Article

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.

To the Editor:

Idiopathic gingival papillokeratosis with crypt formation (IGPC) is an uncommon benign condition that first was reported in 1967.¹ The condition manifests as white plaques with a papillary appearance on the gingival tissue. While data on the prevalence of IGPC are limited, it is known to occur more frequently in younger patients (ie, 9-24 years^1-3) and has been linked to use of orthodontic appliances.^3,4 The lesions typically are asymptomatic with a bilateral appearance along the mucogingival junction. Research on IGPC has not identified the underlying mechanisms that trigger the hyperkeratinization and papillary alterations within the gingival tissue.

Management of IGPC can be challenging due to the rarity of the condition and its uncertain pathogenesis. Wiping or brushing the affected area offers only temporary improvement of symptoms and the appearance of the lesions. Surgical excision is another option; however, it can result in aesthetic and/or functional periodontal defects.² Alternately, employing methods such as wiping or brushing the affected area offers only transient and temporary results in managing the condition. Additional investigative approaches and clinical studies are needed to identify more effective therapeutic modalities for the management of IGPC, particularly in pediatric patients, in whom aesthetic results may take on a heightened importance.^1-3 We report a case of IGPC in which cryotherapy yielded satisfactory results with no recurrence of the lesions.

A 32-year-old woman presented to the dental clinic with white spots on the gingiva of 5 months’ duration. The patient reported a history of smoking cigarettes (3 packs per year) and drinking alcohol in social situations; her medical history was otherwise unremarkable. Clinical examination of the oral cavity revealed a bilateral, irregular, verrucouslike plaque throughout the vestibular upper attached gingiva. An incisional biopsy from the attached gingiva between teeth 13 and 23 was performed. Histopathologic analysis revealed parakeratosis and papillary acanthosis of the gingival mucosa associated with multifocal epithelial invaginations resembling crypts as well as long tapered epithelial ridges with no inflammation in the lamina propria. Based on the histopathologic findings, a diagnosis of IGPC was made (Figure 1).

Given the patient’s clinical presentation, we suggested treatment with cryotherapy as a minimally invasive option that would preserve the gingival architecture and aesthetics while avoiding the potential complications of surgical excision. The patient consented to the procedure, and liquid nitrogen was administered through a handheld device using a 0.6-mm aperture spray tip. During application, the spray tip was positioned at a distance of 0.5 to 1.0 cm from the labial marginal gingiva at about a 45° angle. The freeze/thaw cycle involved a continuous one-way spray application of liquid nitrogen onto the lesion until solid ice formed over the entire area, followed by a waiting period until gradual thawing occurred.

A total of 5 cryotherapy sessions were conducted over an 8-week period; no recurrence of the lesions was observed during a 2-year follow-up period (Figure 2).

We present our case to add to the body of knowledge regarding management options for IGPC, specifically cryotherapy. Historically, brushing with a toothbrush and surgical excision have been the most commonly used interventions.² Gently brushing the affected areas can help stimulate local blood circulation, which can improve the health of the gingival tissue, promote oxygenation and delivery of nutrients to the cells, and aid in the removal of metabolic waste. Surgical excision is the most commonly used treatment method for IGPC to ensure that the lesions are safely and completely removed; however, this option can result in aesthetic and/or functional periodontal defects. There also is a risk for recurrence, although Noonan et al² reported no recurrence 4 years after performing a surgical excision for IGPC.

Cryotherapy reduces tissue sensitivity, provides local anesthesia, and reduces inflammation in the oral mucosa. Moreover, cryotherapy accelerates healing by stimulating vasoconstriction and reactive vasodilation, thus enhancing blood flow, oxygenation, and nutrient delivery for faster cell regeneration of the oral mucosa.^4,5 Cryotherapy generally is regarded as a simple noninvasive procedure that is relatively safe when performed by qualified professionals.^4,5 It can provide benefits such as minimal patient discomfort, rapid recovery, and potential reduction of complications associated with more invasive procedures.⁵

The efficacy of cryotherapy for IGPC may vary based on lesion severity, individual patient response, and the need for repeated treatment sessions. Robust scientific evidence concerning the long-term efficacy of cryotherapy as a treatment for IGPC is limited due to the rarity of this condition.

The etiopathogenesis of IGPC has been hypothesized to involve both genetic and environmental factors with equal significance. This suggestion is based on reports of IGPC occurring in multiple members of the same family and animal model studies indicating that gingival tissue is sensitive to environmental influences, such as nutritional factors.^1,6 However, it is important to emphasize that these hypotheses remain speculative, and the true etiopathogenesis of IGPC remains uncertain.⁶ Microscopically, biopsy fragments from suspected cases of IGPC reveal gingival mucosa characterized by parakeratosis and papillary acanthosis accompanied by multifocal epithelial invaginations resembling crypts.² Additionally, elongated and tapered epithelial ridges without inflammation in the lamina propria may be observed (as in our case), favoring the diagnosis of IGPC.³ The absence of inflammation is noteworthy because it suggests that the observed alterations are not attributed to typical inflammatory processes seen in some gingival conditions.

The limited number of studies reporting successful treatment outcomes with long-term follow-up for IGPC cases underscores the need for further exploration of effective treatment options. Cryotherapy emerges as a promising minimally invasive therapeutic approach, with our case offering support for its potential application. Additional research and clinical trials are essential to validate its efficacy and improve our understanding of cryotherapy as a treatment modality for IGPC lesions.

To the Editor:

Idiopathic gingival papillokeratosis with crypt formation (IGPC) is an uncommon benign condition that first was reported in 1967.¹ The condition manifests as white plaques with a papillary appearance on the gingival tissue. While data on the prevalence of IGPC are limited, it is known to occur more frequently in younger patients (ie, 9-24 years^1-3) and has been linked to use of orthodontic appliances.^3,4 The lesions typically are asymptomatic with a bilateral appearance along the mucogingival junction. Research on IGPC has not identified the underlying mechanisms that trigger the hyperkeratinization and papillary alterations within the gingival tissue.

Management of IGPC can be challenging due to the rarity of the condition and its uncertain pathogenesis. Wiping or brushing the affected area offers only temporary improvement of symptoms and the appearance of the lesions. Surgical excision is another option; however, it can result in aesthetic and/or functional periodontal defects.² Alternately, employing methods such as wiping or brushing the affected area offers only transient and temporary results in managing the condition. Additional investigative approaches and clinical studies are needed to identify more effective therapeutic modalities for the management of IGPC, particularly in pediatric patients, in whom aesthetic results may take on a heightened importance.^1-3 We report a case of IGPC in which cryotherapy yielded satisfactory results with no recurrence of the lesions.

A 32-year-old woman presented to the dental clinic with white spots on the gingiva of 5 months’ duration. The patient reported a history of smoking cigarettes (3 packs per year) and drinking alcohol in social situations; her medical history was otherwise unremarkable. Clinical examination of the oral cavity revealed a bilateral, irregular, verrucouslike plaque throughout the vestibular upper attached gingiva. An incisional biopsy from the attached gingiva between teeth 13 and 23 was performed. Histopathologic analysis revealed parakeratosis and papillary acanthosis of the gingival mucosa associated with multifocal epithelial invaginations resembling crypts as well as long tapered epithelial ridges with no inflammation in the lamina propria. Based on the histopathologic findings, a diagnosis of IGPC was made (Figure 1).

Given the patient’s clinical presentation, we suggested treatment with cryotherapy as a minimally invasive option that would preserve the gingival architecture and aesthetics while avoiding the potential complications of surgical excision. The patient consented to the procedure, and liquid nitrogen was administered through a handheld device using a 0.6-mm aperture spray tip. During application, the spray tip was positioned at a distance of 0.5 to 1.0 cm from the labial marginal gingiva at about a 45° angle. The freeze/thaw cycle involved a continuous one-way spray application of liquid nitrogen onto the lesion until solid ice formed over the entire area, followed by a waiting period until gradual thawing occurred.

A total of 5 cryotherapy sessions were conducted over an 8-week period; no recurrence of the lesions was observed during a 2-year follow-up period (Figure 2).

We present our case to add to the body of knowledge regarding management options for IGPC, specifically cryotherapy. Historically, brushing with a toothbrush and surgical excision have been the most commonly used interventions.² Gently brushing the affected areas can help stimulate local blood circulation, which can improve the health of the gingival tissue, promote oxygenation and delivery of nutrients to the cells, and aid in the removal of metabolic waste. Surgical excision is the most commonly used treatment method for IGPC to ensure that the lesions are safely and completely removed; however, this option can result in aesthetic and/or functional periodontal defects. There also is a risk for recurrence, although Noonan et al² reported no recurrence 4 years after performing a surgical excision for IGPC.

Cryotherapy reduces tissue sensitivity, provides local anesthesia, and reduces inflammation in the oral mucosa. Moreover, cryotherapy accelerates healing by stimulating vasoconstriction and reactive vasodilation, thus enhancing blood flow, oxygenation, and nutrient delivery for faster cell regeneration of the oral mucosa.^4,5 Cryotherapy generally is regarded as a simple noninvasive procedure that is relatively safe when performed by qualified professionals.^4,5 It can provide benefits such as minimal patient discomfort, rapid recovery, and potential reduction of complications associated with more invasive procedures.⁵

The efficacy of cryotherapy for IGPC may vary based on lesion severity, individual patient response, and the need for repeated treatment sessions. Robust scientific evidence concerning the long-term efficacy of cryotherapy as a treatment for IGPC is limited due to the rarity of this condition.

The etiopathogenesis of IGPC has been hypothesized to involve both genetic and environmental factors with equal significance. This suggestion is based on reports of IGPC occurring in multiple members of the same family and animal model studies indicating that gingival tissue is sensitive to environmental influences, such as nutritional factors.^1,6 However, it is important to emphasize that these hypotheses remain speculative, and the true etiopathogenesis of IGPC remains uncertain.⁶ Microscopically, biopsy fragments from suspected cases of IGPC reveal gingival mucosa characterized by parakeratosis and papillary acanthosis accompanied by multifocal epithelial invaginations resembling crypts.² Additionally, elongated and tapered epithelial ridges without inflammation in the lamina propria may be observed (as in our case), favoring the diagnosis of IGPC.³ The absence of inflammation is noteworthy because it suggests that the observed alterations are not attributed to typical inflammatory processes seen in some gingival conditions.

The limited number of studies reporting successful treatment outcomes with long-term follow-up for IGPC cases underscores the need for further exploration of effective treatment options. Cryotherapy emerges as a promising minimally invasive therapeutic approach, with our case offering support for its potential application. Additional research and clinical trials are essential to validate its efficacy and improve our understanding of cryotherapy as a treatment modality for IGPC lesions.

To the Editor:

Idiopathic gingival papillokeratosis with crypt formation (IGPC) is an uncommon benign condition that first was reported in 1967.¹ The condition manifests as white plaques with a papillary appearance on the gingival tissue. While data on the prevalence of IGPC are limited, it is known to occur more frequently in younger patients (ie, 9-24 years^1-3) and has been linked to use of orthodontic appliances.^3,4 The lesions typically are asymptomatic with a bilateral appearance along the mucogingival junction. Research on IGPC has not identified the underlying mechanisms that trigger the hyperkeratinization and papillary alterations within the gingival tissue.

Management of IGPC can be challenging due to the rarity of the condition and its uncertain pathogenesis. Wiping or brushing the affected area offers only temporary improvement of symptoms and the appearance of the lesions. Surgical excision is another option; however, it can result in aesthetic and/or functional periodontal defects.² Alternately, employing methods such as wiping or brushing the affected area offers only transient and temporary results in managing the condition. Additional investigative approaches and clinical studies are needed to identify more effective therapeutic modalities for the management of IGPC, particularly in pediatric patients, in whom aesthetic results may take on a heightened importance.^1-3 We report a case of IGPC in which cryotherapy yielded satisfactory results with no recurrence of the lesions.

A 32-year-old woman presented to the dental clinic with white spots on the gingiva of 5 months’ duration. The patient reported a history of smoking cigarettes (3 packs per year) and drinking alcohol in social situations; her medical history was otherwise unremarkable. Clinical examination of the oral cavity revealed a bilateral, irregular, verrucouslike plaque throughout the vestibular upper attached gingiva. An incisional biopsy from the attached gingiva between teeth 13 and 23 was performed. Histopathologic analysis revealed parakeratosis and papillary acanthosis of the gingival mucosa associated with multifocal epithelial invaginations resembling crypts as well as long tapered epithelial ridges with no inflammation in the lamina propria. Based on the histopathologic findings, a diagnosis of IGPC was made (Figure 1).

Given the patient’s clinical presentation, we suggested treatment with cryotherapy as a minimally invasive option that would preserve the gingival architecture and aesthetics while avoiding the potential complications of surgical excision. The patient consented to the procedure, and liquid nitrogen was administered through a handheld device using a 0.6-mm aperture spray tip. During application, the spray tip was positioned at a distance of 0.5 to 1.0 cm from the labial marginal gingiva at about a 45° angle. The freeze/thaw cycle involved a continuous one-way spray application of liquid nitrogen onto the lesion until solid ice formed over the entire area, followed by a waiting period until gradual thawing occurred.

A total of 5 cryotherapy sessions were conducted over an 8-week period; no recurrence of the lesions was observed during a 2-year follow-up period (Figure 2).

We present our case to add to the body of knowledge regarding management options for IGPC, specifically cryotherapy. Historically, brushing with a toothbrush and surgical excision have been the most commonly used interventions.² Gently brushing the affected areas can help stimulate local blood circulation, which can improve the health of the gingival tissue, promote oxygenation and delivery of nutrients to the cells, and aid in the removal of metabolic waste. Surgical excision is the most commonly used treatment method for IGPC to ensure that the lesions are safely and completely removed; however, this option can result in aesthetic and/or functional periodontal defects. There also is a risk for recurrence, although Noonan et al² reported no recurrence 4 years after performing a surgical excision for IGPC.

Cryotherapy reduces tissue sensitivity, provides local anesthesia, and reduces inflammation in the oral mucosa. Moreover, cryotherapy accelerates healing by stimulating vasoconstriction and reactive vasodilation, thus enhancing blood flow, oxygenation, and nutrient delivery for faster cell regeneration of the oral mucosa.^4,5 Cryotherapy generally is regarded as a simple noninvasive procedure that is relatively safe when performed by qualified professionals.^4,5 It can provide benefits such as minimal patient discomfort, rapid recovery, and potential reduction of complications associated with more invasive procedures.⁵

The efficacy of cryotherapy for IGPC may vary based on lesion severity, individual patient response, and the need for repeated treatment sessions. Robust scientific evidence concerning the long-term efficacy of cryotherapy as a treatment for IGPC is limited due to the rarity of this condition.

The etiopathogenesis of IGPC has been hypothesized to involve both genetic and environmental factors with equal significance. This suggestion is based on reports of IGPC occurring in multiple members of the same family and animal model studies indicating that gingival tissue is sensitive to environmental influences, such as nutritional factors.^1,6 However, it is important to emphasize that these hypotheses remain speculative, and the true etiopathogenesis of IGPC remains uncertain.⁶ Microscopically, biopsy fragments from suspected cases of IGPC reveal gingival mucosa characterized by parakeratosis and papillary acanthosis accompanied by multifocal epithelial invaginations resembling crypts.² Additionally, elongated and tapered epithelial ridges without inflammation in the lamina propria may be observed (as in our case), favoring the diagnosis of IGPC.³ The absence of inflammation is noteworthy because it suggests that the observed alterations are not attributed to typical inflammatory processes seen in some gingival conditions.

The limited number of studies reporting successful treatment outcomes with long-term follow-up for IGPC cases underscores the need for further exploration of effective treatment options. Cryotherapy emerges as a promising minimally invasive therapeutic approach, with our case offering support for its potential application. Additional research and clinical trials are essential to validate its efficacy and improve our understanding of cryotherapy as a treatment modality for IGPC lesions.

THE DIAGNOSIS: Atypical Spitz Tumor

The shave biopsy revealed extensive dermal proliferation with spitzoid cytomorphology containing large, spindled nuclei; prominent nucleoli; and abundant homogenous cytoplasm arranged in haphazard fascicles. The proliferation was associated with prominent pseudoepitheliomatous hyperplasia of the overlying epidermis, and anaplastic lymphoma kinase immunohistochemistry showed diffuse strong positivity. Fluorescence in situ hybridization confirmed fusion of the tropomyosin 3 (TPM3) and anaplastic lymphoma kinase (ALK) genes, which finalized the diagnosis of an ALK-mutated atypical spitz tumor. Due to the location and size of the lesion, Mohs micrographic surgery was performed to excise the tumor and clear the margins.

Spitz nevi are uncommon benign melanocytic neoplasms that typically occur in pediatric populations.¹ Atypical spitz nevi comprised fewer than 17% of all childhood melanocytic nevi in the United States and can be considered in the broader category of spitzoid tumors. Spitz nevi are divided into 3 classes: Spitz nevus, atypical Spitz nevus, and spitzoid melanoma. Atypical Spitz nevi have typical Spitz nevus and spitzoid melanoma features and often can be difficult to distinguish on dermoscopy. Malignant Spitz tumors typically occur in the fifth decade of life, though the age distribution can vary widely.¹

Black patients are less likely to be diagnosed with Spitz nevi, potentially due to a lower prevalence in this population, thus limiting the clinician’s clinical exposure and leading to increased rates of misdiagnoses.² Spitz nevi usually manifest as well-circumscribed, dome-shaped papules and frequently are described as pink to red due to increased vascularity and limited melanin content¹; however, these lesions may appear more violaceous, dusky, or dark brown in darker skin types. Additionally, approximately 71% of patients in a clinical review of Spitz nevi had a pigmented lesion, ranging from light brown to black.³ It is important for dermatologists to understand that the contrast in color between the nevus and the surrounding skin may not be as striking, prominent, or clinically concerning, particularly in darker skin types, such as in our patient.

Spitz nevi frequently manifest as rapidly growing solitary lesions most frequently developing in the lower legs (shown in 41% of lesions in one report).⁴ However, a recent retrospective review indicated that Spitz nevi in Black patients most commonly were found on the upper extremities, as was seen in our patient.² Compared to typical and common Spitz nevi, atypical Spitz nevi often are greater than 10 mm in diameter and have features of ulceration.

