 34.40 (12.46) to 26.76 (11.22) at 12 weeks (P=.0055,) and 22.39 (11.30) at 24 weeks (P=.0001). Additionally, 64% (16/25) of patients showed improved quality of life as evaluated by the Dermatology Life Quality Index (DLQI), which decreased from a mean (SD) score of 15.00 (4.96) to 10.08 (5.96)(P=.0017) at 12 weeks and 7.65 (7.12)(P=.000009) at 24 weeks on treatment.⁴⁸ In a retrospective study of 53 patients with HS taking metformin started at 500 mg daily and increased to 500 mg twice daily after 2 weeks (when tolerated), 68% (36/53) showed some clinical response, with 19% (7/36) of those patients having achieved complete response to metformin monotherapy (defined as no active HS).⁵¹ Similarly, a retrospective study of pediatric patients with HS evaluating metformin (doses ranging from 500-2000 mg daily) as an adjunct therapy described a subset of patients with decreased frequency of HS flares with metformin.⁵² These studies emphasize the safety profile of metformin and support its current use as an adjunctive therapy for HS.

Acne Vulgaris—Acne vulgaris (AV) is a chronic inflammatory disorder affecting the pilosebaceous follicles.¹¹ Similar to HS, AV has metabolic and hormonal influences that can be targeted by metformin.⁵³ In AV, androgens lead to increased sebum production by binding to androgen receptors on sebocytes, which in turn attracts Cutibacterium acnes and promotes hyperkeratinization, inducing inflammation.⁵⁴ Thus, the antiandrogenic effects of metformin may be beneficial for treatment of AV. Additionally, sebocytes express receptors for insulin and IGF-1, which can increase the size and number of sebocytes, as well as promote lipogenesis and inflammatory response, influencing sebum production.⁵⁴ Serum levels for IGF-1 have been observed to be increased in patients with AV⁵⁵ and reduced by metformin.⁵⁶ A recent meta-analysis assessing the efficacy of metformin on AV indicated that 87% (13/15) of studies noted disease improvement on metformin, with 47% (7/15) of studies showing statistically significant (P<0.05) decreases in acne severity.57 Although most studies showed improvement, 47% (7/15) did not find significant differences between metformin and other interventions, indicating the availability of comparable treatment options. Overall, there has been a positive association between metformin use and acne improvement.⁵⁷ However, it is important to note that most studies have focused on females with PCOS,⁵⁷ and the main benefits of metformin in acne might be seen when managing comorbid conditions, particularly those associated with metabolic dysregulation and insulin resistance. Further studies are needed to determine the generalizability of prior results.

Psoriasis—Psoriasis is a chronic autoinflammatory disease characterized by epidermal hyperplasia with multiple cutaneous manifestations and potential for multiorgan involvement. Comorbid conditions include psoriatic arthritis, metabolic syndrome, and cardiovascular disease.⁵⁸ Current treatment options depend on several factors (eg, disease severity, location of cutaneous lesions, comorbidities) and include topical, systemic, and phototherapy options, many of which target the immune system.^58,59 A meta-analysis of 3 RCTs showed that metformin (500 mg/d or 1000 mg/d) was associated with significantly improved Psoriasis Area and Severity Index (PASI) 75% reductions (odds ratio [OR], 22.02; 95% CI, 2.12-228.49; P=.01) and 75% reductions in erythema, scaling, and induration (OR, 9.12; 95% CI, 2.13-39.02; P=.003) compared to placebo.⁶⁰ In addition, an RCT evaluating the efficacy of metformin (1000 mg/d) or pioglitazone (30 mg/d) for 12 weeks in patients with psoriasis with metabolic syndrome found significant improvements in PASI75 (P=.001) and erythema, scaling, and induration (P=.016) scores as well as in Physician Global Assessment scores (P=.012) compared to placebo and no differences compared to pioglitazone.⁶¹ While current psoriasis management guidelines do not include metformin, its use may be worth consideration as an adjunct therapy in patients with psoriasis and comorbidities such as T2DM and metabolic syndrome.⁵⁹ Metformin’s potential benefits in psoriasis may lie outside its metabolic influences and occur secondary to its immunomodulatory effects, including targeting of the Th17 axis or cytokine-specific pathways such as TNF-α, which are known to be involved in psoriasis pathogenesis.⁵⁸

Central Centrifugal Cicatricial Alopecia—Central centrifugal cicatricial alopecia (CCCA) is a form of scarring alopecia characterized by chronic inflammation leading to permanent loss of hair follicles on the crown of the scalp.⁶² Current treatments include topical and intralesional corticosteroids, as well as oral antibiotics. In addition, therapies including the antimalarial hydroxychloroquine and immunosuppressants mycophenolate and cyclosporine are used in refractory disease.^63,64 A case report described 2 patients with hair regrowth after 4 and 6 months of treatment with topical metformin 10% compounded in a proprietary transdermal vehicle.⁶⁵ The authors speculated that metformin’s effects on CCCA could be attributed to its known agonistic effects on the adenosine monophosphate-activated protein kinase (AMPK) pathway with subsequent reduction in inflammation-induced fibrosis.^65,66 Microarray⁶⁷ and proteomic⁶⁸ analysis have shown that AMPK is known to be downregulated in CCCA , making it an interesting therapeutic target in this disease. A recent retrospective case series demonstrated that 67% (8/12) of patients with refractory CCCA had symptomatic improvement, and 50% (6/12) showed hair regrowth after 6 months of low-dose (500 mg/d) oral metformin treatment.⁶² In addition, metformin therapy showed antifibrotic and anti-inflammatory effects when comparing scalp biopsies before and after treatment. Results showed decreased expression of fibrosisrelated genes (matrix metalloproteinase 7, collagen type IV á 1 chain), and gene set variation analysis showing reduced Th17 (P=.04) and increased AMPK signaling (P=.02) gene set expression.⁶² These findings are consistent with previous studies describing the upregulation of AMPK66 and downregulation of Th176 following metformin treatment. The immunomodulatory effects of metformin could be attributed to AMPK-mediated mTOR and NF-κB downregulation,⁶² although more studies are needed to understand these mechanisms and further explore the use of metformin in CCCA.