Diagnosing atypical spitzoid melanocytic lesions requires adequate clinical suspicion and confirmation via biopsy. Under dermoscopy, typical Spitz nevi often display a starburst or globular pattern with pinpoint vessels, though it can have variable manifestations of both patterns. Atypical Spitz nevi can be challenging to distinguish from melanoma on dermoscopy since both conditions can have atypical pigment networks or structureless homogenous areas.¹ Consequently, there often is a lower threshold for biopsy and possible follow-up excision for atypical Spitz nevi. Histopathology of atypical Spitz nevi includes epithelioid and spindle melanocytes but can share features of melanomas, including areas of prominent pagetoid spread, asymmetry, and poor circumscription.⁵ Furthermore, atypical Spitz nevi with ALK gene fusion, as seen in our patient, have been shown in the literature to demonstrate distinct histopathologic features, such as wedge-shaped extension into the dermis or a bulbous lower border that can resemble pseudoepitheliomatous hyperplasia.⁶

The differential diagnosis for this rapidly growing scaly nodule also should include pyogenic granuloma, bacillary angiomatosis, Kaposi sarcoma, and amelanotic melanoma. Pyogenic granuloma is a rapidly growing, benign, vascular tumor that often becomes ulcerated and can occur in any age group.⁷ Pyogenic granuloma frequently appears at sites of trauma as a solitary, bright pink to red, friable, pedunculated papule and often manifests on the arms, hands, and face, similar to atypical Spitz nevi, though they can appear anywhere on the body. Histology shows a lobular capillary network with a central feeder vessel.⁷

Bacillary angiomatosis is an uncommon cutaneous infection associated with vascular proliferation and neovascularization due to the gram-negative organism Bartonella henselae.⁸ Bacillary nodules typically are reddish to purple and appear on the arms, sometimes with central ulceration and bleeding. Patients may present with multiple papules and nodules of varying sizes, as the lesions can arise in crops and follow a sporotrichoid pattern. Most patients with bacillary angiomatosis are immunosuppressed, though it rarely can affect immunocompetent patients. Histologically, bacillary angiomatosis is similar to pyogenic granuloma, though Gram or Warthin-Starry stains can help differentiate B henselae.⁸

Kaposi sarcoma is a malignant vascular neoplasm that often manifests in immunocompromised patients as violaceous, purple, or red patches, plaques, and nodules on the skin or oral mucosa. Histopathology shows spindle cell proliferation of irregular complex vascular channels dissecting through the dermis. Human herpesvirus 8 immunohistochemistry can be used to confirm diagnosis on histopathology.⁹ In contrast, amelanotic melanoma consists of lack of pigmentation, asymmetry with polymorphous vascular pattern, and high mitotic rate and is commonly found in sun-exposed areas. Dermoscopic features include irregular globules with blue-whitish veil.¹⁰

Treatment of atypical Spitz nevi depends mainly on the age of the patient and the histologic features of the nevus. Adults with atypical Spitz nevi frequently require excision, while the preferred choice for treatment in children with common Spitz nevi is regular clinical monitoring when there are no concerning clinical, dermoscopic, or histologic features.⁸ Compared to common Spitz nevi, atypical Spitz nevi have more melanoma-like features, resulting in a stronger recommendation for excision. Excision allows for a more thorough histologic evaluation and minimizes the likelihood of a recurrent atypical lesion.¹¹ In all cases, close clinical follow-up is recommended to monitor for reoccurrence.

THE DIAGNOSIS: Atypical Spitz Tumor

The shave biopsy revealed extensive dermal proliferation with spitzoid cytomorphology containing large, spindled nuclei; prominent nucleoli; and abundant homogenous cytoplasm arranged in haphazard fascicles. The proliferation was associated with prominent pseudoepitheliomatous hyperplasia of the overlying epidermis, and anaplastic lymphoma kinase immunohistochemistry showed diffuse strong positivity. Fluorescence in situ hybridization confirmed fusion of the tropomyosin 3 (TPM3) and anaplastic lymphoma kinase (ALK) genes, which finalized the diagnosis of an ALK-mutated atypical spitz tumor. Due to the location and size of the lesion, Mohs micrographic surgery was performed to excise the tumor and clear the margins.

Spitz nevi are uncommon benign melanocytic neoplasms that typically occur in pediatric populations.¹ Atypical spitz nevi comprised fewer than 17% of all childhood melanocytic nevi in the United States and can be considered in the broader category of spitzoid tumors. Spitz nevi are divided into 3 classes: Spitz nevus, atypical Spitz nevus, and spitzoid melanoma. Atypical Spitz nevi have typical Spitz nevus and spitzoid melanoma features and often can be difficult to distinguish on dermoscopy. Malignant Spitz tumors typically occur in the fifth decade of life, though the age distribution can vary widely.¹

Black patients are less likely to be diagnosed with Spitz nevi, potentially due to a lower prevalence in this population, thus limiting the clinician’s clinical exposure and leading to increased rates of misdiagnoses.² Spitz nevi usually manifest as well-circumscribed, dome-shaped papules and frequently are described as pink to red due to increased vascularity and limited melanin content¹; however, these lesions may appear more violaceous, dusky, or dark brown in darker skin types. Additionally, approximately 71% of patients in a clinical review of Spitz nevi had a pigmented lesion, ranging from light brown to black.³ It is important for dermatologists to understand that the contrast in color between the nevus and the surrounding skin may not be as striking, prominent, or clinically concerning, particularly in darker skin types, such as in our patient.

Spitz nevi frequently manifest as rapidly growing solitary lesions most frequently developing in the lower legs (shown in 41% of lesions in one report).⁴ However, a recent retrospective review indicated that Spitz nevi in Black patients most commonly were found on the upper extremities, as was seen in our patient.² Compared to typical and common Spitz nevi, atypical Spitz nevi often are greater than 10 mm in diameter and have features of ulceration.

Diagnosing atypical spitzoid melanocytic lesions requires adequate clinical suspicion and confirmation via biopsy. Under dermoscopy, typical Spitz nevi often display a starburst or globular pattern with pinpoint vessels, though it can have variable manifestations of both patterns. Atypical Spitz nevi can be challenging to distinguish from melanoma on dermoscopy since both conditions can have atypical pigment networks or structureless homogenous areas.¹ Consequently, there often is a lower threshold for biopsy and possible follow-up excision for atypical Spitz nevi. Histopathology of atypical Spitz nevi includes epithelioid and spindle melanocytes but can share features of melanomas, including areas of prominent pagetoid spread, asymmetry, and poor circumscription.⁵ Furthermore, atypical Spitz nevi with ALK gene fusion, as seen in our patient, have been shown in the literature to demonstrate distinct histopathologic features, such as wedge-shaped extension into the dermis or a bulbous lower border that can resemble pseudoepitheliomatous hyperplasia.⁶

The differential diagnosis for this rapidly growing scaly nodule also should include pyogenic granuloma, bacillary angiomatosis, Kaposi sarcoma, and amelanotic melanoma. Pyogenic granuloma is a rapidly growing, benign, vascular tumor that often becomes ulcerated and can occur in any age group.⁷ Pyogenic granuloma frequently appears at sites of trauma as a solitary, bright pink to red, friable, pedunculated papule and often manifests on the arms, hands, and face, similar to atypical Spitz nevi, though they can appear anywhere on the body. Histology shows a lobular capillary network with a central feeder vessel.⁷

Bacillary angiomatosis is an uncommon cutaneous infection associated with vascular proliferation and neovascularization due to the gram-negative organism Bartonella henselae.⁸ Bacillary nodules typically are reddish to purple and appear on the arms, sometimes with central ulceration and bleeding. Patients may present with multiple papules and nodules of varying sizes, as the lesions can arise in crops and follow a sporotrichoid pattern. Most patients with bacillary angiomatosis are immunosuppressed, though it rarely can affect immunocompetent patients. Histologically, bacillary angiomatosis is similar to pyogenic granuloma, though Gram or Warthin-Starry stains can help differentiate B henselae.⁸

Kaposi sarcoma is a malignant vascular neoplasm that often manifests in immunocompromised patients as violaceous, purple, or red patches, plaques, and nodules on the skin or oral mucosa. Histopathology shows spindle cell proliferation of irregular complex vascular channels dissecting through the dermis. Human herpesvirus 8 immunohistochemistry can be used to confirm diagnosis on histopathology.⁹ In contrast, amelanotic melanoma consists of lack of pigmentation, asymmetry with polymorphous vascular pattern, and high mitotic rate and is commonly found in sun-exposed areas. Dermoscopic features include irregular globules with blue-whitish veil.¹⁰

Treatment of atypical Spitz nevi depends mainly on the age of the patient and the histologic features of the nevus. Adults with atypical Spitz nevi frequently require excision, while the preferred choice for treatment in children with common Spitz nevi is regular clinical monitoring when there are no concerning clinical, dermoscopic, or histologic features.⁸ Compared to common Spitz nevi, atypical Spitz nevi have more melanoma-like features, resulting in a stronger recommendation for excision. Excision allows for a more thorough histologic evaluation and minimizes the likelihood of a recurrent atypical lesion.¹¹ In all cases, close clinical follow-up is recommended to monitor for reoccurrence.

THE DIAGNOSIS: Atypical Spitz Tumor

The shave biopsy revealed extensive dermal proliferation with spitzoid cytomorphology containing large, spindled nuclei; prominent nucleoli; and abundant homogenous cytoplasm arranged in haphazard fascicles. The proliferation was associated with prominent pseudoepitheliomatous hyperplasia of the overlying epidermis, and anaplastic lymphoma kinase immunohistochemistry showed diffuse strong positivity. Fluorescence in situ hybridization confirmed fusion of the tropomyosin 3 (TPM3) and anaplastic lymphoma kinase (ALK) genes, which finalized the diagnosis of an ALK-mutated atypical spitz tumor. Due to the location and size of the lesion, Mohs micrographic surgery was performed to excise the tumor and clear the margins.

Spitz nevi are uncommon benign melanocytic neoplasms that typically occur in pediatric populations.¹ Atypical spitz nevi comprised fewer than 17% of all childhood melanocytic nevi in the United States and can be considered in the broader category of spitzoid tumors. Spitz nevi are divided into 3 classes: Spitz nevus, atypical Spitz nevus, and spitzoid melanoma. Atypical Spitz nevi have typical Spitz nevus and spitzoid melanoma features and often can be difficult to distinguish on dermoscopy. Malignant Spitz tumors typically occur in the fifth decade of life, though the age distribution can vary widely.¹

Black patients are less likely to be diagnosed with Spitz nevi, potentially due to a lower prevalence in this population, thus limiting the clinician’s clinical exposure and leading to increased rates of misdiagnoses.² Spitz nevi usually manifest as well-circumscribed, dome-shaped papules and frequently are described as pink to red due to increased vascularity and limited melanin content¹; however, these lesions may appear more violaceous, dusky, or dark brown in darker skin types. Additionally, approximately 71% of patients in a clinical review of Spitz nevi had a pigmented lesion, ranging from light brown to black.³ It is important for dermatologists to understand that the contrast in color between the nevus and the surrounding skin may not be as striking, prominent, or clinically concerning, particularly in darker skin types, such as in our patient.

Spitz nevi frequently manifest as rapidly growing solitary lesions most frequently developing in the lower legs (shown in 41% of lesions in one report).⁴ However, a recent retrospective review indicated that Spitz nevi in Black patients most commonly were found on the upper extremities, as was seen in our patient.² Compared to typical and common Spitz nevi, atypical Spitz nevi often are greater than 10 mm in diameter and have features of ulceration.

Diagnosing atypical spitzoid melanocytic lesions requires adequate clinical suspicion and confirmation via biopsy. Under dermoscopy, typical Spitz nevi often display a starburst or globular pattern with pinpoint vessels, though it can have variable manifestations of both patterns. Atypical Spitz nevi can be challenging to distinguish from melanoma on dermoscopy since both conditions can have atypical pigment networks or structureless homogenous areas.¹ Consequently, there often is a lower threshold for biopsy and possible follow-up excision for atypical Spitz nevi. Histopathology of atypical Spitz nevi includes epithelioid and spindle melanocytes but can share features of melanomas, including areas of prominent pagetoid spread, asymmetry, and poor circumscription.⁵ Furthermore, atypical Spitz nevi with ALK gene fusion, as seen in our patient, have been shown in the literature to demonstrate distinct histopathologic features, such as wedge-shaped extension into the dermis or a bulbous lower border that can resemble pseudoepitheliomatous hyperplasia.⁶

The differential diagnosis for this rapidly growing scaly nodule also should include pyogenic granuloma, bacillary angiomatosis, Kaposi sarcoma, and amelanotic melanoma. Pyogenic granuloma is a rapidly growing, benign, vascular tumor that often becomes ulcerated and can occur in any age group.⁷ Pyogenic granuloma frequently appears at sites of trauma as a solitary, bright pink to red, friable, pedunculated papule and often manifests on the arms, hands, and face, similar to atypical Spitz nevi, though they can appear anywhere on the body. Histology shows a lobular capillary network with a central feeder vessel.⁷

Bacillary angiomatosis is an uncommon cutaneous infection associated with vascular proliferation and neovascularization due to the gram-negative organism Bartonella henselae.⁸ Bacillary nodules typically are reddish to purple and appear on the arms, sometimes with central ulceration and bleeding. Patients may present with multiple papules and nodules of varying sizes, as the lesions can arise in crops and follow a sporotrichoid pattern. Most patients with bacillary angiomatosis are immunosuppressed, though it rarely can affect immunocompetent patients. Histologically, bacillary angiomatosis is similar to pyogenic granuloma, though Gram or Warthin-Starry stains can help differentiate B henselae.⁸

Kaposi sarcoma is a malignant vascular neoplasm that often manifests in immunocompromised patients as violaceous, purple, or red patches, plaques, and nodules on the skin or oral mucosa. Histopathology shows spindle cell proliferation of irregular complex vascular channels dissecting through the dermis. Human herpesvirus 8 immunohistochemistry can be used to confirm diagnosis on histopathology.⁹ In contrast, amelanotic melanoma consists of lack of pigmentation, asymmetry with polymorphous vascular pattern, and high mitotic rate and is commonly found in sun-exposed areas. Dermoscopic features include irregular globules with blue-whitish veil.¹⁰

Treatment of atypical Spitz nevi depends mainly on the age of the patient and the histologic features of the nevus. Adults with atypical Spitz nevi frequently require excision, while the preferred choice for treatment in children with common Spitz nevi is regular clinical monitoring when there are no concerning clinical, dermoscopic, or histologic features.⁸ Compared to common Spitz nevi, atypical Spitz nevi have more melanoma-like features, resulting in a stronger recommendation for excision. Excision allows for a more thorough histologic evaluation and minimizes the likelihood of a recurrent atypical lesion.¹¹ In all cases, close clinical follow-up is recommended to monitor for reoccurrence.

THE DIAGNOSIS: Hypertrophic Lupus Erythematosus

The biopsy of the face collected at the initial appointment revealed interface dermatitis with epidermal hyperplasia with no parakeratosis or eosinophils (Figure 1). Microscopic findings were suggestive of hypertrophic lupus erythematosus (HLE) or hypertrophic lichen planus. The rapid plasma reagin and HIV labs collected at the initial appointment were negative, and a review of systems was negative for systemic symptoms. Considering these results and the clinical distribution of the lesions primarily affecting sun-exposed areas of the upper body, a final diagnosis of HLE was made. The patient was counseled on the importance of photoprotection and was started on hydroxychloroquine.

Hypertrophic lupus erythematosus, a rare variant of chronic cutaneous lupus erythematosus (CCLE), typically manifests as verrucous plaques or nodules commonly found on sun-exposed areas of the body, as was observed in our patient on the face, scalp (Figures 2 and 3), chest, and upper extremities.¹ Lesions can have a variable appearance, from hyperkeratotic ulcers to depigmented plaques and keratoacanthomalike lesions.² On histopathology, HLE falls into the category of lichenoid interface dermatitis and commonly demonstrates hyperkeratosis, acanthosis, follicular plugging, superficial and deep infiltrate, and increased mucin deposition in the dermis.³

Although rare, it is critical to remain vigilant for the development of squamous cell carcinoma in patients with chronic untreated CCLE. Hypertrophic lupus erythematosus, specifically, is the most likely variant to give rise to invasive squamous cell carcinoma and can be more aggressive as a result of this malignant transformation.^3,4 Ruling out squamous cell carcinoma in the setting of HLE can be achieved by staining for CD123, as HLE commonly is associated with many CD123+ plasmacytoid dendritic cells adjacent to the epithelium, unlike squamous cell carcinoma.³ Fortunately no evidence of invasive squamous cell carcinoma, including cellular atypia or increased mitotic figures, was seen on histology in our patient.

A thorough history and physical examination are essential for screening for HLE, as positive antinuclear antibodies are observed only in half of the patients diagnosed with CCLE.⁵ Furthermore, antinuclear antibodies sometimes can be negative in patients with HLE who have end-stage organ involvement.

Hypertrophic lupus erythematosus can be challenging to treat. First-line therapies include antimalarials, topical steroids, and sun-protective measures. Intralesional triamcinolone injection also can be used as an adjunctive therapy to expedite the treatment response.⁶ Evidence supports good response following treatment with acitretin or a combination of isotretinoin and hydroxychloroquine.² Another therapeutic strategy is implementing immunosuppressants such as methotrexate, mycophenolate mofetil, and azathioprine for persistent disease. Immunomodulators such as thalidomide historically have been shown to treat severe recalcitrant cases of HLE but typically are reserved for extreme cases due to adverse effects. Biologic agents such as intravenous immunoglobulins and rituximab have been shown to treat CCLE successfully, but routine use is limited due to high cost and lack of strong clinical trials.⁷

There have been reports of experimental therapies such as monoclonal antibodies (eg, anifrolumab and tocilizumab therapy) providing remission for patients with refractory CCLE, but information on their efficacy—specifically in patients with HLE—is lacking.⁸ Chronic cutaneous lupus erythematosus and its variants require further investigation regarding which treatment options provide the greatest benefit while minimizing adverse effects.

It is important to distinguish HLE from other potential diagnoses. Features of HLE can mimic hypertrophic lichen planus; however, the latter typically appears on the legs while HLE appears more commonly on the upper extremities and face in a photodistributed pattern.⁹ Since HLE has a lichenoid appearance histologically, it may appear clinically similar to hypertrophic lichen planus. Although not performed in our patient due to cost, direct immunofluorescence can aid in distinguishing HLE from hypertrophic lichen planus. Chronic cutaneous lupus erythematosus shows a granular pattern of deposition of IgM (primarily), IgG, IgA, and C3. In contrast, hypertrophic lichen planus exhibits cytoid bodies that stain positive for IgM as well as linear deposition of fibrinogen along the basement membrane.^3,10

Blastomycosis also can lead to development of verrucous plaques in sun-exposed areas, but the lesions typically originate as pustules that ulcerate over time. Lesions also can manifest with central scarring and a heaped edge.³ Unlike HLE, pseudoepitheliomatous hyperplasia with mixed infiltrate and intradermal pustules are seen in blastomycosis.³ Fungal organisms often are seen on pathology and are relatively large and uniform in size and shape, are found within giant cells, and have a thick refractile asymmetrical wall.¹¹ In rupioid psoriasis, skin lesions mostly are widespread and are not limited to sun-exposed areas. Additionally, biopsies from active rupioid lesions typically show psoriasiform epidermal hyperplasia with parakeratosis with no interface inflammation—a key differentiator.¹² In secondary syphilis, chancres often are missed and are not reported by patients. Clinically, secondary syphilis often manifests as scaly patches and plaques with palmar involvement and positive rapid plasma reagin, which was negative in our patient.¹³ Histologically, secondary syphilis can exhibit a vacuolar or lichenoid interface dermatitis; however, it typically exhibits slender acanthosis with long rete ridges and neutrophils in the stratum corneum.³ Furthermore, plasma cells are present in about two-thirds of cases in the United States, with obliteration of the lumen of small vessels and perivascular histiocytes and lymphocytes with apparent cytoplasm commonly seen on pathology. Silver staining or immunostaining for Treponema pallidum may reveal the spirochetes that cause this condition.³

THE DIAGNOSIS: Hypertrophic Lupus Erythematosus

The biopsy of the face collected at the initial appointment revealed interface dermatitis with epidermal hyperplasia with no parakeratosis or eosinophils (Figure 1). Microscopic findings were suggestive of hypertrophic lupus erythematosus (HLE) or hypertrophic lichen planus. The rapid plasma reagin and HIV labs collected at the initial appointment were negative, and a review of systems was negative for systemic symptoms. Considering these results and the clinical distribution of the lesions primarily affecting sun-exposed areas of the upper body, a final diagnosis of HLE was made. The patient was counseled on the importance of photoprotection and was started on hydroxychloroquine.

Hypertrophic lupus erythematosus, a rare variant of chronic cutaneous lupus erythematosus (CCLE), typically manifests as verrucous plaques or nodules commonly found on sun-exposed areas of the body, as was observed in our patient on the face, scalp (Figures 2 and 3), chest, and upper extremities.¹ Lesions can have a variable appearance, from hyperkeratotic ulcers to depigmented plaques and keratoacanthomalike lesions.² On histopathology, HLE falls into the category of lichenoid interface dermatitis and commonly demonstrates hyperkeratosis, acanthosis, follicular plugging, superficial and deep infiltrate, and increased mucin deposition in the dermis.³

Although rare, it is critical to remain vigilant for the development of squamous cell carcinoma in patients with chronic untreated CCLE. Hypertrophic lupus erythematosus, specifically, is the most likely variant to give rise to invasive squamous cell carcinoma and can be more aggressive as a result of this malignant transformation.^3,4 Ruling out squamous cell carcinoma in the setting of HLE can be achieved by staining for CD123, as HLE commonly is associated with many CD123+ plasmacytoid dendritic cells adjacent to the epithelium, unlike squamous cell carcinoma.³ Fortunately no evidence of invasive squamous cell carcinoma, including cellular atypia or increased mitotic figures, was seen on histology in our patient.

A thorough history and physical examination are essential for screening for HLE, as positive antinuclear antibodies are observed only in half of the patients diagnosed with CCLE.⁵ Furthermore, antinuclear antibodies sometimes can be negative in patients with HLE who have end-stage organ involvement.

Hypertrophic lupus erythematosus can be challenging to treat. First-line therapies include antimalarials, topical steroids, and sun-protective measures. Intralesional triamcinolone injection also can be used as an adjunctive therapy to expedite the treatment response.⁶ Evidence supports good response following treatment with acitretin or a combination of isotretinoin and hydroxychloroquine.² Another therapeutic strategy is implementing immunosuppressants such as methotrexate, mycophenolate mofetil, and azathioprine for persistent disease. Immunomodulators such as thalidomide historically have been shown to treat severe recalcitrant cases of HLE but typically are reserved for extreme cases due to adverse effects. Biologic agents such as intravenous immunoglobulins and rituximab have been shown to treat CCLE successfully, but routine use is limited due to high cost and lack of strong clinical trials.⁷

There have been reports of experimental therapies such as monoclonal antibodies (eg, anifrolumab and tocilizumab therapy) providing remission for patients with refractory CCLE, but information on their efficacy—specifically in patients with HLE—is lacking.⁸ Chronic cutaneous lupus erythematosus and its variants require further investigation regarding which treatment options provide the greatest benefit while minimizing adverse effects.

It is important to distinguish HLE from other potential diagnoses. Features of HLE can mimic hypertrophic lichen planus; however, the latter typically appears on the legs while HLE appears more commonly on the upper extremities and face in a photodistributed pattern.⁹ Since HLE has a lichenoid appearance histologically, it may appear clinically similar to hypertrophic lichen planus. Although not performed in our patient due to cost, direct immunofluorescence can aid in distinguishing HLE from hypertrophic lichen planus. Chronic cutaneous lupus erythematosus shows a granular pattern of deposition of IgM (primarily), IgG, IgA, and C3. In contrast, hypertrophic lichen planus exhibits cytoid bodies that stain positive for IgM as well as linear deposition of fibrinogen along the basement membrane.^3,10

Blastomycosis also can lead to development of verrucous plaques in sun-exposed areas, but the lesions typically originate as pustules that ulcerate over time. Lesions also can manifest with central scarring and a heaped edge.³ Unlike HLE, pseudoepitheliomatous hyperplasia with mixed infiltrate and intradermal pustules are seen in blastomycosis.³ Fungal organisms often are seen on pathology and are relatively large and uniform in size and shape, are found within giant cells, and have a thick refractile asymmetrical wall.¹¹ In rupioid psoriasis, skin lesions mostly are widespread and are not limited to sun-exposed areas. Additionally, biopsies from active rupioid lesions typically show psoriasiform epidermal hyperplasia with parakeratosis with no interface inflammation—a key differentiator.¹² In secondary syphilis, chancres often are missed and are not reported by patients. Clinically, secondary syphilis often manifests as scaly patches and plaques with palmar involvement and positive rapid plasma reagin, which was negative in our patient.¹³ Histologically, secondary syphilis can exhibit a vacuolar or lichenoid interface dermatitis; however, it typically exhibits slender acanthosis with long rete ridges and neutrophils in the stratum corneum.³ Furthermore, plasma cells are present in about two-thirds of cases in the United States, with obliteration of the lumen of small vessels and perivascular histiocytes and lymphocytes with apparent cytoplasm commonly seen on pathology. Silver staining or immunostaining for Treponema pallidum may reveal the spirochetes that cause this condition.³

THE DIAGNOSIS: Hypertrophic Lupus Erythematosus

The biopsy of the face collected at the initial appointment revealed interface dermatitis with epidermal hyperplasia with no parakeratosis or eosinophils (Figure 1). Microscopic findings were suggestive of hypertrophic lupus erythematosus (HLE) or hypertrophic lichen planus. The rapid plasma reagin and HIV labs collected at the initial appointment were negative, and a review of systems was negative for systemic symptoms. Considering these results and the clinical distribution of the lesions primarily affecting sun-exposed areas of the upper body, a final diagnosis of HLE was made. The patient was counseled on the importance of photoprotection and was started on hydroxychloroquine.

Hypertrophic lupus erythematosus, a rare variant of chronic cutaneous lupus erythematosus (CCLE), typically manifests as verrucous plaques or nodules commonly found on sun-exposed areas of the body, as was observed in our patient on the face, scalp (Figures 2 and 3), chest, and upper extremities.¹ Lesions can have a variable appearance, from hyperkeratotic ulcers to depigmented plaques and keratoacanthomalike lesions.² On histopathology, HLE falls into the category of lichenoid interface dermatitis and commonly demonstrates hyperkeratosis, acanthosis, follicular plugging, superficial and deep infiltrate, and increased mucin deposition in the dermis.³

Although rare, it is critical to remain vigilant for the development of squamous cell carcinoma in patients with chronic untreated CCLE. Hypertrophic lupus erythematosus, specifically, is the most likely variant to give rise to invasive squamous cell carcinoma and can be more aggressive as a result of this malignant transformation.^3,4 Ruling out squamous cell carcinoma in the setting of HLE can be achieved by staining for CD123, as HLE commonly is associated with many CD123+ plasmacytoid dendritic cells adjacent to the epithelium, unlike squamous cell carcinoma.³ Fortunately no evidence of invasive squamous cell carcinoma, including cellular atypia or increased mitotic figures, was seen on histology in our patient.

A thorough history and physical examination are essential for screening for HLE, as positive antinuclear antibodies are observed only in half of the patients diagnosed with CCLE.⁵ Furthermore, antinuclear antibodies sometimes can be negative in patients with HLE who have end-stage organ involvement.

Hypertrophic lupus erythematosus can be challenging to treat. First-line therapies include antimalarials, topical steroids, and sun-protective measures. Intralesional triamcinolone injection also can be used as an adjunctive therapy to expedite the treatment response.⁶ Evidence supports good response following treatment with acitretin or a combination of isotretinoin and hydroxychloroquine.² Another therapeutic strategy is implementing immunosuppressants such as methotrexate, mycophenolate mofetil, and azathioprine for persistent disease. Immunomodulators such as thalidomide historically have been shown to treat severe recalcitrant cases of HLE but typically are reserved for extreme cases due to adverse effects. Biologic agents such as intravenous immunoglobulins and rituximab have been shown to treat CCLE successfully, but routine use is limited due to high cost and lack of strong clinical trials.⁷

There have been reports of experimental therapies such as monoclonal antibodies (eg, anifrolumab and tocilizumab therapy) providing remission for patients with refractory CCLE, but information on their efficacy—specifically in patients with HLE—is lacking.⁸ Chronic cutaneous lupus erythematosus and its variants require further investigation regarding which treatment options provide the greatest benefit while minimizing adverse effects.

It is important to distinguish HLE from other potential diagnoses. Features of HLE can mimic hypertrophic lichen planus; however, the latter typically appears on the legs while HLE appears more commonly on the upper extremities and face in a photodistributed pattern.⁹ Since HLE has a lichenoid appearance histologically, it may appear clinically similar to hypertrophic lichen planus. Although not performed in our patient due to cost, direct immunofluorescence can aid in distinguishing HLE from hypertrophic lichen planus. Chronic cutaneous lupus erythematosus shows a granular pattern of deposition of IgM (primarily), IgG, IgA, and C3. In contrast, hypertrophic lichen planus exhibits cytoid bodies that stain positive for IgM as well as linear deposition of fibrinogen along the basement membrane.^3,10

Blastomycosis also can lead to development of verrucous plaques in sun-exposed areas, but the lesions typically originate as pustules that ulcerate over time. Lesions also can manifest with central scarring and a heaped edge.³ Unlike HLE, pseudoepitheliomatous hyperplasia with mixed infiltrate and intradermal pustules are seen in blastomycosis.³ Fungal organisms often are seen on pathology and are relatively large and uniform in size and shape, are found within giant cells, and have a thick refractile asymmetrical wall.¹¹ In rupioid psoriasis, skin lesions mostly are widespread and are not limited to sun-exposed areas. Additionally, biopsies from active rupioid lesions typically show psoriasiform epidermal hyperplasia with parakeratosis with no interface inflammation—a key differentiator.¹² In secondary syphilis, chancres often are missed and are not reported by patients. Clinically, secondary syphilis often manifests as scaly patches and plaques with palmar involvement and positive rapid plasma reagin, which was negative in our patient.¹³ Histologically, secondary syphilis can exhibit a vacuolar or lichenoid interface dermatitis; however, it typically exhibits slender acanthosis with long rete ridges and neutrophils in the stratum corneum.³ Furthermore, plasma cells are present in about two-thirds of cases in the United States, with obliteration of the lumen of small vessels and perivascular histiocytes and lymphocytes with apparent cytoplasm commonly seen on pathology. Silver staining or immunostaining for Treponema pallidum may reveal the spirochetes that cause this condition.³

New research, with the caveat of a relatively short follow-up, adds to encouraging data showing an overall low risk of the development of thyroid cancer associated with glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment.

However, a notably increased rate of thyroid cancer detections limited only to the first year after drug initiation — but not later, coupled with an increased rate of thyroid cancer screening during that period, raises the suggestion that a thyroid cancer concern among the millions of patients taking the immensely popular drugs could exacerbate the already problematic over-detection of incidental thyroid cancers.

“Our study confirms the increased likelihood of being diagnosed with what appears to be low-risk thyroid cancer after treatment with GLP-1 RAs — but not because patients treated with GLP-1 RAs are more likely to develop thyroid cancer but rather because they are more likely to be diagnosed with it because we, as clinicians, are more likely to look for it,” senior author Rozalina G. McCoy, MD, associate professor and associate division chief for clinical research in the Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine at the University of Maryland School of Medicine, in Baltimore, told this news organization.

The findings were published in JAMA Otolaryngology-Head & Neck Surgery.

Thyroid cancer concerns surrounding GLP-1 RAs stem from preclinical studies showing a risk for medullary thyroid cancer in rodents, resulting in a boxed warning from the US Food and Drug Administration recommending that those with a family history of the condition avoid the drugs.

More recent studies showing GLP-1 receptors in human papillary thyroid cancer cells has further raised concerns of a risk beyond medullary thyroid cancer, however, recent studies evaluating the risk have been inconclusive.

To further investigate, McCoy and colleagues evaluated claims data on 351,913 adult enrollees in Medicare Advantage and fee-for-service plans in the United States who had type 2 diabetes, a moderate risk for cardiovascular disease, and no history of thyroid cancer.

Of the patients, who were about half women, 41,112 started treatments with GLP-1 RAs; 76,093, started with dipeptidyl peptidase-4 (DPP-4) inhibitors; 43,499, with sodium-glucose cotransporter 2 (SGLT2i) inhibitors; and 191,209 with sulfonylurea therapy between January 2014 and December 2021.

After inverse probability weighting, baseline characteristics in the drug groups were well-balanced.

Overall, with median follow-up times of 660 days (range, 254-1157 days) in the GLP-1 RA group; approximately 4 years in the sulfonylurea and DPP-4 inhibitor groups; and about 2.5 years in the SGLT2 inhibitor group, the absolute risk for thyroid cancer diagnoses in the treatment groups were low, with a rate of 0.17% in the GLP-1 RA group, 0.23% in the DPP-4 inhibitor group, 0.17% in the SGLT2 inhibitor group, and 0.20% in the sulfonylurea group.

The modified intention to treat analysis concluded no increase with GLP-1 RA use in thyroid cancer risk compared with the other three diabetes drugs (hazard ratio [HR], 1.24).

 

Higher Cancers Detected in First Year Likely From Higher Screening

Importantly, the risk for thyroid cancer was significantly higher within the first year after GLP-1 RA initiation (HR, 1.85) and was also higher among patients who stayed on the medication and didn’t add other medication (HR, 2.07).

With the latency period for the development of thyroid cancer from external exposures taking several years (such as radiation, taking approximately 2.5 years), some studies in fact exclude patients diagnosed with cancers within a year of starting GLP-1s, as it is implausible for a cancer to develop so soon.

Cancers detected that early therefore are considered to likely have been found due to stepped up screening resulting from an increased concern of thyroid cancer with GLP-1 use.

In support of that theory, the study showed that those in the GLP-1 group had a significantly higher rate of receiving thyroid ultrasounds than those in the non−GLP-1 group, at 1.2% at 6 months for GLP-1RA initiators vs 0.8% for non−GLP-1 RA initiators, and an estimated 2.1% at 12 months for GLP-1RA initiators vs 1.5% for non−GLP-1RA initiators (P < .01).

Though the percentages were small, in relative terms, the 6-month rate of screening in the GLP-1 RA group is a 50% increase, and the 12-month rate represents a 40% increase, McCoy pointed out. 

“If we think about 1.2% of people getting an ultrasound in the context of over 41,000 patients, that is a lot of ultrasounds,” she said. 

“To my knowledge, this is the first study to actually look at rates of thyroid ultrasounds with GLP-1 RA initiation, so it will definitely be important to look at the trends more broadly,” McCoy added.

McCoy noted that a key caveat of the study is the relatively short follow-up of only about 2 years.

“We have not been able to follow patients for decades to know if there is risk of new thyroid cancers developing after prolonged exposure,” she said. “But we generally don’t know this for any medication until it is used by many millions of people for many decades.”

 

Consistent Findings in Recent Research

In another recent study evaluating the risk for thyroid cancer among patients receiving GLP-1s, with a longer follow-up of 3.9 years, Bjorn Pasternak, MD, PhD, of the Division of Clinical Epidemiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden, and colleagues reported similar findings — the overall risk for thyroid cancer with GLP-1s was not increased (HR, 0.93), and the risk beginning 1 year after treatment initiation was lower, at 0.83. 

However, the risk in that study only looking at the first year alone was again higher, at HR 1.47.

“Our analyses indicating a nominally increased risk restricted to the first year after starting treatment might be consistent with an increased detection of thyroid cancer among patients using GLP-1 RAs,” he told this news organization.

In addition to the short follow-up of the current study, Pasternak noted the caveat of the study’s inclusion mainly of patients who initiated the four diabetes drug groups, which is a limitation “because a high proportion of the patients with type 2 diabetes in routine care who start GLP-1 RAs have started it as their third, fourth, or even fifth diabetes drug, especially if they have had diabetes for some time.”

“To capture a larger proportion of the full population of GLP-1 RA users, it would have been preferable to create three different cohorts for the purpose of this study and investigate them separately, including GLP-1 vs DPP4i; GLP-1 vs SGLT2i; GLP-1 vs sulfonylurea,” he said.

 

Rise in Incidental Thyroid Cancer Detection, An Ongoing Concern

The advent of more advanced imaging and thyroid cancer testing in recent years has already led to a significant problem of over-detection and sometimes over-treatment of incidental, small thyroid cancers that will likely remain harmless in the majority of patients. 

With approximately 64 million prescriptions of GLP-1 RAs dispensed between 2000 and 2015 and the percentage increasing at a rate of about 10%-30% per year, increased thyroid testing among those patients could indeed add to the problem.

Meanwhile, thyroid testing is currently not recommended for patients on GLP-1s who do not have a thyroid cancer risk, and the results from the current and Pasternak’s studies, as well as several other recent studies, appear to support those recommendations.

“Collectively, these reassuring data could potentially help reduce [thyroid cancer] over-detection and screening,” Pasternak said. 

McCoy echoed that the evidence indicates that “for the vast majority of people there is no indication that GLP-1 RA causes thyroid cancer.”

She underscored that overdiagnosis can have important implications, sharing her own personal experience on the receiving end of a cancer diagnosis.

“Overdiagnosis of these low-risk thyroid cancers may ultimately lead to more harm for the patient than not making the diagnosis, since surgery for thyroid cancer carries real risks (including of death) and there are downstream consequences to having your thyroid removed and relying on lifelong hormone replacement,” McCoy said.

“As a cancer survivor myself, though of lymphoma, not thyroid cancer, I also know the profound impact that a cancer diagnosis has on the individual and their loved ones,” McCoy said.

“It is not something I would wish for anyone, which is why I always speak to my patients about searching for something we may not want to — or need to — find.”

The authors and Pasternak had no disclosures to report.