Skin Cancer—Metformin also has been evaluated in the setting of skin malignancies, including melanoma, squamous cell carcinoma, and basal cell carcinoma. Preclinical data suggest that metformin decreases cell viability in tumors through interactions with pathways involved in proinflammatory and prosurvival mechanisms such as NF-κB and mTOR.^69,70 Additionally, given metformin’s inhibitory effects on oxidative phosphorylation, it has been postulated that it could be used to overcome treatment resistance driven by metabolic reprogramming.^71,72 Most studies related to metformin and skin malignancies are still in preclinical stages; however, a meta-analysis of RCTs and cohort studies did not find significant associations between metformin use and skin cancer risk, although data trended toward a modest reduction in skin cancer among metformin users.⁷³ A retrospective cohort study of melanoma in patients with T2DM taking metformin (250-2000 mg/d) found that the 5-year incidence of recurrence was lower in the metformin cohort compared to nonusers (43.8% vs 58.2%, respectively)(P=.002), and overall survival rates trended upward in the higher body mass index (>30) and melanoma stages 1 and 2 groups but did not reach statistical significance.⁷⁴ In addition, a whole population casecontrol study in Iceland reported that metformin use at least 2 years before first-time basal cell carcinoma diagnosis was associated with a lower risk for disease (adjusted OR, 0.71; 95% CI, 0.61-0.83) with no significant dose-dependent differences; there were no notable effects on squamous cell carcinoma risk.⁷⁵ Further preclinical and clinical data are needed to elucidate metformin’s effects on skin malignancies.

GLP-1 AND DUAL GLP-1/GIP AGONISTS

Glucagonlike peptide 1 and dual GLP-1/GIP agonists are emerging classes of medications currently approved as adjunct and second-line therapies for T2DM, particularly in patients who are overweight or obese as well as in those who are at risk for hypoglycemia.³ Currently approved GLP-1 agonists for T2DM include semaglutide, dulaglutide, exenatide, liraglutide, and lixisenatide, while tirzepatide is the only approved dual GLP-1/GIP agonist. Activating GLP-1 and GIP receptors stimulates insulin secretion and decreases glucagon production by the pancreas, thereby reducing blood glucose levels. Additionally, some of these medications are approved for obesity given their effects in delayed gastric emptying and increased satiety, among other factors.

Over the past few years, multiple case reports have described the associations between GLP-1 agonist use and improvement of dermatologic conditions, particularly those associated with T2DM and obesity, including HS and psoriasis.^76,77 The mechanisms through which this occurs are not fully elucidated, although basic science and clinical studies have shown that GLP-1 agonists have immunomodulatory effects by reducing proinflammatory cytokines and altering immune cell populations.^77-80 The numerous ongoing clinical trials and research studies will help further elucidate their benefits in other disease settings.⁸¹

Adverse Reactions

Most GLP-1 and GLP-1/GIP agonists are administered subcutaneously, and the most commonly reported cutaneous adverse effects are injection site reactions.⁸² Anaphylactic reactions to these medications also have been reported, although it is unclear if these were specific to the active ingredients or to injection excipients.^83,84 A review of 33 cases of cutaneous reactions to GLP-1 agonists reported 11 (33%) dermal hypersensitivity reactions occurring as early as 4 weeks and as late as 3 years after treatment initiation. It also described 10 (30%) cases of eosinophilic panniculitis that developed within 3 weeks to 5 months of GLP-1 treatment, 3 (9%) cases of bullous pemphigoid that occurred within the first 2 months, 2 (6%) morbilliform drug eruptions that occurred within 5 weeks, 2 (6%) cases of angioedema that occurred 15 minutes to 2 weeks after treatment initiation, and 7 (21%) other isolated cutaneous reactions. Extended-release exenatide had the most reported reactions followed by liraglutide and subcutaneous semaglutide.⁸⁵

In a different study, semaglutide use was most commonly associated with injection site reactions followed by alopecia, especially with oral administration. Unique cases of angioedema (2 days after injection), cutaneous hypersensitivity (within 10 months on treatment), bullous pemphigoid (within 2 months on treatment), eosinophilic fasciitis (within 2 weeks on treatment), and leukocytoclastic vasculitis (unclear timing), most of which resolved after discontinuation, also were reported.⁸⁶ A recent case report linked semaglutide (0.5 mg/wk) to a case of drug-induced systemic lupus erythematosus that developed within 3 months of treatment initiation and described systemic lupus erythematosus–like symptoms in a subset of patients using this medication, namely females older than 60 years, within the first month of treatment.⁸⁷ Hyperhidrosis was listed as a common adverse event in exenatide clinical trials, and various cases of panniculitis with exenatide use have been reported.^82,88 Alopecia, mainly attributed to accelerated telogen effluvium secondary to rapid weight loss, also has been reported, although hair loss is not officially listed as an adverse effect of GLP-1 agonists, and reports are highly variable.⁸⁹ Also secondary to weight loss, facial changes including sunken eyes, development of wrinkles, sagging jowls around the neck and jaw, and a hollowed appearance, among others, are recognized as undesirable adverse effects.⁹⁰ Mansour et al⁹⁰ described the potential challenges and considerations to these rising concerns associated with GLP1-agonist use.

Dermatologic Implications

Hidradenitis Suppurativa—Weight loss commonly is recommended as a lifestyle modification in the management of HS. Multiple reports have described clinical improvement of HS following weight loss with other medical interventions, such as dietary measures and bariatric surgery.^91-94 Thus, it has been postulated that medically supported weight loss with GLP-1 agonists can help improve HS⁹⁵; however, the data on the effectiveness of GLP-1 agonists on HS are still scarce and mostly have been reported in individual patients. One case report described a patient with improvements in their recalcitrant HS and DLQI score following weight loss on liraglutide (initial dose of 0.6 mg/d, titrated to 1.8 mg/d).⁷⁶ In addition, a recent case report described improvements in HS and DLQI score following concomitant tirzepatide (initial dose of 2.5 mg/0.5 mL weekly, titrated to 7.5 mg/0.5 mL weekly) and infliximab treatment.⁹⁶ The off-label use of these medications for HS is debated, and further studies regarding the benefits of GLP-1 agonists on HS still are needed.

Psoriasis—Similarly, several case reports have commented on the effects of GLP-1 agonists on psoriasis.^97,98 An early study found GLP-1 receptors were expressed in psoriasis plaques but not in healthy skin and discussed that this could be due to immune infiltration in the plaques, providing a potential rationale for using anti-inflammatory GLP-1 agonists for psoriasis.⁹⁹ Two prospective cohort studies observed improvements in PASI and DLQI scores in patients with psoriasis and T2DM after liraglutide treatment and noted important changes in immune cell populations.^80,100 A recent RCT also found improvements in DLQI and PASI scores (P<.05) in patients with T2DM following liraglutide (1.8 mg/d) treatment, along with overall decreases in inflammatory cytokines, such as IL-23, IL-17, and TNF-α.⁷⁷ However, another RCT in patients with obesity did not observe significant improvements in PASI and DLQI scores compared to placebo after 8 weeks of liraglutide (initial dose of 0.6 mg/d, titrated to 1.8 mg/d) treatment. ⁹⁹ Although these results could have been influenced by the short length of treatment compared to other studies, which observed participants for more than 10 weeks, they highlight the need for tailored studies considering the different comorbidities to identify patients who could benefit the most from these therapies.

Alopecia—Although some studies have reported increased rates of alopecia following GLP-1 agonist treatment, others have speculated about the potential role of these medications in treating hair loss through improved insulin sensitivity and scalp blood flow.^86,89 For example, a case report described a patient with improvement in androgenetic alopecia within 6 months of tirzepatide monotherapy at 2.5 mg weekly for the first 3 months followed by an increased dose of 5 mg weekly.¹⁰¹ The authors described the role of insulin in increasing dihydrotestosterone levels, which leads to miniaturization of the dermal papilla of hair follicles and argued that improvement of insulin resistance could benefit hair loss. Further studies can help elucidate the role of these medications on alopecia.

FINAL THOUGHTS

Standard T2DM treatments including metformin and GLP-1 and GLP-1/GIP agonists exhibit metabolic, immunologic, and hormonal effects that should be explored in other disease contexts. We reviewed the current data on T2DM medications in dermatologic conditions to highlight the need for additional studies to better understand the role that these medications play across diverse patient populations. Type 2 diabetes mellitus is a common comorbidity in dermatology patients, and understanding the multifactorial effects of these medications can help optimize treatment strategies, especially in patients with coexisting dermatologic and metabolic diseases.

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by uncontrolled hyperglycemia. Over the past few decades, its prevalence has steadily increased, now affecting approximately 10% of adults worldwide and ranking among the top 10 leading causes of death globally.¹ The pathophysiology of T2DM involves persistent hyperglycemia that drives insulin resistance and a progressive decline in insulin production from the pancreas.² Medical management of this condition aims to reduce blood glucose levels or enhance insulin production and sensitivity. Aside from lifestyle modifications, metformin is considered the first-line treatment for glycemic control according to the 2023 American Association of Clinical Endocrinology’s T2DM management algorithm.³ These updated guidelines stratify adjunct treatments by individualized glycemic targets and patient needs. For patients who are overweight or obese, glucagonlike peptide 1 (GLP-1) and dual GLP-1/ gastric inhibitory polypeptide (GIP) agonists are the preferred adjunct or second-line treatments.³

In this review, we highlight the dermatologic adverse effects and potential therapeutic benefits of metformin as well as GLP-1 and GLP-1/GIP agonists.

METFORMIN

Metformin is a biguanide agent used as a first-line treatment for T2DM because of its ability to reduce hepatic glucose production and increase peripheral tissue glucose uptake.⁴ In addition to its effects on glucose, metformin has been shown to have anti-inflammatory properties via inhibition of the nuclear factor κB and mammalian target of rapamycin (mTOR) pathways, leading to decreased production of cytokines associated with T helper (Th) 1 and Th17 cell responses, such as IL-17, interferon gamma (IFN-γ), and tumor necrosis factor α (TNF-α).^5-7 These findings have spurred interest among clinicians in the potential use of metformin for inflammatory conditions, including dermatologic diseases such as psoriasis and hidradenitis suppurativa (HS).⁸

Adverse Effects

Metformin is administered orally and generally is well tolerated. The most common adverse effects include gastrointestinal symptoms such as diarrhea, nausea, vomiting, and abdominal pain.⁹ While cutaneous adverse effects are rare, multiple dermatologic adverse reactions to metformin have been reported,^10,11 including leukocytoclastic vasculitis,^11-13 fixed drug eruptions,^14-17 drug rash with eosinophilia and systemic symptoms (DRESS) syndrome,¹⁸ and photosensitivity reactions.¹⁹ Leukocytoclastic vasculitis and DRESS syndrome typically develop within the first month following metformin initiation, while fixed drug eruption and photosensitivity reactions have more variable timing, occurring weeks to years after treatment initiation.^12-19

Dermatologic Implications

Acanthosis Nigricans—Acanthosis nigricans (AN) is characterized by hyperpigmentation and velvety skin thickening, typically in intertriginous areas such as the back of the neck, axillae, and groin.²⁰ It commonly is associated with insulin resistance and obesity.^21-23 Treatments for AN primarily center around insulin sensitivity and weight loss,^24,25 with some benefit observed from the use of keratolytic agents.^26,27 Metformin may have utility in treating AN through its effects on insulin sensitivity and glycemic control. Multiple case reports have noted marked improvements in AN in patients with and without obesity with the addition of metformin to their existing treatment regimens in doses ranging from 500 mg to 1700 mg daily.^28-30 However, an unblinded randomized controlled trial (RCT) comparing the efficacy of metformin (500 mg 3 times daily) with rosiglitazone (4 mg/d), another T2DM medication, on AN neck lesions in patients who were overweight and obese found no significant effects in lesion severity and only modest improvements in skin texture in both groups at 12 weeks following treatment initiation.³¹ Another RCT comparing metformin (500 mg twice daily) with a twice-daily capsule containing α-lipoic acid, biotin, chromium polynicotinate, and zinc sulfate, showed significant (P<.001) improvements in AN neck lesions in both groups after 12 weeks.³² According to Sung et al,⁸ longer duration of therapy (>6 months), higher doses (1700–2000 mg), and lower baseline weight were associated with higher efficacy of metformin for treatment of AN. Overall, the use of metformin as an adjunct treatment for AN, particularly in patients with underlying hyperglycemia, is supported in the literature, but further studies are needed to clarify dosing, duration of therapy, and patient populations that will benefit most from adding metformin to their treatment regimens.