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

New research, with the caveat of a relatively short follow-up, adds to encouraging data showing an overall low risk of the development of thyroid cancer associated with glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment.

However, a notably increased rate of thyroid cancer detections limited only to the first year after drug initiation — but not later, coupled with an increased rate of thyroid cancer screening during that period, raises the suggestion that a thyroid cancer concern among the millions of patients taking the immensely popular drugs could exacerbate the already problematic over-detection of incidental thyroid cancers.

“Our study confirms the increased likelihood of being diagnosed with what appears to be low-risk thyroid cancer after treatment with GLP-1 RAs — but not because patients treated with GLP-1 RAs are more likely to develop thyroid cancer but rather because they are more likely to be diagnosed with it because we, as clinicians, are more likely to look for it,” senior author Rozalina G. McCoy, MD, associate professor and associate division chief for clinical research in the Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine at the University of Maryland School of Medicine, in Baltimore, told this news organization.

The findings were published in JAMA Otolaryngology-Head & Neck Surgery.

Thyroid cancer concerns surrounding GLP-1 RAs stem from preclinical studies showing a risk for medullary thyroid cancer in rodents, resulting in a boxed warning from the US Food and Drug Administration recommending that those with a family history of the condition avoid the drugs.

More recent studies showing GLP-1 receptors in human papillary thyroid cancer cells has further raised concerns of a risk beyond medullary thyroid cancer, however, recent studies evaluating the risk have been inconclusive.

To further investigate, McCoy and colleagues evaluated claims data on 351,913 adult enrollees in Medicare Advantage and fee-for-service plans in the United States who had type 2 diabetes, a moderate risk for cardiovascular disease, and no history of thyroid cancer.

Of the patients, who were about half women, 41,112 started treatments with GLP-1 RAs; 76,093, started with dipeptidyl peptidase-4 (DPP-4) inhibitors; 43,499, with sodium-glucose cotransporter 2 (SGLT2i) inhibitors; and 191,209 with sulfonylurea therapy between January 2014 and December 2021.

After inverse probability weighting, baseline characteristics in the drug groups were well-balanced.

Overall, with median follow-up times of 660 days (range, 254-1157 days) in the GLP-1 RA group; approximately 4 years in the sulfonylurea and DPP-4 inhibitor groups; and about 2.5 years in the SGLT2 inhibitor group, the absolute risk for thyroid cancer diagnoses in the treatment groups were low, with a rate of 0.17% in the GLP-1 RA group, 0.23% in the DPP-4 inhibitor group, 0.17% in the SGLT2 inhibitor group, and 0.20% in the sulfonylurea group.

The modified intention to treat analysis concluded no increase with GLP-1 RA use in thyroid cancer risk compared with the other three diabetes drugs (hazard ratio [HR], 1.24).

 

Higher Cancers Detected in First Year Likely From Higher Screening

Importantly, the risk for thyroid cancer was significantly higher within the first year after GLP-1 RA initiation (HR, 1.85) and was also higher among patients who stayed on the medication and didn’t add other medication (HR, 2.07).

With the latency period for the development of thyroid cancer from external exposures taking several years (such as radiation, taking approximately 2.5 years), some studies in fact exclude patients diagnosed with cancers within a year of starting GLP-1s, as it is implausible for a cancer to develop so soon.

Cancers detected that early therefore are considered to likely have been found due to stepped up screening resulting from an increased concern of thyroid cancer with GLP-1 use.

In support of that theory, the study showed that those in the GLP-1 group had a significantly higher rate of receiving thyroid ultrasounds than those in the non−GLP-1 group, at 1.2% at 6 months for GLP-1RA initiators vs 0.8% for non−GLP-1 RA initiators, and an estimated 2.1% at 12 months for GLP-1RA initiators vs 1.5% for non−GLP-1RA initiators (P < .01).

Though the percentages were small, in relative terms, the 6-month rate of screening in the GLP-1 RA group is a 50% increase, and the 12-month rate represents a 40% increase, McCoy pointed out. 

“If we think about 1.2% of people getting an ultrasound in the context of over 41,000 patients, that is a lot of ultrasounds,” she said. 

“To my knowledge, this is the first study to actually look at rates of thyroid ultrasounds with GLP-1 RA initiation, so it will definitely be important to look at the trends more broadly,” McCoy added.

McCoy noted that a key caveat of the study is the relatively short follow-up of only about 2 years.

“We have not been able to follow patients for decades to know if there is risk of new thyroid cancers developing after prolonged exposure,” she said. “But we generally don’t know this for any medication until it is used by many millions of people for many decades.”

 

Consistent Findings in Recent Research

In another recent study evaluating the risk for thyroid cancer among patients receiving GLP-1s, with a longer follow-up of 3.9 years, Bjorn Pasternak, MD, PhD, of the Division of Clinical Epidemiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden, and colleagues reported similar findings — the overall risk for thyroid cancer with GLP-1s was not increased (HR, 0.93), and the risk beginning 1 year after treatment initiation was lower, at 0.83. 

However, the risk in that study only looking at the first year alone was again higher, at HR 1.47.

“Our analyses indicating a nominally increased risk restricted to the first year after starting treatment might be consistent with an increased detection of thyroid cancer among patients using GLP-1 RAs,” he told this news organization.

In addition to the short follow-up of the current study, Pasternak noted the caveat of the study’s inclusion mainly of patients who initiated the four diabetes drug groups, which is a limitation “because a high proportion of the patients with type 2 diabetes in routine care who start GLP-1 RAs have started it as their third, fourth, or even fifth diabetes drug, especially if they have had diabetes for some time.”

“To capture a larger proportion of the full population of GLP-1 RA users, it would have been preferable to create three different cohorts for the purpose of this study and investigate them separately, including GLP-1 vs DPP4i; GLP-1 vs SGLT2i; GLP-1 vs sulfonylurea,” he said.

 

Rise in Incidental Thyroid Cancer Detection, An Ongoing Concern

The advent of more advanced imaging and thyroid cancer testing in recent years has already led to a significant problem of over-detection and sometimes over-treatment of incidental, small thyroid cancers that will likely remain harmless in the majority of patients. 

With approximately 64 million prescriptions of GLP-1 RAs dispensed between 2000 and 2015 and the percentage increasing at a rate of about 10%-30% per year, increased thyroid testing among those patients could indeed add to the problem.

Meanwhile, thyroid testing is currently not recommended for patients on GLP-1s who do not have a thyroid cancer risk, and the results from the current and Pasternak’s studies, as well as several other recent studies, appear to support those recommendations.

“Collectively, these reassuring data could potentially help reduce [thyroid cancer] over-detection and screening,” Pasternak said. 

McCoy echoed that the evidence indicates that “for the vast majority of people there is no indication that GLP-1 RA causes thyroid cancer.”

She underscored that overdiagnosis can have important implications, sharing her own personal experience on the receiving end of a cancer diagnosis.

“Overdiagnosis of these low-risk thyroid cancers may ultimately lead to more harm for the patient than not making the diagnosis, since surgery for thyroid cancer carries real risks (including of death) and there are downstream consequences to having your thyroid removed and relying on lifelong hormone replacement,” McCoy said.

“As a cancer survivor myself, though of lymphoma, not thyroid cancer, I also know the profound impact that a cancer diagnosis has on the individual and their loved ones,” McCoy said.

“It is not something I would wish for anyone, which is why I always speak to my patients about searching for something we may not want to — or need to — find.”

The authors and Pasternak had no disclosures to report.

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

New research, with the caveat of a relatively short follow-up, adds to encouraging data showing an overall low risk of the development of thyroid cancer associated with glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment.

However, a notably increased rate of thyroid cancer detections limited only to the first year after drug initiation — but not later, coupled with an increased rate of thyroid cancer screening during that period, raises the suggestion that a thyroid cancer concern among the millions of patients taking the immensely popular drugs could exacerbate the already problematic over-detection of incidental thyroid cancers.

“Our study confirms the increased likelihood of being diagnosed with what appears to be low-risk thyroid cancer after treatment with GLP-1 RAs — but not because patients treated with GLP-1 RAs are more likely to develop thyroid cancer but rather because they are more likely to be diagnosed with it because we, as clinicians, are more likely to look for it,” senior author Rozalina G. McCoy, MD, associate professor and associate division chief for clinical research in the Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine at the University of Maryland School of Medicine, in Baltimore, told this news organization.

The findings were published in JAMA Otolaryngology-Head & Neck Surgery.

Thyroid cancer concerns surrounding GLP-1 RAs stem from preclinical studies showing a risk for medullary thyroid cancer in rodents, resulting in a boxed warning from the US Food and Drug Administration recommending that those with a family history of the condition avoid the drugs.

More recent studies showing GLP-1 receptors in human papillary thyroid cancer cells has further raised concerns of a risk beyond medullary thyroid cancer, however, recent studies evaluating the risk have been inconclusive.

To further investigate, McCoy and colleagues evaluated claims data on 351,913 adult enrollees in Medicare Advantage and fee-for-service plans in the United States who had type 2 diabetes, a moderate risk for cardiovascular disease, and no history of thyroid cancer.

Of the patients, who were about half women, 41,112 started treatments with GLP-1 RAs; 76,093, started with dipeptidyl peptidase-4 (DPP-4) inhibitors; 43,499, with sodium-glucose cotransporter 2 (SGLT2i) inhibitors; and 191,209 with sulfonylurea therapy between January 2014 and December 2021.

After inverse probability weighting, baseline characteristics in the drug groups were well-balanced.

Overall, with median follow-up times of 660 days (range, 254-1157 days) in the GLP-1 RA group; approximately 4 years in the sulfonylurea and DPP-4 inhibitor groups; and about 2.5 years in the SGLT2 inhibitor group, the absolute risk for thyroid cancer diagnoses in the treatment groups were low, with a rate of 0.17% in the GLP-1 RA group, 0.23% in the DPP-4 inhibitor group, 0.17% in the SGLT2 inhibitor group, and 0.20% in the sulfonylurea group.

The modified intention to treat analysis concluded no increase with GLP-1 RA use in thyroid cancer risk compared with the other three diabetes drugs (hazard ratio [HR], 1.24).

 

Higher Cancers Detected in First Year Likely From Higher Screening

Importantly, the risk for thyroid cancer was significantly higher within the first year after GLP-1 RA initiation (HR, 1.85) and was also higher among patients who stayed on the medication and didn’t add other medication (HR, 2.07).

With the latency period for the development of thyroid cancer from external exposures taking several years (such as radiation, taking approximately 2.5 years), some studies in fact exclude patients diagnosed with cancers within a year of starting GLP-1s, as it is implausible for a cancer to develop so soon.

Cancers detected that early therefore are considered to likely have been found due to stepped up screening resulting from an increased concern of thyroid cancer with GLP-1 use.

In support of that theory, the study showed that those in the GLP-1 group had a significantly higher rate of receiving thyroid ultrasounds than those in the non−GLP-1 group, at 1.2% at 6 months for GLP-1RA initiators vs 0.8% for non−GLP-1 RA initiators, and an estimated 2.1% at 12 months for GLP-1RA initiators vs 1.5% for non−GLP-1RA initiators (P < .01).

Though the percentages were small, in relative terms, the 6-month rate of screening in the GLP-1 RA group is a 50% increase, and the 12-month rate represents a 40% increase, McCoy pointed out. 

“If we think about 1.2% of people getting an ultrasound in the context of over 41,000 patients, that is a lot of ultrasounds,” she said. 

“To my knowledge, this is the first study to actually look at rates of thyroid ultrasounds with GLP-1 RA initiation, so it will definitely be important to look at the trends more broadly,” McCoy added.

McCoy noted that a key caveat of the study is the relatively short follow-up of only about 2 years.

“We have not been able to follow patients for decades to know if there is risk of new thyroid cancers developing after prolonged exposure,” she said. “But we generally don’t know this for any medication until it is used by many millions of people for many decades.”

 

Consistent Findings in Recent Research

In another recent study evaluating the risk for thyroid cancer among patients receiving GLP-1s, with a longer follow-up of 3.9 years, Bjorn Pasternak, MD, PhD, of the Division of Clinical Epidemiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden, and colleagues reported similar findings — the overall risk for thyroid cancer with GLP-1s was not increased (HR, 0.93), and the risk beginning 1 year after treatment initiation was lower, at 0.83. 

However, the risk in that study only looking at the first year alone was again higher, at HR 1.47.

“Our analyses indicating a nominally increased risk restricted to the first year after starting treatment might be consistent with an increased detection of thyroid cancer among patients using GLP-1 RAs,” he told this news organization.

In addition to the short follow-up of the current study, Pasternak noted the caveat of the study’s inclusion mainly of patients who initiated the four diabetes drug groups, which is a limitation “because a high proportion of the patients with type 2 diabetes in routine care who start GLP-1 RAs have started it as their third, fourth, or even fifth diabetes drug, especially if they have had diabetes for some time.”

“To capture a larger proportion of the full population of GLP-1 RA users, it would have been preferable to create three different cohorts for the purpose of this study and investigate them separately, including GLP-1 vs DPP4i; GLP-1 vs SGLT2i; GLP-1 vs sulfonylurea,” he said.

 

Rise in Incidental Thyroid Cancer Detection, An Ongoing Concern

The advent of more advanced imaging and thyroid cancer testing in recent years has already led to a significant problem of over-detection and sometimes over-treatment of incidental, small thyroid cancers that will likely remain harmless in the majority of patients. 

With approximately 64 million prescriptions of GLP-1 RAs dispensed between 2000 and 2015 and the percentage increasing at a rate of about 10%-30% per year, increased thyroid testing among those patients could indeed add to the problem.

Meanwhile, thyroid testing is currently not recommended for patients on GLP-1s who do not have a thyroid cancer risk, and the results from the current and Pasternak’s studies, as well as several other recent studies, appear to support those recommendations.

“Collectively, these reassuring data could potentially help reduce [thyroid cancer] over-detection and screening,” Pasternak said. 

McCoy echoed that the evidence indicates that “for the vast majority of people there is no indication that GLP-1 RA causes thyroid cancer.”

She underscored that overdiagnosis can have important implications, sharing her own personal experience on the receiving end of a cancer diagnosis.

“Overdiagnosis of these low-risk thyroid cancers may ultimately lead to more harm for the patient than not making the diagnosis, since surgery for thyroid cancer carries real risks (including of death) and there are downstream consequences to having your thyroid removed and relying on lifelong hormone replacement,” McCoy said.

“As a cancer survivor myself, though of lymphoma, not thyroid cancer, I also know the profound impact that a cancer diagnosis has on the individual and their loved ones,” McCoy said.

“It is not something I would wish for anyone, which is why I always speak to my patients about searching for something we may not want to — or need to — find.”

The authors and Pasternak had no disclosures to report.

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

A study of more than 2 million veterans with diabetes builds on evidence of broad-ranging benefits and risks of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in the clinical setting, providing an “atlas” mapping extensive outcomes and some new insights to potentially explore in more rigorous clinical trials.

“This is the largest study on GLP-1 receptor agonists,” first author Ziyad Al-Aly, MD, chief of research and development at the US Department of Veterans Affairs (VA) St. Louis Healthcare System, in St. Louis, told this news organization regarding the research, published this week, in Nature Medicine.

“The [study] reflects the real experiences of people using GLP-1 RAs [in the VA] clinical setting,” he said.

“Altogether, our discovery approach confirms previous studies and clinical trials and also uncovers previously unreported benefits and risks of GLP-1 RAs,” the authors wrote.

For the comprehensive study, Al-Aly and his colleagues evaluated data from the US Department of Veterans Affairs on more than 2 million veterans treated for diabetes between October 2017 and December 2023, assessing GLP-1 RA treatment in comparison with other diabetes therapies regarding a striking 175 clinical outcomes.

Of the patients, 215,970 initiated treatment with GLP-1 RAs; 159,465 started sulfonylureas, 117,989 dipeptidyl peptidase 4 inhibitors, and 258,614 were initiated on sodium-glucose cotransporter-2 inhibitors.

The study also included a composite group of the latter three drug groups (n = 536,068), and a control group of 1,203,097 of patients receiving usual care, who were compared with usual care with the addition of GLP-1 RAs.

After inverse probability weighting, the groups were well-balanced in terms of their baseline characteristics. While the majority in the VA cohort overall were White men, the study adjusted for gender, age, race, comorbidities, and an extensive array of covariates.

With an average follow-up of 3.68 years, after the multivariate adjustment, GLP-1 RAs showed “effectiveness and risks that extended beyond those currently recognized,” in comparison with each of the treatment groups and with the main control group of usual care, the authors reported.

For the largest comparison with the main control group of usual care alone, the addition of GLP-1 RAs was associated with a decreased risk in 24% of the outcomes evaluated, and an increased risk in 10.86% of outcomes, with no significant difference for the remaining 65.14% of outcomes.

Of the various benefits, key improvements included a reduced risk for several substance use disorders including alcohol (hazard ratio [HR], 0.89) and opioid (HR, 0.87) use, suicidal ideation, attempt or intentional self-harm (HR, 0.90), seizures (HR, 0.90), neurocognitive disorders including Alzheimer disease (HR, 0.88) and dementia (HR, 0.92), coagulation and clotting disorders (HR, 0.92), and cardiac arrest (HR, 0.78).

Further benefits vs usual care alone included a reduced risk for infectious illnesses (HR, 0.88), acute kidney injury (HR, 0.88), and chronic kidney disease (CKD) (HR, 0.97; P <.05 for all the outcomes).

In terms of risks associated with GLP-1 RAs, in addition to the well-known risks for nausea and vomiting, additional increased risks vs usual care included gastrointestinal disorders such as noninfectious gastroenteritis (HR, 1.12), hypotension (HR, 1.06), arthritis (HR, 1.11), tendinitis and synovitis (HR, 1.10), interstitial nephritis (HR, 1.06), nephrolithiasis (HR, 1.15), and the known risk for drug-induced acute pancreatitis (HR, 2.46).

 

Neuropsychiatric Effects

Among the various benefits in the study, Al-Aly said some of the most intriguing are those involving the brain.

“I am struck by the consistent effects on many neuropsychiatric disorders — this aligns with data showing the presence of GLP-1 receptors in the brain and evidence showing that GLP-1s permeates through the blood brain barrier and acts on the brain to reduce inflammation and oxidative stress, improve neuroplasticity, etc.,” he said.

“Clearly, there is a neurotropic effect. There is also the possibility of an effect on the immune system/fighting infection — with reduced risks of infections, sepsis, etc.”

The reductions in suicidal ideation are encouraging after earlier reports of suicidal thoughts and self-injury among young users of GLP-1 RAs prompted concerns, including a 2023 review of the drug use by the European Medicines Agency that ultimately found no causal association, the authors added. The US Food and Drug Administration also found no association with GLP-1s and suicide risk.