Hirsutism—Hirsutism, which is characterized by excessive hair growth in androgen-dependent areas, can be challenging to treat. Metformin has been shown to reduce circulating insulin, luteinizing hormone, androstenedione, and testosterone, thus improving underlying hyperandrogenism, particularly in patients with polycystic ovary syndrome (PCOS).^33-35 Although single studies evaluating the efficacy of metformin for treatment of hirsutism in patients with PCOS have shown potential benefits,^36-38 meta-analyses showed no significant effects of metformin compared to placebo or oral contraceptives and decreased benefits compared to spironolactone and flutamide.³⁹ Given these findings showing that metformin was no more effective than placebo or other treatments, the current Endocrine Society guidelines recommend against the use of metformin for hirsutism.^39,40 There may be a role for metformin as an adjuvant therapy in certain populations (eg, patients with comorbid T2DM), although further studies stratifying risk factors such as body mass index and age are needed.⁴¹

Hidradenitis Suppurativa—Hidradenitis suppurativa is a follicular occlusive disease characterized by recurrent inflamed nodules leading to chronic dermal abscesses, fibrosis, and sinus tract formation primarily in intertriginous areas such as the axillae and groin.⁴² Medical management depends on disease severity but usually involves antibiotic treatment with adjunct therapies such as oral contraceptives, antiandrogenic medications (eg, spironolactone), biologic medications, and metformin.⁴² Preclinical and clinical data suggest that metformin can impact HS through metabolic and immunomodulatory mechanisms.^5,42 Like many chronic inflammatory disorders, HS is associated with metabolic syndrome.^43,44 A study evaluating insulin secretion after oral glucose tolerance testing showed increased insulin levels in patients with HS compared to controls (P=.02), with 60% (6/10) of patients with HS meeting criteria for insulin resistance. In addition, serum insulin levels in insulin-resistant patients with HS correlated with increased lesional skin mTOR gene expression at 30 (r=.80) and 60 (r=1.00) minutes, and mTOR was found to be upregulated in lesional and extralesional skin in patients with HS compared to healthy controls (P<.01).45 Insulin activates mTOR signaling, which mediates cell growth and survival, among other processes.⁴⁶ Thus, metformin’s ability to increase insulin sensitivity and inhibit mTOR signaling could be beneficial in the setting of HS. Additionally, insulin and insulinlike growth factor 1 (IGF-1) increase androgen signaling, a process that has been implicated in HS.⁴⁷

Metformin also may impact HS through its effects on testosterone and other hormones.⁴⁸ A study evaluating peripheral blood mononuclear cells in patients with HS showed reduced IL-17, IFN-γ, TNF-α, and IL-6 levels in patients who were taking metformin (dose not reported) for longer than 6 months compared to patients who were not on metformin. Further analysis of ex vivo HS lesions cultured with metformin showed decreased IL-17, IFN-γ, TNF-α, and IL-8 expression in tissue, suggesting an antiinflammatory role of metformin in HS.⁵

Although there are no known RCTs assessing the efficacy of metformin in HS, existing clinical data are supportive of the use of metformin for refractory HS.⁴⁹ Following a case report describing a patient with T2DM and stable HS while on metformin,⁵⁰ several cohort studies have assessed the efficacy of metformin for the treatment of HS. A prospective study evaluating the efficacy of metformin monotherapy (starting dose of 500 mg/d, titrated to 500 mg 3 times daily) in patients with and without T2DM with HS refractory to other therapies found clinical improvement in 72% (18/25) of patients using the Sartorius Hidradenitis Suppurativa Score, improving from a mean (SD) score of 34.40 (12.46) to 26.76 (11.22) at 12 weeks (P=.0055,) and 22.39 (11.30) at 24 weeks (P=.0001). Additionally, 64% (16/25) of patients showed improved quality of life as evaluated by the Dermatology Life Quality Index (DLQI), which decreased from a mean (SD) score of 15.00 (4.96) to 10.08 (5.96)(P=.0017) at 12 weeks and 7.65 (7.12)(P=.000009) at 24 weeks on treatment.⁴⁸ In a retrospective study of 53 patients with HS taking metformin started at 500 mg daily and increased to 500 mg twice daily after 2 weeks (when tolerated), 68% (36/53) showed some clinical response, with 19% (7/36) of those patients having achieved complete response to metformin monotherapy (defined as no active HS).⁵¹ Similarly, a retrospective study of pediatric patients with HS evaluating metformin (doses ranging from 500-2000 mg daily) as an adjunct therapy described a subset of patients with decreased frequency of HS flares with metformin.⁵² These studies emphasize the safety profile of metformin and support its current use as an adjunctive therapy for HS.

Acne Vulgaris—Acne vulgaris (AV) is a chronic inflammatory disorder affecting the pilosebaceous follicles.¹¹ Similar to HS, AV has metabolic and hormonal influences that can be targeted by metformin.⁵³ In AV, androgens lead to increased sebum production by binding to androgen receptors on sebocytes, which in turn attracts Cutibacterium acnes and promotes hyperkeratinization, inducing inflammation.⁵⁴ Thus, the antiandrogenic effects of metformin may be beneficial for treatment of AV. Additionally, sebocytes express receptors for insulin and IGF-1, which can increase the size and number of sebocytes, as well as promote lipogenesis and inflammatory response, influencing sebum production.⁵⁴ Serum levels for IGF-1 have been observed to be increased in patients with AV⁵⁵ and reduced by metformin.⁵⁶ A recent meta-analysis assessing the efficacy of metformin on AV indicated that 87% (13/15) of studies noted disease improvement on metformin, with 47% (7/15) of studies showing statistically significant (P<0.05) decreases in acne severity.57 Although most studies showed improvement, 47% (7/15) did not find significant differences between metformin and other interventions, indicating the availability of comparable treatment options. Overall, there has been a positive association between metformin use and acne improvement.⁵⁷ However, it is important to note that most studies have focused on females with PCOS,⁵⁷ and the main benefits of metformin in acne might be seen when managing comorbid conditions, particularly those associated with metabolic dysregulation and insulin resistance. Further studies are needed to determine the generalizability of prior results.

Psoriasis—Psoriasis is a chronic autoinflammatory disease characterized by epidermal hyperplasia with multiple cutaneous manifestations and potential for multiorgan involvement. Comorbid conditions include psoriatic arthritis, metabolic syndrome, and cardiovascular disease.⁵⁸ Current treatment options depend on several factors (eg, disease severity, location of cutaneous lesions, comorbidities) and include topical, systemic, and phototherapy options, many of which target the immune system.^58,59 A meta-analysis of 3 RCTs showed that metformin (500 mg/d or 1000 mg/d) was associated with significantly improved Psoriasis Area and Severity Index (PASI) 75% reductions (odds ratio [OR], 22.02; 95% CI, 2.12-228.49; P=.01) and 75% reductions in erythema, scaling, and induration (OR, 9.12; 95% CI, 2.13-39.02; P=.003) compared to placebo.⁶⁰ In addition, an RCT evaluating the efficacy of metformin (1000 mg/d) or pioglitazone (30 mg/d) for 12 weeks in patients with psoriasis with metabolic syndrome found significant improvements in PASI75 (P=.001) and erythema, scaling, and induration (P=.016) scores as well as in Physician Global Assessment scores (P=.012) compared to placebo and no differences compared to pioglitazone.⁶¹ While current psoriasis management guidelines do not include metformin, its use may be worth consideration as an adjunct therapy in patients with psoriasis and comorbidities such as T2DM and metabolic syndrome.⁵⁹ Metformin’s potential benefits in psoriasis may lie outside its metabolic influences and occur secondary to its immunomodulatory effects, including targeting of the Th17 axis or cytokine-specific pathways such as TNF-α, which are known to be involved in psoriasis pathogenesis.⁵⁸

Central Centrifugal Cicatricial Alopecia—Central centrifugal cicatricial alopecia (CCCA) is a form of scarring alopecia characterized by chronic inflammation leading to permanent loss of hair follicles on the crown of the scalp.⁶² Current treatments include topical and intralesional corticosteroids, as well as oral antibiotics. In addition, therapies including the antimalarial hydroxychloroquine and immunosuppressants mycophenolate and cyclosporine are used in refractory disease.^63,64 A case report described 2 patients with hair regrowth after 4 and 6 months of treatment with topical metformin 10% compounded in a proprietary transdermal vehicle.⁶⁵ The authors speculated that metformin’s effects on CCCA could be attributed to its known agonistic effects on the adenosine monophosphate-activated protein kinase (AMPK) pathway with subsequent reduction in inflammation-induced fibrosis.^65,66 Microarray⁶⁷ and proteomic⁶⁸ analysis have shown that AMPK is known to be downregulated in CCCA , making it an interesting therapeutic target in this disease. A recent retrospective case series demonstrated that 67% (8/12) of patients with refractory CCCA had symptomatic improvement, and 50% (6/12) showed hair regrowth after 6 months of low-dose (500 mg/d) oral metformin treatment.⁶² In addition, metformin therapy showed antifibrotic and anti-inflammatory effects when comparing scalp biopsies before and after treatment. Results showed decreased expression of fibrosisrelated genes (matrix metalloproteinase 7, collagen type IV á 1 chain), and gene set variation analysis showing reduced Th17 (P=.04) and increased AMPK signaling (P=.02) gene set expression.⁶² These findings are consistent with previous studies describing the upregulation of AMPK66 and downregulation of Th176 following metformin treatment. The immunomodulatory effects of metformin could be attributed to AMPK-mediated mTOR and NF-κB downregulation,⁶² although more studies are needed to understand these mechanisms and further explore the use of metformin in CCCA.

Skin Cancer—Metformin also has been evaluated in the setting of skin malignancies, including melanoma, squamous cell carcinoma, and basal cell carcinoma. Preclinical data suggest that metformin decreases cell viability in tumors through interactions with pathways involved in proinflammatory and prosurvival mechanisms such as NF-κB and mTOR.^69,70 Additionally, given metformin’s inhibitory effects on oxidative phosphorylation, it has been postulated that it could be used to overcome treatment resistance driven by metabolic reprogramming.^71,72 Most studies related to metformin and skin malignancies are still in preclinical stages; however, a meta-analysis of RCTs and cohort studies did not find significant associations between metformin use and skin cancer risk, although data trended toward a modest reduction in skin cancer among metformin users.⁷³ A retrospective cohort study of melanoma in patients with T2DM taking metformin (250-2000 mg/d) found that the 5-year incidence of recurrence was lower in the metformin cohort compared to nonusers (43.8% vs 58.2%, respectively)(P=.002), and overall survival rates trended upward in the higher body mass index (>30) and melanoma stages 1 and 2 groups but did not reach statistical significance.⁷⁴ In addition, a whole population casecontrol study in Iceland reported that metformin use at least 2 years before first-time basal cell carcinoma diagnosis was associated with a lower risk for disease (adjusted OR, 0.71; 95% CI, 0.61-0.83) with no significant dose-dependent differences; there were no notable effects on squamous cell carcinoma risk.⁷⁵ Further preclinical and clinical data are needed to elucidate metformin’s effects on skin malignancies.

GLP-1 AND DUAL GLP-1/GIP AGONISTS

Glucagonlike peptide 1 and dual GLP-1/GIP agonists are emerging classes of medications currently approved as adjunct and second-line therapies for T2DM, particularly in patients who are overweight or obese as well as in those who are at risk for hypoglycemia.³ Currently approved GLP-1 agonists for T2DM include semaglutide, dulaglutide, exenatide, liraglutide, and lixisenatide, while tirzepatide is the only approved dual GLP-1/GIP agonist. Activating GLP-1 and GIP receptors stimulates insulin secretion and decreases glucagon production by the pancreas, thereby reducing blood glucose levels. Additionally, some of these medications are approved for obesity given their effects in delayed gastric emptying and increased satiety, among other factors.

Over the past few years, multiple case reports have described the associations between GLP-1 agonist use and improvement of dermatologic conditions, particularly those associated with T2DM and obesity, including HS and psoriasis.^76,77 The mechanisms through which this occurs are not fully elucidated, although basic science and clinical studies have shown that GLP-1 agonists have immunomodulatory effects by reducing proinflammatory cytokines and altering immune cell populations.^77-80 The numerous ongoing clinical trials and research studies will help further elucidate their benefits in other disease settings.⁸¹

Adverse Reactions

Most GLP-1 and GLP-1/GIP agonists are administered subcutaneously, and the most commonly reported cutaneous adverse effects are injection site reactions.⁸² Anaphylactic reactions to these medications also have been reported, although it is unclear if these were specific to the active ingredients or to injection excipients.^83,84 A review of 33 cases of cutaneous reactions to GLP-1 agonists reported 11 (33%) dermal hypersensitivity reactions occurring as early as 4 weeks and as late as 3 years after treatment initiation. It also described 10 (30%) cases of eosinophilic panniculitis that developed within 3 weeks to 5 months of GLP-1 treatment, 3 (9%) cases of bullous pemphigoid that occurred within the first 2 months, 2 (6%) morbilliform drug eruptions that occurred within 5 weeks, 2 (6%) cases of angioedema that occurred 15 minutes to 2 weeks after treatment initiation, and 7 (21%) other isolated cutaneous reactions. Extended-release exenatide had the most reported reactions followed by liraglutide and subcutaneous semaglutide.⁸⁵