The reductions in addictive behaviors are also encouraging and are consistent with the role of GLP-1 receptors in the brain in terms of impulse control and reward signaling that can relate to addictive behaviors, Al-Aly explained.

The reduced risks for dementia and Alzheimer disease are likewise consistent with preclinical studies in animal models of Alzheimer disease, as well as clinical studies showing a reduced risk for dementia in patients with type 2 diabetes, the authors noted.

The observed reduced risk for seizures further “adds to an emerging body of knowledge, both mechanistic and early clinical data, indicative of the anticonvulsant properties of GLP-1 RA use,” they added.

“GLP-1 RAs should be further evaluated in future studies as potential adjuvant therapeutics for epilepsy and its associated comorbidities,” the authors suggested.

 

Kidneys

While the findings support evidence of protective effects of GLP-1 RAs on the kidneys and a reduction in CKD risk, notable risks observed, also involving the kidneys, include nephrolithiasis or kidney stones.

Al-Aly noted the mechanisms with kidney stone formation are very different from CKD, and he speculated that the risk for the former could in fact stem from potentially low hydration with GLP-1 RA use.

“When patients are on GLP-1 RAs, they definitely eat a lot less to lose weight, but they also hydrate themselves less,” he explained in a press briefing. “They drink less water because they feel full very quickly after eating, and I’m just theorizing, but perhaps chronic dehydration [is behind] the increased risk of kidney stones.”

 

Modest Effects?

While, overall, the benefits of GLP-1 RA drugs showed modest benefits ranging between a 10% and 20% reduction for most outcomes, Al-Aly said those effects are still important.

“The modest effect does not negate the potential value of these drugs, especially for conditions where few effective treatment options exist, for example, dementia,” he said in the press statement.

“This may also imply that these drugs are most beneficial when used in conjunction with other interventions, such as lifestyle changes or other medications.”

 

Potential Confounders A Concern

Commenting on the study, David M. Nathan, MD, founder of the MGH Diabetes Center and a professor of medicine at Harvard Medical School, in Boston, Massachusetts, noted that, while the study is hypothesis-generating, the key limitation is its observational nature.

“The authors did a perfectly respectable job of doing all you can do to adjust for [confounders], but with these kinds of studies, as much as you try to statistically account for differences in the populations before they were put on the drug, you can never truly adjust for all the potential confounders that may influence the results,” he told this news organization.

In addition, the 3.8-year follow-up time of the study, as the authors acknowledge, is especially short considering that GLP-1 RAs are generally recommended to be taken indefinitely.

“You have to take these drugs presumably for a lifetime and we have no idea what the longer-term benefits and risks are,” Nathan said.

Nathan, who was among the first investigators to evaluate GLP-1 RAs about 30 years ago, underscored that “I do think that these drugs are generally really spectacular; they’ve taken over the world and they are probably the single greatest pharmaceutical story of the 21st century.”

“But much more rigorous randomized trials would be needed to prove study results that haven’t already been established in previous clinical trials,” he said.

“The types of [randomized] trials that are necessary are very expensive and require a huge amount of work, but at the end of the day, they provide proof as to what does and doesn’t work, and what the true risks are,” he added. “Whether the GLP-RAs will cure all ills and bring about world peace needs to be proved.”

In further comments provided through the Science Media Center, Stephen O’Rahilly, FRS, a professor of clinical biochemistry and medicine and director of the Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, England, echoed Nathan’s concern that “studies such as these have to be interpreted very cautiously as the people studied have not been randomly allocated to GLP-1 RA treatment, so any difference between those taking and not taking the class of drug could potentially be attributable to factors other than the drug.”

He noted, however, that “the study provides useful reassurance about the safety of this class of drugs. The expected benefits on heart disease, stroke and other cardiovascular and most kidney diseases are clearly seen.”

Al-Aly reported being an uncompensated consultant for Pfizer. Nathan, who has previously conducted clinical trials on GLP-1 RAs, currently has no relationships to report. O’Rahilly reported receiving remuneration from several pharmaceutical companies for scientific advice relating to the development of drugs for metabolic diseases, but none involving GLP-1 RAs in the past 3 years.

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

A study of more than 2 million veterans with diabetes builds on evidence of broad-ranging benefits and risks of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in the clinical setting, providing an “atlas” mapping extensive outcomes and some new insights to potentially explore in more rigorous clinical trials.

“This is the largest study on GLP-1 receptor agonists,” first author Ziyad Al-Aly, MD, chief of research and development at the US Department of Veterans Affairs (VA) St. Louis Healthcare System, in St. Louis, told this news organization regarding the research, published this week, in Nature Medicine.

“The [study] reflects the real experiences of people using GLP-1 RAs [in the VA] clinical setting,” he said.

“Altogether, our discovery approach confirms previous studies and clinical trials and also uncovers previously unreported benefits and risks of GLP-1 RAs,” the authors wrote.

For the comprehensive study, Al-Aly and his colleagues evaluated data from the US Department of Veterans Affairs on more than 2 million veterans treated for diabetes between October 2017 and December 2023, assessing GLP-1 RA treatment in comparison with other diabetes therapies regarding a striking 175 clinical outcomes.

Of the patients, 215,970 initiated treatment with GLP-1 RAs; 159,465 started sulfonylureas, 117,989 dipeptidyl peptidase 4 inhibitors, and 258,614 were initiated on sodium-glucose cotransporter-2 inhibitors.

The study also included a composite group of the latter three drug groups (n = 536,068), and a control group of 1,203,097 of patients receiving usual care, who were compared with usual care with the addition of GLP-1 RAs.

After inverse probability weighting, the groups were well-balanced in terms of their baseline characteristics. While the majority in the VA cohort overall were White men, the study adjusted for gender, age, race, comorbidities, and an extensive array of covariates.

With an average follow-up of 3.68 years, after the multivariate adjustment, GLP-1 RAs showed “effectiveness and risks that extended beyond those currently recognized,” in comparison with each of the treatment groups and with the main control group of usual care, the authors reported.

For the largest comparison with the main control group of usual care alone, the addition of GLP-1 RAs was associated with a decreased risk in 24% of the outcomes evaluated, and an increased risk in 10.86% of outcomes, with no significant difference for the remaining 65.14% of outcomes.

Of the various benefits, key improvements included a reduced risk for several substance use disorders including alcohol (hazard ratio [HR], 0.89) and opioid (HR, 0.87) use, suicidal ideation, attempt or intentional self-harm (HR, 0.90), seizures (HR, 0.90), neurocognitive disorders including Alzheimer disease (HR, 0.88) and dementia (HR, 0.92), coagulation and clotting disorders (HR, 0.92), and cardiac arrest (HR, 0.78).

Further benefits vs usual care alone included a reduced risk for infectious illnesses (HR, 0.88), acute kidney injury (HR, 0.88), and chronic kidney disease (CKD) (HR, 0.97; P <.05 for all the outcomes).

In terms of risks associated with GLP-1 RAs, in addition to the well-known risks for nausea and vomiting, additional increased risks vs usual care included gastrointestinal disorders such as noninfectious gastroenteritis (HR, 1.12), hypotension (HR, 1.06), arthritis (HR, 1.11), tendinitis and synovitis (HR, 1.10), interstitial nephritis (HR, 1.06), nephrolithiasis (HR, 1.15), and the known risk for drug-induced acute pancreatitis (HR, 2.46).

 

Neuropsychiatric Effects

Among the various benefits in the study, Al-Aly said some of the most intriguing are those involving the brain.

“I am struck by the consistent effects on many neuropsychiatric disorders — this aligns with data showing the presence of GLP-1 receptors in the brain and evidence showing that GLP-1s permeates through the blood brain barrier and acts on the brain to reduce inflammation and oxidative stress, improve neuroplasticity, etc.,” he said.

“Clearly, there is a neurotropic effect. There is also the possibility of an effect on the immune system/fighting infection — with reduced risks of infections, sepsis, etc.”

The reductions in suicidal ideation are encouraging after earlier reports of suicidal thoughts and self-injury among young users of GLP-1 RAs prompted concerns, including a 2023 review of the drug use by the European Medicines Agency that ultimately found no causal association, the authors added. The US Food and Drug Administration also found no association with GLP-1s and suicide risk.

The reductions in addictive behaviors are also encouraging and are consistent with the role of GLP-1 receptors in the brain in terms of impulse control and reward signaling that can relate to addictive behaviors, Al-Aly explained.

The reduced risks for dementia and Alzheimer disease are likewise consistent with preclinical studies in animal models of Alzheimer disease, as well as clinical studies showing a reduced risk for dementia in patients with type 2 diabetes, the authors noted.

The observed reduced risk for seizures further “adds to an emerging body of knowledge, both mechanistic and early clinical data, indicative of the anticonvulsant properties of GLP-1 RA use,” they added.

“GLP-1 RAs should be further evaluated in future studies as potential adjuvant therapeutics for epilepsy and its associated comorbidities,” the authors suggested.

 

Kidneys

While the findings support evidence of protective effects of GLP-1 RAs on the kidneys and a reduction in CKD risk, notable risks observed, also involving the kidneys, include nephrolithiasis or kidney stones.

Al-Aly noted the mechanisms with kidney stone formation are very different from CKD, and he speculated that the risk for the former could in fact stem from potentially low hydration with GLP-1 RA use.

“When patients are on GLP-1 RAs, they definitely eat a lot less to lose weight, but they also hydrate themselves less,” he explained in a press briefing. “They drink less water because they feel full very quickly after eating, and I’m just theorizing, but perhaps chronic dehydration [is behind] the increased risk of kidney stones.”

 

Modest Effects?

While, overall, the benefits of GLP-1 RA drugs showed modest benefits ranging between a 10% and 20% reduction for most outcomes, Al-Aly said those effects are still important.

“The modest effect does not negate the potential value of these drugs, especially for conditions where few effective treatment options exist, for example, dementia,” he said in the press statement.

“This may also imply that these drugs are most beneficial when used in conjunction with other interventions, such as lifestyle changes or other medications.”

 

Potential Confounders A Concern

Commenting on the study, David M. Nathan, MD, founder of the MGH Diabetes Center and a professor of medicine at Harvard Medical School, in Boston, Massachusetts, noted that, while the study is hypothesis-generating, the key limitation is its observational nature.

“The authors did a perfectly respectable job of doing all you can do to adjust for [confounders], but with these kinds of studies, as much as you try to statistically account for differences in the populations before they were put on the drug, you can never truly adjust for all the potential confounders that may influence the results,” he told this news organization.

In addition, the 3.8-year follow-up time of the study, as the authors acknowledge, is especially short considering that GLP-1 RAs are generally recommended to be taken indefinitely.

“You have to take these drugs presumably for a lifetime and we have no idea what the longer-term benefits and risks are,” Nathan said.

Nathan, who was among the first investigators to evaluate GLP-1 RAs about 30 years ago, underscored that “I do think that these drugs are generally really spectacular; they’ve taken over the world and they are probably the single greatest pharmaceutical story of the 21st century.”

“But much more rigorous randomized trials would be needed to prove study results that haven’t already been established in previous clinical trials,” he said.

“The types of [randomized] trials that are necessary are very expensive and require a huge amount of work, but at the end of the day, they provide proof as to what does and doesn’t work, and what the true risks are,” he added. “Whether the GLP-RAs will cure all ills and bring about world peace needs to be proved.”

In further comments provided through the Science Media Center, Stephen O’Rahilly, FRS, a professor of clinical biochemistry and medicine and director of the Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, England, echoed Nathan’s concern that “studies such as these have to be interpreted very cautiously as the people studied have not been randomly allocated to GLP-1 RA treatment, so any difference between those taking and not taking the class of drug could potentially be attributable to factors other than the drug.”

He noted, however, that “the study provides useful reassurance about the safety of this class of drugs. The expected benefits on heart disease, stroke and other cardiovascular and most kidney diseases are clearly seen.”

Al-Aly reported being an uncompensated consultant for Pfizer. Nathan, who has previously conducted clinical trials on GLP-1 RAs, currently has no relationships to report. O’Rahilly reported receiving remuneration from several pharmaceutical companies for scientific advice relating to the development of drugs for metabolic diseases, but none involving GLP-1 RAs in the past 3 years.

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

A study of more than 2 million veterans with diabetes builds on evidence of broad-ranging benefits and risks of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in the clinical setting, providing an “atlas” mapping extensive outcomes and some new insights to potentially explore in more rigorous clinical trials.

“This is the largest study on GLP-1 receptor agonists,” first author Ziyad Al-Aly, MD, chief of research and development at the US Department of Veterans Affairs (VA) St. Louis Healthcare System, in St. Louis, told this news organization regarding the research, published this week, in Nature Medicine.

“The [study] reflects the real experiences of people using GLP-1 RAs [in the VA] clinical setting,” he said.

“Altogether, our discovery approach confirms previous studies and clinical trials and also uncovers previously unreported benefits and risks of GLP-1 RAs,” the authors wrote.

For the comprehensive study, Al-Aly and his colleagues evaluated data from the US Department of Veterans Affairs on more than 2 million veterans treated for diabetes between October 2017 and December 2023, assessing GLP-1 RA treatment in comparison with other diabetes therapies regarding a striking 175 clinical outcomes.

Of the patients, 215,970 initiated treatment with GLP-1 RAs; 159,465 started sulfonylureas, 117,989 dipeptidyl peptidase 4 inhibitors, and 258,614 were initiated on sodium-glucose cotransporter-2 inhibitors.

The study also included a composite group of the latter three drug groups (n = 536,068), and a control group of 1,203,097 of patients receiving usual care, who were compared with usual care with the addition of GLP-1 RAs.

After inverse probability weighting, the groups were well-balanced in terms of their baseline characteristics. While the majority in the VA cohort overall were White men, the study adjusted for gender, age, race, comorbidities, and an extensive array of covariates.

With an average follow-up of 3.68 years, after the multivariate adjustment, GLP-1 RAs showed “effectiveness and risks that extended beyond those currently recognized,” in comparison with each of the treatment groups and with the main control group of usual care, the authors reported.

For the largest comparison with the main control group of usual care alone, the addition of GLP-1 RAs was associated with a decreased risk in 24% of the outcomes evaluated, and an increased risk in 10.86% of outcomes, with no significant difference for the remaining 65.14% of outcomes.

Of the various benefits, key improvements included a reduced risk for several substance use disorders including alcohol (hazard ratio [HR], 0.89) and opioid (HR, 0.87) use, suicidal ideation, attempt or intentional self-harm (HR, 0.90), seizures (HR, 0.90), neurocognitive disorders including Alzheimer disease (HR, 0.88) and dementia (HR, 0.92), coagulation and clotting disorders (HR, 0.92), and cardiac arrest (HR, 0.78).

Further benefits vs usual care alone included a reduced risk for infectious illnesses (HR, 0.88), acute kidney injury (HR, 0.88), and chronic kidney disease (CKD) (HR, 0.97; P <.05 for all the outcomes).

In terms of risks associated with GLP-1 RAs, in addition to the well-known risks for nausea and vomiting, additional increased risks vs usual care included gastrointestinal disorders such as noninfectious gastroenteritis (HR, 1.12), hypotension (HR, 1.06), arthritis (HR, 1.11), tendinitis and synovitis (HR, 1.10), interstitial nephritis (HR, 1.06), nephrolithiasis (HR, 1.15), and the known risk for drug-induced acute pancreatitis (HR, 2.46).

 

Neuropsychiatric Effects

Among the various benefits in the study, Al-Aly said some of the most intriguing are those involving the brain.

“I am struck by the consistent effects on many neuropsychiatric disorders — this aligns with data showing the presence of GLP-1 receptors in the brain and evidence showing that GLP-1s permeates through the blood brain barrier and acts on the brain to reduce inflammation and oxidative stress, improve neuroplasticity, etc.,” he said.

“Clearly, there is a neurotropic effect. There is also the possibility of an effect on the immune system/fighting infection — with reduced risks of infections, sepsis, etc.”

The reductions in suicidal ideation are encouraging after earlier reports of suicidal thoughts and self-injury among young users of GLP-1 RAs prompted concerns, including a 2023 review of the drug use by the European Medicines Agency that ultimately found no causal association, the authors added. The US Food and Drug Administration also found no association with GLP-1s and suicide risk.

The reductions in addictive behaviors are also encouraging and are consistent with the role of GLP-1 receptors in the brain in terms of impulse control and reward signaling that can relate to addictive behaviors, Al-Aly explained.

The reduced risks for dementia and Alzheimer disease are likewise consistent with preclinical studies in animal models of Alzheimer disease, as well as clinical studies showing a reduced risk for dementia in patients with type 2 diabetes, the authors noted.

The observed reduced risk for seizures further “adds to an emerging body of knowledge, both mechanistic and early clinical data, indicative of the anticonvulsant properties of GLP-1 RA use,” they added.

“GLP-1 RAs should be further evaluated in future studies as potential adjuvant therapeutics for epilepsy and its associated comorbidities,” the authors suggested.

 

Kidneys

While the findings support evidence of protective effects of GLP-1 RAs on the kidneys and a reduction in CKD risk, notable risks observed, also involving the kidneys, include nephrolithiasis or kidney stones.

Al-Aly noted the mechanisms with kidney stone formation are very different from CKD, and he speculated that the risk for the former could in fact stem from potentially low hydration with GLP-1 RA use.

“When patients are on GLP-1 RAs, they definitely eat a lot less to lose weight, but they also hydrate themselves less,” he explained in a press briefing. “They drink less water because they feel full very quickly after eating, and I’m just theorizing, but perhaps chronic dehydration [is behind] the increased risk of kidney stones.”

 

Modest Effects?

While, overall, the benefits of GLP-1 RA drugs showed modest benefits ranging between a 10% and 20% reduction for most outcomes, Al-Aly said those effects are still important.

“The modest effect does not negate the potential value of these drugs, especially for conditions where few effective treatment options exist, for example, dementia,” he said in the press statement.

“This may also imply that these drugs are most beneficial when used in conjunction with other interventions, such as lifestyle changes or other medications.”

 

Potential Confounders A Concern

Commenting on the study, David M. Nathan, MD, founder of the MGH Diabetes Center and a professor of medicine at Harvard Medical School, in Boston, Massachusetts, noted that, while the study is hypothesis-generating, the key limitation is its observational nature.

“The authors did a perfectly respectable job of doing all you can do to adjust for [confounders], but with these kinds of studies, as much as you try to statistically account for differences in the populations before they were put on the drug, you can never truly adjust for all the potential confounders that may influence the results,” he told this news organization.

In addition, the 3.8-year follow-up time of the study, as the authors acknowledge, is especially short considering that GLP-1 RAs are generally recommended to be taken indefinitely.

“You have to take these drugs presumably for a lifetime and we have no idea what the longer-term benefits and risks are,” Nathan said.

Nathan, who was among the first investigators to evaluate GLP-1 RAs about 30 years ago, underscored that “I do think that these drugs are generally really spectacular; they’ve taken over the world and they are probably the single greatest pharmaceutical story of the 21st century.”

“But much more rigorous randomized trials would be needed to prove study results that haven’t already been established in previous clinical trials,” he said.

“The types of [randomized] trials that are necessary are very expensive and require a huge amount of work, but at the end of the day, they provide proof as to what does and doesn’t work, and what the true risks are,” he added. “Whether the GLP-RAs will cure all ills and bring about world peace needs to be proved.”

In further comments provided through the Science Media Center, Stephen O’Rahilly, FRS, a professor of clinical biochemistry and medicine and director of the Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, England, echoed Nathan’s concern that “studies such as these have to be interpreted very cautiously as the people studied have not been randomly allocated to GLP-1 RA treatment, so any difference between those taking and not taking the class of drug could potentially be attributable to factors other than the drug.”

He noted, however, that “the study provides useful reassurance about the safety of this class of drugs. The expected benefits on heart disease, stroke and other cardiovascular and most kidney diseases are clearly seen.”

Al-Aly reported being an uncompensated consultant for Pfizer. Nathan, who has previously conducted clinical trials on GLP-1 RAs, currently has no relationships to report. O’Rahilly reported receiving remuneration from several pharmaceutical companies for scientific advice relating to the development of drugs for metabolic diseases, but none involving GLP-1 RAs in the past 3 years.

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

THE DIAGNOSIS: Rheumatoid Vasculitis

A diagnosis of rheumatoid vasculitis (RV) was made based on the clinical features, histopathology, and laboratory results in the setting of rheumatoid arthritis (RA). The distal gangrene was surgically managed with bilateral transmetatarsal amputation followed by ankle collagen graft placement. The patient was started on a prednisone taper for 1 month (40 mg/d for 3 days, then 30 mg/d for 3 days, then 20 mg/d for 24 days) before transitioning to rituximab (375 mg/m² once weekly for 4 weeks), which improved the size and depth of the ulcers.

Rheumatoid vasculitis is an inflammatory disease that affects small- to medium-sized blood vessels in patients with RA. The pathogenesis involves immune complex deposition and complement system activation, leading to vessel wall destruction.¹ Rheumatoid vasculitis is an extra-articular complication of RA that primarily is observed in seropositive patients with long-standing severe disease.^1,2 The mean duration between RA diagnosis and RV onset is 10 to 14 years.² Rheumatoid vasculitis manifests heterogeneously and can affect many organs; however, it most frequently affects the skin. Cutaneous manifestations vary in severity. Palpable purpura, pyoderma gangrenosum, and distal ulcers can be seen in addition to extensive digital ischemia with necrosis, as was present in our patient.¹

When RA patients present with skin changes that are concerning for vasculitis, RV should be suspected. Currently, there are no validated diagnostic criteria for RV. Diagnosis is made based on clinical presentation and tissue biopsy. Histopathology shows small- and medium-sized vessel wall destruction with neutrophilic, granulomatous, or lymphocytic infiltration, which may be observed only in the lower dermis sparing superficial vessels.³ Direct immunofluorescence shows IgM, IgA, and C3 deposition within and around vessels.^3,4 Laboratory findings including elevated inflammatory markers, positive rheumatoid factor, positive anti–cyclic citrullinated peptide, and hypocomplementemia support a diagnosis of RV.^1,2

Mortality rates for RV remain high, necessitating aggressive treatment. High-dose corticosteroids typically are combined with immunosuppressant or biologic agents, frequently cyclophosphamide or rituximab.¹ Consistent with other reported cases, our patient’s ulcers improved with rituximab and oral steroids.

The differential diagnosis for our patient included type I cryoglobulinemia, cutaneous polyarteritis nodosa (CPAN), peripheral vascular disease (PVD), and nonuremic calciphylaxis. Type I cryoglobulinemia manifests due to direct occlusion of vessels by precipitation of monoclonal immunoglobulin.⁵ It commonly is associated with lymphoproliferative diseases such as Waldenström macroglobulinemia and multiple myeloma. While our patient’s history of RA was a risk factor for mixed cryoglobulinemia as opposed to type I cryoglobulinemia, the clinical presentation aligned more closely with type I cryoglobulinemia. The clinical manifestations of type I cryoglobulinemia are related to intravascular obstruction, including Raynaud phenomenon, retiform purpura, ischemic ulcers, distal gangrene, and cold-induced urticaria.^6-8 Type I cryoglobulinemia also frequently has neurologic and renal manifestations. Histopathology, along with the detection of serum cryoglobulins, is the gold standard for diagnosing cryoglobulinemia.⁶ On histopathology, type I cryoglobulinemia typically shows a thrombotic vasculopathy with amorphous eosinophilic periodic acid–Schiff–positive thrombi.⁷ False-negative results are particularly common with serum cryoglobulins, so repeat testing often is needed. While many clinical features overlap, RV is the most likely diagnosis in a patient with long-standing RA who is negative for cryoglobulins and has no history of lymphoproliferative disorders.

Cutaneous polyarteritis nodosa is a necrotizing vasculitis that similarly affects small- and medium-sized vessels. The exact etiology is unknown, but the high prevalence of anti–phosphatidylserine/prothrombin complex antibodies among patients with CPAN suggests that prothrombin bound to apoptotic endothelial cells may initiate the immune response.⁹ Underlying infection and inflammatory and autoimmune diseases (including group A beta-hemolytic streptococcus, hepatitis B, inflammatory bowel disease, myasthenia gravis, and RA) also may trigger CPAN.^9,10,11 The most common clinical manifestations of CPAN are tender subcutaneous nodules, livedo reticularis, leg ulcers, and cutaneous necrosis. Extracutaneous symptoms such as myalgias and arthralgias also can be associated with CPAN. There is no specific serologic test to diagnose CPAN; the diagnosis is made based on clinicopathologic correlation, with characteristic histopathology showing leukocytoclastic vasculitis in the small- and medium-sized arteries of the deep dermis or hypodermis.⁹

Peripheral vascular disease is a manifestation of atherosclerosis that affects the legs. Risk factors for atherosclerosis, especially smoking and diabetes mellitus, similarly increase the risk for PVD.¹² The most common clinical manifestation of PVD is intermittent claudication, but rarely PVD can progress to critical limb ischemia, which is characterized by pain at rest, nonhealing ulcers, or gangrene of the legs.¹² Common findings on physical examination include diminished or absent pedal pulses, abnormal skin color, and skin that is cool to the touch.¹² The standard diagnostic test for PVD affecting the legs is evaluation via the ankle-brachial index, with a score of 0.90 or lower being diagnostic of PVD, a score of 0.91 to 1.00 being borderline, and a score of 1.01 to 1.40 being normal.¹³

Calciphylaxis most frequently is seen in patients with end-stage kidney disease; however, it also has been less commonly reported in patients with normal kidney function, known as nonuremic calciphylaxis. It is characterized by calcification of arteries, arterioles, and soft tissues, which can lead to thrombosis and eventually ischemia and necrosis of the skin.¹⁴ Calciphylaxis initially causes tender, indurated, erythematous to purpuric plaques that quickly progress to retiform and stellate ulcers with overlying necrotic eschars.¹⁵ Disease typically occurs on the legs and areas that are rich in adipose tissue, such as the abdomen and thighs.¹⁶ Skin biopsy is needed for diagnosis of calciphylaxis. Characteristic histopathologic findings include calcification, microvascular thrombosis, and fibrointimal hyperplasia of small dermal and subcutaneous arteries and arterioles.¹⁶

We present a rare case of RV in a patient with well-controlled RA. While the incidence of RV is decreasing in the United States and United Kingdom due to the initiation of earlier and more aggressive RA therapies, mortality remains high.¹ Thus, it is important to include RV in the differential diagnosis when there are skin changes concerning vasculitis in patients with seropositive, longstanding RA, even if the RA is well controlled.

THE DIAGNOSIS: Rheumatoid Vasculitis

A diagnosis of rheumatoid vasculitis (RV) was made based on the clinical features, histopathology, and laboratory results in the setting of rheumatoid arthritis (RA). The distal gangrene was surgically managed with bilateral transmetatarsal amputation followed by ankle collagen graft placement. The patient was started on a prednisone taper for 1 month (40 mg/d for 3 days, then 30 mg/d for 3 days, then 20 mg/d for 24 days) before transitioning to rituximab (375 mg/m² once weekly for 4 weeks), which improved the size and depth of the ulcers.

Rheumatoid vasculitis is an inflammatory disease that affects small- to medium-sized blood vessels in patients with RA. The pathogenesis involves immune complex deposition and complement system activation, leading to vessel wall destruction.¹ Rheumatoid vasculitis is an extra-articular complication of RA that primarily is observed in seropositive patients with long-standing severe disease.^1,2 The mean duration between RA diagnosis and RV onset is 10 to 14 years.² Rheumatoid vasculitis manifests heterogeneously and can affect many organs; however, it most frequently affects the skin. Cutaneous manifestations vary in severity. Palpable purpura, pyoderma gangrenosum, and distal ulcers can be seen in addition to extensive digital ischemia with necrosis, as was present in our patient.¹

When RA patients present with skin changes that are concerning for vasculitis, RV should be suspected. Currently, there are no validated diagnostic criteria for RV. Diagnosis is made based on clinical presentation and tissue biopsy. Histopathology shows small- and medium-sized vessel wall destruction with neutrophilic, granulomatous, or lymphocytic infiltration, which may be observed only in the lower dermis sparing superficial vessels.³ Direct immunofluorescence shows IgM, IgA, and C3 deposition within and around vessels.^3,4 Laboratory findings including elevated inflammatory markers, positive rheumatoid factor, positive anti–cyclic citrullinated peptide, and hypocomplementemia support a diagnosis of RV.^1,2

Mortality rates for RV remain high, necessitating aggressive treatment. High-dose corticosteroids typically are combined with immunosuppressant or biologic agents, frequently cyclophosphamide or rituximab.¹ Consistent with other reported cases, our patient’s ulcers improved with rituximab and oral steroids.

The differential diagnosis for our patient included type I cryoglobulinemia, cutaneous polyarteritis nodosa (CPAN), peripheral vascular disease (PVD), and nonuremic calciphylaxis. Type I cryoglobulinemia manifests due to direct occlusion of vessels by precipitation of monoclonal immunoglobulin.⁵ It commonly is associated with lymphoproliferative diseases such as Waldenström macroglobulinemia and multiple myeloma. While our patient’s history of RA was a risk factor for mixed cryoglobulinemia as opposed to type I cryoglobulinemia, the clinical presentation aligned more closely with type I cryoglobulinemia. The clinical manifestations of type I cryoglobulinemia are related to intravascular obstruction, including Raynaud phenomenon, retiform purpura, ischemic ulcers, distal gangrene, and cold-induced urticaria.^6-8 Type I cryoglobulinemia also frequently has neurologic and renal manifestations. Histopathology, along with the detection of serum cryoglobulins, is the gold standard for diagnosing cryoglobulinemia.⁶ On histopathology, type I cryoglobulinemia typically shows a thrombotic vasculopathy with amorphous eosinophilic periodic acid–Schiff–positive thrombi.⁷ False-negative results are particularly common with serum cryoglobulins, so repeat testing often is needed. While many clinical features overlap, RV is the most likely diagnosis in a patient with long-standing RA who is negative for cryoglobulins and has no history of lymphoproliferative disorders.

Cutaneous polyarteritis nodosa is a necrotizing vasculitis that similarly affects small- and medium-sized vessels. The exact etiology is unknown, but the high prevalence of anti–phosphatidylserine/prothrombin complex antibodies among patients with CPAN suggests that prothrombin bound to apoptotic endothelial cells may initiate the immune response.⁹ Underlying infection and inflammatory and autoimmune diseases (including group A beta-hemolytic streptococcus, hepatitis B, inflammatory bowel disease, myasthenia gravis, and RA) also may trigger CPAN.^9,10,11 The most common clinical manifestations of CPAN are tender subcutaneous nodules, livedo reticularis, leg ulcers, and cutaneous necrosis. Extracutaneous symptoms such as myalgias and arthralgias also can be associated with CPAN. There is no specific serologic test to diagnose CPAN; the diagnosis is made based on clinicopathologic correlation, with characteristic histopathology showing leukocytoclastic vasculitis in the small- and medium-sized arteries of the deep dermis or hypodermis.⁹

Peripheral vascular disease is a manifestation of atherosclerosis that affects the legs. Risk factors for atherosclerosis, especially smoking and diabetes mellitus, similarly increase the risk for PVD.¹² The most common clinical manifestation of PVD is intermittent claudication, but rarely PVD can progress to critical limb ischemia, which is characterized by pain at rest, nonhealing ulcers, or gangrene of the legs.¹² Common findings on physical examination include diminished or absent pedal pulses, abnormal skin color, and skin that is cool to the touch.¹² The standard diagnostic test for PVD affecting the legs is evaluation via the ankle-brachial index, with a score of 0.90 or lower being diagnostic of PVD, a score of 0.91 to 1.00 being borderline, and a score of 1.01 to 1.40 being normal.¹³

Calciphylaxis most frequently is seen in patients with end-stage kidney disease; however, it also has been less commonly reported in patients with normal kidney function, known as nonuremic calciphylaxis. It is characterized by calcification of arteries, arterioles, and soft tissues, which can lead to thrombosis and eventually ischemia and necrosis of the skin.¹⁴ Calciphylaxis initially causes tender, indurated, erythematous to purpuric plaques that quickly progress to retiform and stellate ulcers with overlying necrotic eschars.¹⁵ Disease typically occurs on the legs and areas that are rich in adipose tissue, such as the abdomen and thighs.¹⁶ Skin biopsy is needed for diagnosis of calciphylaxis. Characteristic histopathologic findings include calcification, microvascular thrombosis, and fibrointimal hyperplasia of small dermal and subcutaneous arteries and arterioles.¹⁶

We present a rare case of RV in a patient with well-controlled RA. While the incidence of RV is decreasing in the United States and United Kingdom due to the initiation of earlier and more aggressive RA therapies, mortality remains high.¹ Thus, it is important to include RV in the differential diagnosis when there are skin changes concerning vasculitis in patients with seropositive, longstanding RA, even if the RA is well controlled.

THE DIAGNOSIS: Rheumatoid Vasculitis

A diagnosis of rheumatoid vasculitis (RV) was made based on the clinical features, histopathology, and laboratory results in the setting of rheumatoid arthritis (RA). The distal gangrene was surgically managed with bilateral transmetatarsal amputation followed by ankle collagen graft placement. The patient was started on a prednisone taper for 1 month (40 mg/d for 3 days, then 30 mg/d for 3 days, then 20 mg/d for 24 days) before transitioning to rituximab (375 mg/m² once weekly for 4 weeks), which improved the size and depth of the ulcers.

Rheumatoid vasculitis is an inflammatory disease that affects small- to medium-sized blood vessels in patients with RA. The pathogenesis involves immune complex deposition and complement system activation, leading to vessel wall destruction.¹ Rheumatoid vasculitis is an extra-articular complication of RA that primarily is observed in seropositive patients with long-standing severe disease.^1,2 The mean duration between RA diagnosis and RV onset is 10 to 14 years.² Rheumatoid vasculitis manifests heterogeneously and can affect many organs; however, it most frequently affects the skin. Cutaneous manifestations vary in severity. Palpable purpura, pyoderma gangrenosum, and distal ulcers can be seen in addition to extensive digital ischemia with necrosis, as was present in our patient.¹

When RA patients present with skin changes that are concerning for vasculitis, RV should be suspected. Currently, there are no validated diagnostic criteria for RV. Diagnosis is made based on clinical presentation and tissue biopsy. Histopathology shows small- and medium-sized vessel wall destruction with neutrophilic, granulomatous, or lymphocytic infiltration, which may be observed only in the lower dermis sparing superficial vessels.³ Direct immunofluorescence shows IgM, IgA, and C3 deposition within and around vessels.^3,4 Laboratory findings including elevated inflammatory markers, positive rheumatoid factor, positive anti–cyclic citrullinated peptide, and hypocomplementemia support a diagnosis of RV.^1,2

Mortality rates for RV remain high, necessitating aggressive treatment. High-dose corticosteroids typically are combined with immunosuppressant or biologic agents, frequently cyclophosphamide or rituximab.¹ Consistent with other reported cases, our patient’s ulcers improved with rituximab and oral steroids.

The differential diagnosis for our patient included type I cryoglobulinemia, cutaneous polyarteritis nodosa (CPAN), peripheral vascular disease (PVD), and nonuremic calciphylaxis. Type I cryoglobulinemia manifests due to direct occlusion of vessels by precipitation of monoclonal immunoglobulin.⁵ It commonly is associated with lymphoproliferative diseases such as Waldenström macroglobulinemia and multiple myeloma. While our patient’s history of RA was a risk factor for mixed cryoglobulinemia as opposed to type I cryoglobulinemia, the clinical presentation aligned more closely with type I cryoglobulinemia. The clinical manifestations of type I cryoglobulinemia are related to intravascular obstruction, including Raynaud phenomenon, retiform purpura, ischemic ulcers, distal gangrene, and cold-induced urticaria.^6-8 Type I cryoglobulinemia also frequently has neurologic and renal manifestations. Histopathology, along with the detection of serum cryoglobulins, is the gold standard for diagnosing cryoglobulinemia.⁶ On histopathology, type I cryoglobulinemia typically shows a thrombotic vasculopathy with amorphous eosinophilic periodic acid–Schiff–positive thrombi.⁷ False-negative results are particularly common with serum cryoglobulins, so repeat testing often is needed. While many clinical features overlap, RV is the most likely diagnosis in a patient with long-standing RA who is negative for cryoglobulins and has no history of lymphoproliferative disorders.