In a different study, semaglutide use was most commonly associated with injection site reactions followed by alopecia, especially with oral administration. Unique cases of angioedema (2 days after injection), cutaneous hypersensitivity (within 10 months on treatment), bullous pemphigoid (within 2 months on treatment), eosinophilic fasciitis (within 2 weeks on treatment), and leukocytoclastic vasculitis (unclear timing), most of which resolved after discontinuation, also were reported.⁸⁶ A recent case report linked semaglutide (0.5 mg/wk) to a case of drug-induced systemic lupus erythematosus that developed within 3 months of treatment initiation and described systemic lupus erythematosus–like symptoms in a subset of patients using this medication, namely females older than 60 years, within the first month of treatment.⁸⁷ Hyperhidrosis was listed as a common adverse event in exenatide clinical trials, and various cases of panniculitis with exenatide use have been reported.^82,88 Alopecia, mainly attributed to accelerated telogen effluvium secondary to rapid weight loss, also has been reported, although hair loss is not officially listed as an adverse effect of GLP-1 agonists, and reports are highly variable.⁸⁹ Also secondary to weight loss, facial changes including sunken eyes, development of wrinkles, sagging jowls around the neck and jaw, and a hollowed appearance, among others, are recognized as undesirable adverse effects.⁹⁰ Mansour et al⁹⁰ described the potential challenges and considerations to these rising concerns associated with GLP1-agonist use.

Dermatologic Implications

Hidradenitis Suppurativa—Weight loss commonly is recommended as a lifestyle modification in the management of HS. Multiple reports have described clinical improvement of HS following weight loss with other medical interventions, such as dietary measures and bariatric surgery.^91-94 Thus, it has been postulated that medically supported weight loss with GLP-1 agonists can help improve HS⁹⁵; however, the data on the effectiveness of GLP-1 agonists on HS are still scarce and mostly have been reported in individual patients. One case report described a patient with improvements in their recalcitrant HS and DLQI score following weight loss on liraglutide (initial dose of 0.6 mg/d, titrated to 1.8 mg/d).⁷⁶ In addition, a recent case report described improvements in HS and DLQI score following concomitant tirzepatide (initial dose of 2.5 mg/0.5 mL weekly, titrated to 7.5 mg/0.5 mL weekly) and infliximab treatment.⁹⁶ The off-label use of these medications for HS is debated, and further studies regarding the benefits of GLP-1 agonists on HS still are needed.

Psoriasis—Similarly, several case reports have commented on the effects of GLP-1 agonists on psoriasis.^97,98 An early study found GLP-1 receptors were expressed in psoriasis plaques but not in healthy skin and discussed that this could be due to immune infiltration in the plaques, providing a potential rationale for using anti-inflammatory GLP-1 agonists for psoriasis.⁹⁹ Two prospective cohort studies observed improvements in PASI and DLQI scores in patients with psoriasis and T2DM after liraglutide treatment and noted important changes in immune cell populations.^80,100 A recent RCT also found improvements in DLQI and PASI scores (P<.05) in patients with T2DM following liraglutide (1.8 mg/d) treatment, along with overall decreases in inflammatory cytokines, such as IL-23, IL-17, and TNF-α.⁷⁷ However, another RCT in patients with obesity did not observe significant improvements in PASI and DLQI scores compared to placebo after 8 weeks of liraglutide (initial dose of 0.6 mg/d, titrated to 1.8 mg/d) treatment. ⁹⁹ Although these results could have been influenced by the short length of treatment compared to other studies, which observed participants for more than 10 weeks, they highlight the need for tailored studies considering the different comorbidities to identify patients who could benefit the most from these therapies.

Alopecia—Although some studies have reported increased rates of alopecia following GLP-1 agonist treatment, others have speculated about the potential role of these medications in treating hair loss through improved insulin sensitivity and scalp blood flow.^86,89 For example, a case report described a patient with improvement in androgenetic alopecia within 6 months of tirzepatide monotherapy at 2.5 mg weekly for the first 3 months followed by an increased dose of 5 mg weekly.¹⁰¹ The authors described the role of insulin in increasing dihydrotestosterone levels, which leads to miniaturization of the dermal papilla of hair follicles and argued that improvement of insulin resistance could benefit hair loss. Further studies can help elucidate the role of these medications on alopecia.

FINAL THOUGHTS

Standard T2DM treatments including metformin and GLP-1 and GLP-1/GIP agonists exhibit metabolic, immunologic, and hormonal effects that should be explored in other disease contexts. We reviewed the current data on T2DM medications in dermatologic conditions to highlight the need for additional studies to better understand the role that these medications play across diverse patient populations. Type 2 diabetes mellitus is a common comorbidity in dermatology patients, and understanding the multifactorial effects of these medications can help optimize treatment strategies, especially in patients with coexisting dermatologic and metabolic diseases.

NEW YORK CITY — The idea of having dermatologists and rheumatologists under one roof to see patients with psoriasis prone to psoriatic arthritis (PsA) — a concept known as combined clinics — has been around for more than a decade, and the idea of personalized medicine for these patients even longer than that, yet both approaches to care have encountered a host of obstacles, a longtime research rheumatologist said.

“It’s important that we work together, but there is a problem in terms of staffing — managing the meetings with patients together — and in the states in particular it’s a matter of who’s charging for what,” Dafna Gladman, MD, a rheumatologist at the University of Toronto, in Ontario, Canada, told attendees at the annual New York University (NYU) Langone Advanced Seminar in Psoriasis and Psoriatic Arthritis. Her institution has one of the 44 worldwide combined clinics registered in the Psoriasis & Psoriatic Arthritis Clinics Multicenter Advancement Network (PPACMAN), of which Gladman is an advisory board member.

 

Barriers to Combined Clinics

“Some of the barriers are physical in the sense that, for the dermatologists and rheumatologists to work at the same time, you need the right space, and in many places, you just don’t have the space to have the two specialists sitting at the same time,” Gladman told Medscape Medical News.

Some centers get around this by having the dermatology and rheumatology clinics next to or near each other. “So these two specialists are close enough to be able to go from room to room,” she added.

Another challenge facing combined clinics lies in the nature of how dermatologists and rheumatologists see patients. “The dermatologist sees patients a lot faster than the rheumatologist, so if the dermatologist and rheumatologist are sitting together, the dermatologist may not see as many patients as they would otherwise and therefore may not get reimbursed properly,” Gladman said.

To overcome these challenges, different models have emerged, Gladman said. If space allows, the ideal model is to have both specialties in one clinic, she said, while compensating for the different pace at which dermatologists and rheumatologists see patients.

The other model is to locate the two clinics close enough so that a person with suspected PsA can get to the rheumatology clinic soon after their dermatologic consult, or the rheumatologist can go to the dermatology clinic, Gladman said. Or the situation may be reversed when the rheumatologist needs a dermatology consult, she added.

When that’s not possible, a virtual visit may be the solution, Gladman said. She noted that PPACMAN offers ways to overcome the challenges of running a combined clinic.

Whatever combined clinic model a center chooses, clinicians must be mindful of preventing patients from falling through the cracks, Gladman said.

“When you treat patients separately, the patient sees the rheumatologist, and the rheumatologist wants to do one thing; then they go to the dermatologist and the dermatologist wants to do another thing, and the patient doesn’t do anything because they don’t know what to choose,” she said.

The combined clinic allows the patient to get the opinions of both specialists and avoid the uncertainty about the course of treatment, Gladman added.

Some combined clinics may also house other specialists, such as gastroenterologists, cardiologists, and nurse practitioners, noted Jose U. Scher, MD, director of the Arthritis Clinic and Psoriatic Arthritis Center at NYU Langone Health in New York City. Such centers are typically in academic centers “given challenges with space, scheduling, and reimbursement,” he told Medscape Medical News. NYU has a PPACMAN-registered combined clinic.

Regardless of how combined clinics are organized, Scher said, “We have found that the most important aspect of combined clinics is the open communication and integration of care between and amongst specialists and patients.”

 

The Potential of Personalized Medicine

“Personalized medicine is where we need to get to,” Gladman told seminar attendees. She said she had hoped it would be further along by now and be more integrated into the care of patients with psoriasis and PsA. “The idea is to identify psoriasis patients that are destined to develop psoriatic arthritis,” she said.

Besides that, identifying biomarkers is key to advancing personalized medicine for psoriasis, Gladman noted.

“In the skin, it’s easy; even the patient can assess their psoriasis,” she said. “But in the joints, it’s very difficult, so it would be nice to have some kind of biomarker, whether it’s the blood or an imaging modality. We want to identify the biomarkers for drug response or lack thereof so we know what drugs would be appropriate for the individual patient, and therefore, we can provide the right drug for the right person and fortunately at the right time.”

In explaining why personalized medicine isn’t further along in dermatology and rheumatology, Gladman told Medscape Medical News, “It’s a matter of finding the right things; we haven’t solved the mystery.” She cited a previous discussion at the seminar about the pathogenesis of PsA. “One person thinks it’s the bone marrow and another thinks it’s the T cells, so we haven’t quite put it all together to have a definitive answer.”

Personalized medicine in psoriasis and PsA is a “key unmet need,” Scher said. “Multiomics” — a biological analysis approach that uses multiple “omes,” such as the genome and microbiome — digital features, and wearables “can unlock novel diagnostic and therapeutic pathways that are desperately needed to enhance clinical response in PsA,” he said.

Also emerging are humanized animal models for laboratory research, which Scher called “potentially very useful tools to personalize approaches to PsA pathogenesis and treatment.”

Gladman disclosed financial relationships with AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, and UCB. Scher had no relevant financial relationships.

A version of this article first appeared on Medscape.com.

NEW YORK CITY — The idea of having dermatologists and rheumatologists under one roof to see patients with psoriasis prone to psoriatic arthritis (PsA) — a concept known as combined clinics — has been around for more than a decade, and the idea of personalized medicine for these patients even longer than that, yet both approaches to care have encountered a host of obstacles, a longtime research rheumatologist said.

“It’s important that we work together, but there is a problem in terms of staffing — managing the meetings with patients together — and in the states in particular it’s a matter of who’s charging for what,” Dafna Gladman, MD, a rheumatologist at the University of Toronto, in Ontario, Canada, told attendees at the annual New York University (NYU) Langone Advanced Seminar in Psoriasis and Psoriatic Arthritis. Her institution has one of the 44 worldwide combined clinics registered in the Psoriasis & Psoriatic Arthritis Clinics Multicenter Advancement Network (PPACMAN), of which Gladman is an advisory board member.

 

Barriers to Combined Clinics

“Some of the barriers are physical in the sense that, for the dermatologists and rheumatologists to work at the same time, you need the right space, and in many places, you just don’t have the space to have the two specialists sitting at the same time,” Gladman told Medscape Medical News.

Some centers get around this by having the dermatology and rheumatology clinics next to or near each other. “So these two specialists are close enough to be able to go from room to room,” she added.

Another challenge facing combined clinics lies in the nature of how dermatologists and rheumatologists see patients. “The dermatologist sees patients a lot faster than the rheumatologist, so if the dermatologist and rheumatologist are sitting together, the dermatologist may not see as many patients as they would otherwise and therefore may not get reimbursed properly,” Gladman said.

To overcome these challenges, different models have emerged, Gladman said. If space allows, the ideal model is to have both specialties in one clinic, she said, while compensating for the different pace at which dermatologists and rheumatologists see patients.

The other model is to locate the two clinics close enough so that a person with suspected PsA can get to the rheumatology clinic soon after their dermatologic consult, or the rheumatologist can go to the dermatology clinic, Gladman said. Or the situation may be reversed when the rheumatologist needs a dermatology consult, she added.

When that’s not possible, a virtual visit may be the solution, Gladman said. She noted that PPACMAN offers ways to overcome the challenges of running a combined clinic.

Whatever combined clinic model a center chooses, clinicians must be mindful of preventing patients from falling through the cracks, Gladman said.

“When you treat patients separately, the patient sees the rheumatologist, and the rheumatologist wants to do one thing; then they go to the dermatologist and the dermatologist wants to do another thing, and the patient doesn’t do anything because they don’t know what to choose,” she said.

The combined clinic allows the patient to get the opinions of both specialists and avoid the uncertainty about the course of treatment, Gladman added.

Some combined clinics may also house other specialists, such as gastroenterologists, cardiologists, and nurse practitioners, noted Jose U. Scher, MD, director of the Arthritis Clinic and Psoriatic Arthritis Center at NYU Langone Health in New York City. Such centers are typically in academic centers “given challenges with space, scheduling, and reimbursement,” he told Medscape Medical News. NYU has a PPACMAN-registered combined clinic.

Regardless of how combined clinics are organized, Scher said, “We have found that the most important aspect of combined clinics is the open communication and integration of care between and amongst specialists and patients.”

 

The Potential of Personalized Medicine

“Personalized medicine is where we need to get to,” Gladman told seminar attendees. She said she had hoped it would be further along by now and be more integrated into the care of patients with psoriasis and PsA. “The idea is to identify psoriasis patients that are destined to develop psoriatic arthritis,” she said.