Cutaneous polyarteritis nodosa is a necrotizing vasculitis that similarly affects small- and medium-sized vessels. The exact etiology is unknown, but the high prevalence of anti–phosphatidylserine/prothrombin complex antibodies among patients with CPAN suggests that prothrombin bound to apoptotic endothelial cells may initiate the immune response.⁹ Underlying infection and inflammatory and autoimmune diseases (including group A beta-hemolytic streptococcus, hepatitis B, inflammatory bowel disease, myasthenia gravis, and RA) also may trigger CPAN.^9,10,11 The most common clinical manifestations of CPAN are tender subcutaneous nodules, livedo reticularis, leg ulcers, and cutaneous necrosis. Extracutaneous symptoms such as myalgias and arthralgias also can be associated with CPAN. There is no specific serologic test to diagnose CPAN; the diagnosis is made based on clinicopathologic correlation, with characteristic histopathology showing leukocytoclastic vasculitis in the small- and medium-sized arteries of the deep dermis or hypodermis.⁹

Peripheral vascular disease is a manifestation of atherosclerosis that affects the legs. Risk factors for atherosclerosis, especially smoking and diabetes mellitus, similarly increase the risk for PVD.¹² The most common clinical manifestation of PVD is intermittent claudication, but rarely PVD can progress to critical limb ischemia, which is characterized by pain at rest, nonhealing ulcers, or gangrene of the legs.¹² Common findings on physical examination include diminished or absent pedal pulses, abnormal skin color, and skin that is cool to the touch.¹² The standard diagnostic test for PVD affecting the legs is evaluation via the ankle-brachial index, with a score of 0.90 or lower being diagnostic of PVD, a score of 0.91 to 1.00 being borderline, and a score of 1.01 to 1.40 being normal.¹³

Calciphylaxis most frequently is seen in patients with end-stage kidney disease; however, it also has been less commonly reported in patients with normal kidney function, known as nonuremic calciphylaxis. It is characterized by calcification of arteries, arterioles, and soft tissues, which can lead to thrombosis and eventually ischemia and necrosis of the skin.¹⁴ Calciphylaxis initially causes tender, indurated, erythematous to purpuric plaques that quickly progress to retiform and stellate ulcers with overlying necrotic eschars.¹⁵ Disease typically occurs on the legs and areas that are rich in adipose tissue, such as the abdomen and thighs.¹⁶ Skin biopsy is needed for diagnosis of calciphylaxis. Characteristic histopathologic findings include calcification, microvascular thrombosis, and fibrointimal hyperplasia of small dermal and subcutaneous arteries and arterioles.¹⁶

We present a rare case of RV in a patient with well-controlled RA. While the incidence of RV is decreasing in the United States and United Kingdom due to the initiation of earlier and more aggressive RA therapies, mortality remains high.¹ Thus, it is important to include RV in the differential diagnosis when there are skin changes concerning vasculitis in patients with seropositive, longstanding RA, even if the RA is well controlled.

To the Editor:

Cutaneous metastasis of prostate cancer is rare and portends a bleak prognosis. Diagnosis of the primary cancer can be challenging, as skin metastasis can mimic a variety of conditions. We report a case of metastatic prostatic adenocarcinoma confirmed via biopsy of a new skin lesion.

A 97-year-old man presented to the dermatology clinic for routine follow-up of psoriasis. During the visit, a family member mentioned a new bleeding lesion on the left shoulder. It was not known how long the lesion had been present. Four months prior, the patient had a prostate-specific antigen (PSA) level of 582 ng/mL (reference range, 0-6.5 ng/mL), and computed tomography of the chest had shown innumerable pulmonary nodules in addition to lymphadenopathy of the left axilla, clavicle, and mediastinum. The imaging was ordered by the patient’s urologist as part of routine workup, as he had a history of obstructive renal failure and was being monitored for an indwelling catheter. Two months later, a bone scan ordered by the urologist due to high PSA levels showed extensive osteoblastic metastatic disease throughout the axial and proximal appendicular skeleton. The elevated PSA levels and findings of pulmonary and osteoblastic metastasis suggested a diagnosis of metastatic prostatic adenocarcinoma, but no confirmatory biopsy was performed following the imaging because the patient’s family declined additional workup or intervention.

Physical examination at the current presentation revealed an 8-mm brown papule with an overlying blue-white veil (Figure 1). There were no other skin findings. Primary differential diagnoses included metastatic prostate cancer, nodular melanoma, and traumatized seborrheic keratosis. A shave biopsy of the lesion showed multiple glandular structures infiltrating the dermis lined by monomorphic epithelial cells with prominent eosinophilic nucleoli (Figures 2 and 3). Focal cribriform architecture of the glands was present as well as dermal hemorrhage and a lymphohistiocytic infiltrate (Figure 2A). Interestingly, in-transit vascular metastases were confirmed with the support of ERG, CD34, and CD31 immunohistochemical staining of the vessels.

Immunohistochemical staining was positive for PSA (Figure 2B), NKX 3.1, and ERG in the invasive glandular structures, which also displayed patchy weak staining with AMACR. Staining was negative for prostein, cytokeratin (CK) 7, CK20, CK5/6, p63, p40, CDX2, and thyroid transcription factor 1. These findings were consistent with a diagnosis of cutaneous metastatic prostatic adenocarcinoma. Next-generation sequencing showed trans-membrane protease serine 2:v-ets erythroblastosis virus E26 oncogene homolog (TMPRSS2-ERG) fusion compatible with the positive ERG immunohistochemical staining. The patient and family declined any treatment due to his age, comorbidities, and rapid decline. He died 2 months after diagnosis of the skin metastasis.

Aside from nonmelanoma skin cancer, prostate cancer is the most common cancer and the second leading cause of cancer-related deaths among men in the United States.¹ It most commonly metastasizes to the bones, nonregional lymph nodes, liver, and thorax.² Metastasis to the skin is very rare, with only a 0.36% incidence.³ When prostate cancer does metastasize to the skin, the prognosis is poor, with an estimated mean survival of 7 months after diagnosis of cutaneous metastasis.⁴ Our patient’s survival time was even shorter—only 2 months after diagnosis of cutaneous metastasis, likely the result of his late diagnosis.

Clinically, cutaneous metastasis of prostate cancer can manifest as a wide variety of lesions; in one report of 78 cases, 56 (72%) were hard nodules, 11 (14%) were single nodules, 5 (7%) were edema or lymphedema, and 5 (7%) were an unspecific rash.⁴ Diagnosis of cutaneous metastasis of prostate cancer can be challenging, as it often is mistaken for other skin conditions including herpes zoster, basal cell carcinoma, angiosarcoma, cellulitis, mammary Paget disease, telangiectasia, pyoderma, morphea, and trichoepithelioma.⁵ In our patient, the clinical appearance of the lesion resembled a nodular melanoma. Thus, in patients with a history of prostate cancer, it is important to keep cutaneous metastasis in the differential when examining the skin because of the prognostic implications. Cutaneous metastasis of prostate cancer often indicates a poor prognosis.

In a report of 78 patients, the most common sites of skin metastasis for prostate cancer were the inguinal area and penis (28% [22/78]), abdomen (23% [18/78]), head and neck (16% [12/78]), and chest (14% [11/78]); the extremities and back were less frequently involved (10% [8/78] and 9% [7/78], respectively).⁴ Generally, cutaneous metastasis of internal malignancies involves the deep dermis and the subcutaneous tissue. It is common for cutaneous metastases to show histologic features of the primary tumor, as we saw in our patient. In a case series with 45 histologic diagnoses of cutaneous metastases from internal malignancies, 75.5% (34/45) of cases showed morphologic features of the primary tumor.⁶ However, this is not always the case, and the histologic appearance may vary. Metastatic prostate cancer may manifest as sheets, nests, or cords and often may have nuclear pleomorphism with prominent nucleoli.⁷

Immunohistochemical staining can help make a definitive diagnosis and differentiate the source of the tumor. Prostate cancer metastases often will stain positive for NKX3.1, PSA, AMACR, ERG, PSMA, and prosaposin, with PSA being the most specific marker.^7,8 In our patient, no prostate biopsy had been performed, thus the skin biopsy was the diagnostic tissue for the prostatic adenocarcinoma.

Next-generation sequencing showed a TMPRSS2- ERG fusion, which commonly is seen in prostate cancer.⁹ A search of Google Scholar using the terms next-generation sequencing, cutaneous metastasis, and prostate adenocarcinoma yielded 3 additional cases of cutaneous metastasis of prostate cancer in which next-generation sequencing was performed.^10-12 One case showed mutations of the tumor protein 53 (TP53) and phosphatase and tensin homolog (PTEN) genes; one showed just a TP53 mutation; and one showed inactivation of the breast cancer predisposition gene 2 (BRCA2) and amplification of MYC proto-oncogene, BHLH transcription factor (MYC) and fibroblast growth factor receptor 1 (FGFR1).^10,11,12 While limited by a small number of reported cases, there does not appear to be a repeating mutation to suggest a genetic mechanism of skin metastasis.

The route of cutaneous metastasis of prostate cancer still is unclear, but hypothesized mechanisms include hematogenous or lymphatic spread, direct infiltration, or implantation from a surgical scar.¹¹ When cutaneous involvement occurs in an area far from the primary tumor, it is thought to be the result of hematogenous spread, which would be consistent with our patient’s findings.¹³ Given the role of Batson venous plexus as a conduit from the prostate to the vertebral column for metastatic spread and considering the location of the lesion on our patient’s back, we hypothesized that the mechanism of metastasis to the skin was from vascular extension of the metastatic foci involving the vertebrae.

Our case highlights the importance of considering cutaneous involvement of prostatic adenocarcinoma in patients with new skin lesions, particularly in the setting of a known or suspected prostate malignancy. Skin metastasis can have a range of manifestations and provides prognostic information that can help determine the course of treatment.

To the Editor:

Cutaneous metastasis of prostate cancer is rare and portends a bleak prognosis. Diagnosis of the primary cancer can be challenging, as skin metastasis can mimic a variety of conditions. We report a case of metastatic prostatic adenocarcinoma confirmed via biopsy of a new skin lesion.

A 97-year-old man presented to the dermatology clinic for routine follow-up of psoriasis. During the visit, a family member mentioned a new bleeding lesion on the left shoulder. It was not known how long the lesion had been present. Four months prior, the patient had a prostate-specific antigen (PSA) level of 582 ng/mL (reference range, 0-6.5 ng/mL), and computed tomography of the chest had shown innumerable pulmonary nodules in addition to lymphadenopathy of the left axilla, clavicle, and mediastinum. The imaging was ordered by the patient’s urologist as part of routine workup, as he had a history of obstructive renal failure and was being monitored for an indwelling catheter. Two months later, a bone scan ordered by the urologist due to high PSA levels showed extensive osteoblastic metastatic disease throughout the axial and proximal appendicular skeleton. The elevated PSA levels and findings of pulmonary and osteoblastic metastasis suggested a diagnosis of metastatic prostatic adenocarcinoma, but no confirmatory biopsy was performed following the imaging because the patient’s family declined additional workup or intervention.

Physical examination at the current presentation revealed an 8-mm brown papule with an overlying blue-white veil (Figure 1). There were no other skin findings. Primary differential diagnoses included metastatic prostate cancer, nodular melanoma, and traumatized seborrheic keratosis. A shave biopsy of the lesion showed multiple glandular structures infiltrating the dermis lined by monomorphic epithelial cells with prominent eosinophilic nucleoli (Figures 2 and 3). Focal cribriform architecture of the glands was present as well as dermal hemorrhage and a lymphohistiocytic infiltrate (Figure 2A). Interestingly, in-transit vascular metastases were confirmed with the support of ERG, CD34, and CD31 immunohistochemical staining of the vessels.

Immunohistochemical staining was positive for PSA (Figure 2B), NKX 3.1, and ERG in the invasive glandular structures, which also displayed patchy weak staining with AMACR. Staining was negative for prostein, cytokeratin (CK) 7, CK20, CK5/6, p63, p40, CDX2, and thyroid transcription factor 1. These findings were consistent with a diagnosis of cutaneous metastatic prostatic adenocarcinoma. Next-generation sequencing showed trans-membrane protease serine 2:v-ets erythroblastosis virus E26 oncogene homolog (TMPRSS2-ERG) fusion compatible with the positive ERG immunohistochemical staining. The patient and family declined any treatment due to his age, comorbidities, and rapid decline. He died 2 months after diagnosis of the skin metastasis.

Aside from nonmelanoma skin cancer, prostate cancer is the most common cancer and the second leading cause of cancer-related deaths among men in the United States.¹ It most commonly metastasizes to the bones, nonregional lymph nodes, liver, and thorax.² Metastasis to the skin is very rare, with only a 0.36% incidence.³ When prostate cancer does metastasize to the skin, the prognosis is poor, with an estimated mean survival of 7 months after diagnosis of cutaneous metastasis.⁴ Our patient’s survival time was even shorter—only 2 months after diagnosis of cutaneous metastasis, likely the result of his late diagnosis.

Clinically, cutaneous metastasis of prostate cancer can manifest as a wide variety of lesions; in one report of 78 cases, 56 (72%) were hard nodules, 11 (14%) were single nodules, 5 (7%) were edema or lymphedema, and 5 (7%) were an unspecific rash.⁴ Diagnosis of cutaneous metastasis of prostate cancer can be challenging, as it often is mistaken for other skin conditions including herpes zoster, basal cell carcinoma, angiosarcoma, cellulitis, mammary Paget disease, telangiectasia, pyoderma, morphea, and trichoepithelioma.⁵ In our patient, the clinical appearance of the lesion resembled a nodular melanoma. Thus, in patients with a history of prostate cancer, it is important to keep cutaneous metastasis in the differential when examining the skin because of the prognostic implications. Cutaneous metastasis of prostate cancer often indicates a poor prognosis.

In a report of 78 patients, the most common sites of skin metastasis for prostate cancer were the inguinal area and penis (28% [22/78]), abdomen (23% [18/78]), head and neck (16% [12/78]), and chest (14% [11/78]); the extremities and back were less frequently involved (10% [8/78] and 9% [7/78], respectively).⁴ Generally, cutaneous metastasis of internal malignancies involves the deep dermis and the subcutaneous tissue. It is common for cutaneous metastases to show histologic features of the primary tumor, as we saw in our patient. In a case series with 45 histologic diagnoses of cutaneous metastases from internal malignancies, 75.5% (34/45) of cases showed morphologic features of the primary tumor.⁶ However, this is not always the case, and the histologic appearance may vary. Metastatic prostate cancer may manifest as sheets, nests, or cords and often may have nuclear pleomorphism with prominent nucleoli.⁷

Immunohistochemical staining can help make a definitive diagnosis and differentiate the source of the tumor. Prostate cancer metastases often will stain positive for NKX3.1, PSA, AMACR, ERG, PSMA, and prosaposin, with PSA being the most specific marker.^7,8 In our patient, no prostate biopsy had been performed, thus the skin biopsy was the diagnostic tissue for the prostatic adenocarcinoma.

Next-generation sequencing showed a TMPRSS2- ERG fusion, which commonly is seen in prostate cancer.⁹ A search of Google Scholar using the terms next-generation sequencing, cutaneous metastasis, and prostate adenocarcinoma yielded 3 additional cases of cutaneous metastasis of prostate cancer in which next-generation sequencing was performed.^10-12 One case showed mutations of the tumor protein 53 (TP53) and phosphatase and tensin homolog (PTEN) genes; one showed just a TP53 mutation; and one showed inactivation of the breast cancer predisposition gene 2 (BRCA2) and amplification of MYC proto-oncogene, BHLH transcription factor (MYC) and fibroblast growth factor receptor 1 (FGFR1).^10,11,12 While limited by a small number of reported cases, there does not appear to be a repeating mutation to suggest a genetic mechanism of skin metastasis.

The route of cutaneous metastasis of prostate cancer still is unclear, but hypothesized mechanisms include hematogenous or lymphatic spread, direct infiltration, or implantation from a surgical scar.¹¹ When cutaneous involvement occurs in an area far from the primary tumor, it is thought to be the result of hematogenous spread, which would be consistent with our patient’s findings.¹³ Given the role of Batson venous plexus as a conduit from the prostate to the vertebral column for metastatic spread and considering the location of the lesion on our patient’s back, we hypothesized that the mechanism of metastasis to the skin was from vascular extension of the metastatic foci involving the vertebrae.

Our case highlights the importance of considering cutaneous involvement of prostatic adenocarcinoma in patients with new skin lesions, particularly in the setting of a known or suspected prostate malignancy. Skin metastasis can have a range of manifestations and provides prognostic information that can help determine the course of treatment.

To the Editor:

Cutaneous metastasis of prostate cancer is rare and portends a bleak prognosis. Diagnosis of the primary cancer can be challenging, as skin metastasis can mimic a variety of conditions. We report a case of metastatic prostatic adenocarcinoma confirmed via biopsy of a new skin lesion.

A 97-year-old man presented to the dermatology clinic for routine follow-up of psoriasis. During the visit, a family member mentioned a new bleeding lesion on the left shoulder. It was not known how long the lesion had been present. Four months prior, the patient had a prostate-specific antigen (PSA) level of 582 ng/mL (reference range, 0-6.5 ng/mL), and computed tomography of the chest had shown innumerable pulmonary nodules in addition to lymphadenopathy of the left axilla, clavicle, and mediastinum. The imaging was ordered by the patient’s urologist as part of routine workup, as he had a history of obstructive renal failure and was being monitored for an indwelling catheter. Two months later, a bone scan ordered by the urologist due to high PSA levels showed extensive osteoblastic metastatic disease throughout the axial and proximal appendicular skeleton. The elevated PSA levels and findings of pulmonary and osteoblastic metastasis suggested a diagnosis of metastatic prostatic adenocarcinoma, but no confirmatory biopsy was performed following the imaging because the patient’s family declined additional workup or intervention.

Physical examination at the current presentation revealed an 8-mm brown papule with an overlying blue-white veil (Figure 1). There were no other skin findings. Primary differential diagnoses included metastatic prostate cancer, nodular melanoma, and traumatized seborrheic keratosis. A shave biopsy of the lesion showed multiple glandular structures infiltrating the dermis lined by monomorphic epithelial cells with prominent eosinophilic nucleoli (Figures 2 and 3). Focal cribriform architecture of the glands was present as well as dermal hemorrhage and a lymphohistiocytic infiltrate (Figure 2A). Interestingly, in-transit vascular metastases were confirmed with the support of ERG, CD34, and CD31 immunohistochemical staining of the vessels.

Immunohistochemical staining was positive for PSA (Figure 2B), NKX 3.1, and ERG in the invasive glandular structures, which also displayed patchy weak staining with AMACR. Staining was negative for prostein, cytokeratin (CK) 7, CK20, CK5/6, p63, p40, CDX2, and thyroid transcription factor 1. These findings were consistent with a diagnosis of cutaneous metastatic prostatic adenocarcinoma. Next-generation sequencing showed trans-membrane protease serine 2:v-ets erythroblastosis virus E26 oncogene homolog (TMPRSS2-ERG) fusion compatible with the positive ERG immunohistochemical staining. The patient and family declined any treatment due to his age, comorbidities, and rapid decline. He died 2 months after diagnosis of the skin metastasis.

Aside from nonmelanoma skin cancer, prostate cancer is the most common cancer and the second leading cause of cancer-related deaths among men in the United States.¹ It most commonly metastasizes to the bones, nonregional lymph nodes, liver, and thorax.² Metastasis to the skin is very rare, with only a 0.36% incidence.³ When prostate cancer does metastasize to the skin, the prognosis is poor, with an estimated mean survival of 7 months after diagnosis of cutaneous metastasis.⁴ Our patient’s survival time was even shorter—only 2 months after diagnosis of cutaneous metastasis, likely the result of his late diagnosis.