Besides that, identifying biomarkers is key to advancing personalized medicine for psoriasis, Gladman noted.

“In the skin, it’s easy; even the patient can assess their psoriasis,” she said. “But in the joints, it’s very difficult, so it would be nice to have some kind of biomarker, whether it’s the blood or an imaging modality. We want to identify the biomarkers for drug response or lack thereof so we know what drugs would be appropriate for the individual patient, and therefore, we can provide the right drug for the right person and fortunately at the right time.”

In explaining why personalized medicine isn’t further along in dermatology and rheumatology, Gladman told Medscape Medical News, “It’s a matter of finding the right things; we haven’t solved the mystery.” She cited a previous discussion at the seminar about the pathogenesis of PsA. “One person thinks it’s the bone marrow and another thinks it’s the T cells, so we haven’t quite put it all together to have a definitive answer.”

Personalized medicine in psoriasis and PsA is a “key unmet need,” Scher said. “Multiomics” — a biological analysis approach that uses multiple “omes,” such as the genome and microbiome — digital features, and wearables “can unlock novel diagnostic and therapeutic pathways that are desperately needed to enhance clinical response in PsA,” he said.

Also emerging are humanized animal models for laboratory research, which Scher called “potentially very useful tools to personalize approaches to PsA pathogenesis and treatment.”

Gladman disclosed financial relationships with AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, and UCB. Scher had no relevant financial relationships.

A version of this article first appeared on Medscape.com.

NEW YORK CITY — The idea of having dermatologists and rheumatologists under one roof to see patients with psoriasis prone to psoriatic arthritis (PsA) — a concept known as combined clinics — has been around for more than a decade, and the idea of personalized medicine for these patients even longer than that, yet both approaches to care have encountered a host of obstacles, a longtime research rheumatologist said.

“It’s important that we work together, but there is a problem in terms of staffing — managing the meetings with patients together — and in the states in particular it’s a matter of who’s charging for what,” Dafna Gladman, MD, a rheumatologist at the University of Toronto, in Ontario, Canada, told attendees at the annual New York University (NYU) Langone Advanced Seminar in Psoriasis and Psoriatic Arthritis. Her institution has one of the 44 worldwide combined clinics registered in the Psoriasis & Psoriatic Arthritis Clinics Multicenter Advancement Network (PPACMAN), of which Gladman is an advisory board member.

 

Barriers to Combined Clinics

“Some of the barriers are physical in the sense that, for the dermatologists and rheumatologists to work at the same time, you need the right space, and in many places, you just don’t have the space to have the two specialists sitting at the same time,” Gladman told Medscape Medical News.

Some centers get around this by having the dermatology and rheumatology clinics next to or near each other. “So these two specialists are close enough to be able to go from room to room,” she added.

Another challenge facing combined clinics lies in the nature of how dermatologists and rheumatologists see patients. “The dermatologist sees patients a lot faster than the rheumatologist, so if the dermatologist and rheumatologist are sitting together, the dermatologist may not see as many patients as they would otherwise and therefore may not get reimbursed properly,” Gladman said.

To overcome these challenges, different models have emerged, Gladman said. If space allows, the ideal model is to have both specialties in one clinic, she said, while compensating for the different pace at which dermatologists and rheumatologists see patients.

The other model is to locate the two clinics close enough so that a person with suspected PsA can get to the rheumatology clinic soon after their dermatologic consult, or the rheumatologist can go to the dermatology clinic, Gladman said. Or the situation may be reversed when the rheumatologist needs a dermatology consult, she added.

When that’s not possible, a virtual visit may be the solution, Gladman said. She noted that PPACMAN offers ways to overcome the challenges of running a combined clinic.

Whatever combined clinic model a center chooses, clinicians must be mindful of preventing patients from falling through the cracks, Gladman said.

“When you treat patients separately, the patient sees the rheumatologist, and the rheumatologist wants to do one thing; then they go to the dermatologist and the dermatologist wants to do another thing, and the patient doesn’t do anything because they don’t know what to choose,” she said.

The combined clinic allows the patient to get the opinions of both specialists and avoid the uncertainty about the course of treatment, Gladman added.

Some combined clinics may also house other specialists, such as gastroenterologists, cardiologists, and nurse practitioners, noted Jose U. Scher, MD, director of the Arthritis Clinic and Psoriatic Arthritis Center at NYU Langone Health in New York City. Such centers are typically in academic centers “given challenges with space, scheduling, and reimbursement,” he told Medscape Medical News. NYU has a PPACMAN-registered combined clinic.

Regardless of how combined clinics are organized, Scher said, “We have found that the most important aspect of combined clinics is the open communication and integration of care between and amongst specialists and patients.”

 

The Potential of Personalized Medicine

“Personalized medicine is where we need to get to,” Gladman told seminar attendees. She said she had hoped it would be further along by now and be more integrated into the care of patients with psoriasis and PsA. “The idea is to identify psoriasis patients that are destined to develop psoriatic arthritis,” she said.

Besides that, identifying biomarkers is key to advancing personalized medicine for psoriasis, Gladman noted.

“In the skin, it’s easy; even the patient can assess their psoriasis,” she said. “But in the joints, it’s very difficult, so it would be nice to have some kind of biomarker, whether it’s the blood or an imaging modality. We want to identify the biomarkers for drug response or lack thereof so we know what drugs would be appropriate for the individual patient, and therefore, we can provide the right drug for the right person and fortunately at the right time.”

In explaining why personalized medicine isn’t further along in dermatology and rheumatology, Gladman told Medscape Medical News, “It’s a matter of finding the right things; we haven’t solved the mystery.” She cited a previous discussion at the seminar about the pathogenesis of PsA. “One person thinks it’s the bone marrow and another thinks it’s the T cells, so we haven’t quite put it all together to have a definitive answer.”

Personalized medicine in psoriasis and PsA is a “key unmet need,” Scher said. “Multiomics” — a biological analysis approach that uses multiple “omes,” such as the genome and microbiome — digital features, and wearables “can unlock novel diagnostic and therapeutic pathways that are desperately needed to enhance clinical response in PsA,” he said.

Also emerging are humanized animal models for laboratory research, which Scher called “potentially very useful tools to personalize approaches to PsA pathogenesis and treatment.”

Gladman disclosed financial relationships with AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, and UCB. Scher had no relevant financial relationships.

A version of this article first appeared on Medscape.com.