Clinically, cutaneous metastasis of prostate cancer can manifest as a wide variety of lesions; in one report of 78 cases, 56 (72%) were hard nodules, 11 (14%) were single nodules, 5 (7%) were edema or lymphedema, and 5 (7%) were an unspecific rash.⁴ Diagnosis of cutaneous metastasis of prostate cancer can be challenging, as it often is mistaken for other skin conditions including herpes zoster, basal cell carcinoma, angiosarcoma, cellulitis, mammary Paget disease, telangiectasia, pyoderma, morphea, and trichoepithelioma.⁵ In our patient, the clinical appearance of the lesion resembled a nodular melanoma. Thus, in patients with a history of prostate cancer, it is important to keep cutaneous metastasis in the differential when examining the skin because of the prognostic implications. Cutaneous metastasis of prostate cancer often indicates a poor prognosis.

In a report of 78 patients, the most common sites of skin metastasis for prostate cancer were the inguinal area and penis (28% [22/78]), abdomen (23% [18/78]), head and neck (16% [12/78]), and chest (14% [11/78]); the extremities and back were less frequently involved (10% [8/78] and 9% [7/78], respectively).⁴ Generally, cutaneous metastasis of internal malignancies involves the deep dermis and the subcutaneous tissue. It is common for cutaneous metastases to show histologic features of the primary tumor, as we saw in our patient. In a case series with 45 histologic diagnoses of cutaneous metastases from internal malignancies, 75.5% (34/45) of cases showed morphologic features of the primary tumor.⁶ However, this is not always the case, and the histologic appearance may vary. Metastatic prostate cancer may manifest as sheets, nests, or cords and often may have nuclear pleomorphism with prominent nucleoli.⁷

Immunohistochemical staining can help make a definitive diagnosis and differentiate the source of the tumor. Prostate cancer metastases often will stain positive for NKX3.1, PSA, AMACR, ERG, PSMA, and prosaposin, with PSA being the most specific marker.^7,8 In our patient, no prostate biopsy had been performed, thus the skin biopsy was the diagnostic tissue for the prostatic adenocarcinoma.

Next-generation sequencing showed a TMPRSS2- ERG fusion, which commonly is seen in prostate cancer.⁹ A search of Google Scholar using the terms next-generation sequencing, cutaneous metastasis, and prostate adenocarcinoma yielded 3 additional cases of cutaneous metastasis of prostate cancer in which next-generation sequencing was performed.^10-12 One case showed mutations of the tumor protein 53 (TP53) and phosphatase and tensin homolog (PTEN) genes; one showed just a TP53 mutation; and one showed inactivation of the breast cancer predisposition gene 2 (BRCA2) and amplification of MYC proto-oncogene, BHLH transcription factor (MYC) and fibroblast growth factor receptor 1 (FGFR1).^10,11,12 While limited by a small number of reported cases, there does not appear to be a repeating mutation to suggest a genetic mechanism of skin metastasis.

The route of cutaneous metastasis of prostate cancer still is unclear, but hypothesized mechanisms include hematogenous or lymphatic spread, direct infiltration, or implantation from a surgical scar.¹¹ When cutaneous involvement occurs in an area far from the primary tumor, it is thought to be the result of hematogenous spread, which would be consistent with our patient’s findings.¹³ Given the role of Batson venous plexus as a conduit from the prostate to the vertebral column for metastatic spread and considering the location of the lesion on our patient’s back, we hypothesized that the mechanism of metastasis to the skin was from vascular extension of the metastatic foci involving the vertebrae.

Our case highlights the importance of considering cutaneous involvement of prostatic adenocarcinoma in patients with new skin lesions, particularly in the setting of a known or suspected prostate malignancy. Skin metastasis can have a range of manifestations and provides prognostic information that can help determine the course of treatment.

Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by firm hyperkeratotic nodules that develops when patients persistently scratch or rub intensely itchy areas of the skin. This potent itch-scratch cycle can be traced back to a dysfunctional interplay between cutaneous nerve fibers and the local immune environment.^1-3 Pruritis lasting at least 6 weeks is a hallmark symptom of PN and can be accompanied by pain and/or a burning sensation.⁴ The lesions are symmetrically distributed in areas that are easy to scratch (eg, arms, legs, trunk), typically sparing the face, palms, and soles; however, facial lesions have been reported in pediatric patients with PN, who also are more likely to have back, hand, and foot involvement.^5,6

PN can greatly affect patients’ quality of life, leading to increased rates of depression and anxiety.^7-9 Patients with severe symptoms also report increased sleep disturbance, distraction from work, selfconsciousness leading to social isolation, and missed days of work/school.⁹ In one study, patients with PN reported missing at least 1 day of work, school, training, or learning; giving up a leisure activity or sport; or refusing an invitation to dinner or a party in the past 3 months due to the disease.¹⁰

Epidemiology

PN has a prevalence of 72 per 100,000 individuals in the United States, most commonly affecting adults aged 51 to 65 years and disproportionately affecting African American and female patients.^11-13 Most patients with PN experience a 2-year delay in diagnosis after initial onset of symptoms. ¹⁰ Adults with PN have an increased likelihood of having other dermatologic conditions, including atopic dermatitis (AD) and psoriasis.¹¹ Nearly two-thirds of pediatric patients with PN present with AD, and those with AD showed more resistance to first-line treatment options.⁵

Key Clinical Features

Compared to White patients, who typically present with lesions that appear erythematous or pink, patients with darker skin tones may present with hyperpigmented nodules that are larger and darker.¹² The pruritic nodules often show signs of scratching or picking (eg, excoriations, lichenification, and angulated erosions).⁴

Worth Noting

Diagnosis of PN is made clinically, but skin biopsy may be helpful to rule out alternative diseases. Histologically, the hairy palm sign may be present in addition to other histologic features commonly associated with excessive scratching or rubbing of the skin.

Patients with PN have a high risk for HIV, which is not surprising considering HIV is a known systemic cause of generalized chronic pruritus. Other associations include type 2 diabetes mellitus and thyroid, kidney, and liver disease. ^11,13 Workup for patients with PN should include a complete blood count with differential; liver and renal function testing; and testing for C-reactive protein, thyroid-stimulating hormone, and lactate dehydrogenase.^4,14 Hemoglobin A1c and HIV testing as well as a hepatitis panel should be considered when appropriate. Because generalized pruritus may be a sign of malignancy, chest radiography and lymph node and abdominal ultrasonography should be performed in patients who have experienced itch for less than 1 year along with B symptoms (fever, night sweats, ≥ 10% weight loss over 6 months, fatigue).¹⁴ Frequent scratching can disrupt the skin barrier, contributing to the increased risk for skin infections.¹³ All patients with a suspected PN diagnosis also should undergo screening for depression and anxiety, as patients with PN are at an increased risk for these conditions.⁴

Treatment of PN starts with breaking the itch-scratch cycle by addressing the underlying cause of the pruritus. Therapies are focused on addressing the immunologic and neural components of the disease. Topical treatments include moderate to strong corticosteroids, calcineurin inhibitors (tacrolimus or pimecrolimus), capsaicin, and antipruritic emollients. Systemic agents include phototherapy (narrow-band UVB or excimer laser), gabapentin, pregabalin, paroxetine, and amitriptyline to address the neural component of itch. Methotrexate or cyclosporine can be used to address the immunologic component of PN and diminish the itch. That said, methotrexate and cyclosporine often are inadequate to control pruritus. ¹⁰ Of note, sedating antihistamines are not effective in treating itch in PN but can be used as an adjuvant therapy for sleep disturbances in these patients.¹⁵

The only drugs currently approved by the US Food and Drug Administration to treat PN are the biologics dupilumab (targeting the IL-4 receptor) approved in 2022 and nemolizumab (targeting the IL-31 receptor) approved in 2024.^16-18 The evidence that these injectable biologics work is heartening in a condition that has historically been very challenging to treat.^16,18 It should be noted that the high cost of these 2 medications can restrict access to care for patients who are uninsured or underinsured.

Resolution of a prurigo nodule may result in a hyperpigmented macule taking months to years to fade.

Health Disparity Highlight

Patients with PN have a considerable comorbidity burden, negative impact on quality of life, and increased health care utilization rates.¹² PN is 3.4 times more common in Black patients than White patients.¹³ Black patients with PN have increased mortality, higher health care utilization rates, and increased systemic inflammation compared to White patients.^12,19,20

Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by firm hyperkeratotic nodules that develops when patients persistently scratch or rub intensely itchy areas of the skin. This potent itch-scratch cycle can be traced back to a dysfunctional interplay between cutaneous nerve fibers and the local immune environment.^1-3 Pruritis lasting at least 6 weeks is a hallmark symptom of PN and can be accompanied by pain and/or a burning sensation.⁴ The lesions are symmetrically distributed in areas that are easy to scratch (eg, arms, legs, trunk), typically sparing the face, palms, and soles; however, facial lesions have been reported in pediatric patients with PN, who also are more likely to have back, hand, and foot involvement.^5,6

PN can greatly affect patients’ quality of life, leading to increased rates of depression and anxiety.^7-9 Patients with severe symptoms also report increased sleep disturbance, distraction from work, selfconsciousness leading to social isolation, and missed days of work/school.⁹ In one study, patients with PN reported missing at least 1 day of work, school, training, or learning; giving up a leisure activity or sport; or refusing an invitation to dinner or a party in the past 3 months due to the disease.¹⁰

Epidemiology

PN has a prevalence of 72 per 100,000 individuals in the United States, most commonly affecting adults aged 51 to 65 years and disproportionately affecting African American and female patients.^11-13 Most patients with PN experience a 2-year delay in diagnosis after initial onset of symptoms. ¹⁰ Adults with PN have an increased likelihood of having other dermatologic conditions, including atopic dermatitis (AD) and psoriasis.¹¹ Nearly two-thirds of pediatric patients with PN present with AD, and those with AD showed more resistance to first-line treatment options.⁵

Key Clinical Features

Compared to White patients, who typically present with lesions that appear erythematous or pink, patients with darker skin tones may present with hyperpigmented nodules that are larger and darker.¹² The pruritic nodules often show signs of scratching or picking (eg, excoriations, lichenification, and angulated erosions).⁴

Worth Noting

Diagnosis of PN is made clinically, but skin biopsy may be helpful to rule out alternative diseases. Histologically, the hairy palm sign may be present in addition to other histologic features commonly associated with excessive scratching or rubbing of the skin.

Patients with PN have a high risk for HIV, which is not surprising considering HIV is a known systemic cause of generalized chronic pruritus. Other associations include type 2 diabetes mellitus and thyroid, kidney, and liver disease. ^11,13 Workup for patients with PN should include a complete blood count with differential; liver and renal function testing; and testing for C-reactive protein, thyroid-stimulating hormone, and lactate dehydrogenase.^4,14 Hemoglobin A1c and HIV testing as well as a hepatitis panel should be considered when appropriate. Because generalized pruritus may be a sign of malignancy, chest radiography and lymph node and abdominal ultrasonography should be performed in patients who have experienced itch for less than 1 year along with B symptoms (fever, night sweats, ≥ 10% weight loss over 6 months, fatigue).¹⁴ Frequent scratching can disrupt the skin barrier, contributing to the increased risk for skin infections.¹³ All patients with a suspected PN diagnosis also should undergo screening for depression and anxiety, as patients with PN are at an increased risk for these conditions.⁴

Treatment of PN starts with breaking the itch-scratch cycle by addressing the underlying cause of the pruritus. Therapies are focused on addressing the immunologic and neural components of the disease. Topical treatments include moderate to strong corticosteroids, calcineurin inhibitors (tacrolimus or pimecrolimus), capsaicin, and antipruritic emollients. Systemic agents include phototherapy (narrow-band UVB or excimer laser), gabapentin, pregabalin, paroxetine, and amitriptyline to address the neural component of itch. Methotrexate or cyclosporine can be used to address the immunologic component of PN and diminish the itch. That said, methotrexate and cyclosporine often are inadequate to control pruritus. ¹⁰ Of note, sedating antihistamines are not effective in treating itch in PN but can be used as an adjuvant therapy for sleep disturbances in these patients.¹⁵

The only drugs currently approved by the US Food and Drug Administration to treat PN are the biologics dupilumab (targeting the IL-4 receptor) approved in 2022 and nemolizumab (targeting the IL-31 receptor) approved in 2024.^16-18 The evidence that these injectable biologics work is heartening in a condition that has historically been very challenging to treat.^16,18 It should be noted that the high cost of these 2 medications can restrict access to care for patients who are uninsured or underinsured.

Resolution of a prurigo nodule may result in a hyperpigmented macule taking months to years to fade.

Health Disparity Highlight

Patients with PN have a considerable comorbidity burden, negative impact on quality of life, and increased health care utilization rates.¹² PN is 3.4 times more common in Black patients than White patients.¹³ Black patients with PN have increased mortality, higher health care utilization rates, and increased systemic inflammation compared to White patients.^12,19,20

Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by firm hyperkeratotic nodules that develops when patients persistently scratch or rub intensely itchy areas of the skin. This potent itch-scratch cycle can be traced back to a dysfunctional interplay between cutaneous nerve fibers and the local immune environment.^1-3 Pruritis lasting at least 6 weeks is a hallmark symptom of PN and can be accompanied by pain and/or a burning sensation.⁴ The lesions are symmetrically distributed in areas that are easy to scratch (eg, arms, legs, trunk), typically sparing the face, palms, and soles; however, facial lesions have been reported in pediatric patients with PN, who also are more likely to have back, hand, and foot involvement.^5,6

PN can greatly affect patients’ quality of life, leading to increased rates of depression and anxiety.^7-9 Patients with severe symptoms also report increased sleep disturbance, distraction from work, selfconsciousness leading to social isolation, and missed days of work/school.⁹ In one study, patients with PN reported missing at least 1 day of work, school, training, or learning; giving up a leisure activity or sport; or refusing an invitation to dinner or a party in the past 3 months due to the disease.¹⁰

Epidemiology

PN has a prevalence of 72 per 100,000 individuals in the United States, most commonly affecting adults aged 51 to 65 years and disproportionately affecting African American and female patients.^11-13 Most patients with PN experience a 2-year delay in diagnosis after initial onset of symptoms. ¹⁰ Adults with PN have an increased likelihood of having other dermatologic conditions, including atopic dermatitis (AD) and psoriasis.¹¹ Nearly two-thirds of pediatric patients with PN present with AD, and those with AD showed more resistance to first-line treatment options.⁵

Key Clinical Features

Compared to White patients, who typically present with lesions that appear erythematous or pink, patients with darker skin tones may present with hyperpigmented nodules that are larger and darker.¹² The pruritic nodules often show signs of scratching or picking (eg, excoriations, lichenification, and angulated erosions).⁴

Worth Noting

Diagnosis of PN is made clinically, but skin biopsy may be helpful to rule out alternative diseases. Histologically, the hairy palm sign may be present in addition to other histologic features commonly associated with excessive scratching or rubbing of the skin.

Patients with PN have a high risk for HIV, which is not surprising considering HIV is a known systemic cause of generalized chronic pruritus. Other associations include type 2 diabetes mellitus and thyroid, kidney, and liver disease. ^11,13 Workup for patients with PN should include a complete blood count with differential; liver and renal function testing; and testing for C-reactive protein, thyroid-stimulating hormone, and lactate dehydrogenase.^4,14 Hemoglobin A1c and HIV testing as well as a hepatitis panel should be considered when appropriate. Because generalized pruritus may be a sign of malignancy, chest radiography and lymph node and abdominal ultrasonography should be performed in patients who have experienced itch for less than 1 year along with B symptoms (fever, night sweats, ≥ 10% weight loss over 6 months, fatigue).¹⁴ Frequent scratching can disrupt the skin barrier, contributing to the increased risk for skin infections.¹³ All patients with a suspected PN diagnosis also should undergo screening for depression and anxiety, as patients with PN are at an increased risk for these conditions.⁴

Treatment of PN starts with breaking the itch-scratch cycle by addressing the underlying cause of the pruritus. Therapies are focused on addressing the immunologic and neural components of the disease. Topical treatments include moderate to strong corticosteroids, calcineurin inhibitors (tacrolimus or pimecrolimus), capsaicin, and antipruritic emollients. Systemic agents include phototherapy (narrow-band UVB or excimer laser), gabapentin, pregabalin, paroxetine, and amitriptyline to address the neural component of itch. Methotrexate or cyclosporine can be used to address the immunologic component of PN and diminish the itch. That said, methotrexate and cyclosporine often are inadequate to control pruritus. ¹⁰ Of note, sedating antihistamines are not effective in treating itch in PN but can be used as an adjuvant therapy for sleep disturbances in these patients.¹⁵

The only drugs currently approved by the US Food and Drug Administration to treat PN are the biologics dupilumab (targeting the IL-4 receptor) approved in 2022 and nemolizumab (targeting the IL-31 receptor) approved in 2024.^16-18 The evidence that these injectable biologics work is heartening in a condition that has historically been very challenging to treat.^16,18 It should be noted that the high cost of these 2 medications can restrict access to care for patients who are uninsured or underinsured.

Resolution of a prurigo nodule may result in a hyperpigmented macule taking months to years to fade.

Health Disparity Highlight

Patients with PN have a considerable comorbidity burden, negative impact on quality of life, and increased health care utilization rates.¹² PN is 3.4 times more common in Black patients than White patients.¹³ Black patients with PN have increased mortality, higher health care utilization rates, and increased systemic inflammation compared to White patients.^12,19,20

Neurologic disorders are major causes of death and disability. Globally, the burden of neurologic disorders continues to increase. The prevalence of disabling neurologic disorders significantly increases with age. As people live longer, health care systems will face increasing demands for treatment, rehabilitation, and support services for neurologic disorders. The scarcity of established modifiable risks for most of the neurologic burden demonstrates how new knowledge is required to develop effective prevention and treatment strategies.¹

A single-center study for chronic headache at a rural institution found that, when combined with public education, clinician education not only can increase access to care but also reduce specialist overuse, hospitalizations, polypharmacy, and emergency department visits.² A predicted shortage of neurologists has sparked increased interest in the field and individual neurology educators are helping fuel its popularity.^3-5

TELE-EDUCATION

Educating the next generation of health professionals is 1 of 4 statutory missions of the US Department of Veterans Affairs (VA).⁶ Tele-education (also known as telelearning and distance learning) deviates from traditional in-person classroom settings, in which the lecture has been a core pedagogic method.⁷ Audio, video, and online technologies provide health education and can overcome geographic barriers for rural and remote clinicians.⁸ Recent technological improvements have allowed for inexpensive and efficient dissemination of educational materials, including video lectures, podcasts, online modules, assessment materials, and even entire curricula.⁹

There has been an increase in the awareness of the parallel curriculum involving self-directed and asynchronous learning opportunities. ¹⁰ Several studies report knowledge gained via tele-education is comparable to conventional classroom learning.^11-13 A systematic review of e-learning perceptions among health care students suggested benefits (eg, learning flexibility, pedagogical design, online interactions, basic computer skills, and access to technology) and drawbacks (eg, limited acquisition of clinical skills, internet connection problems, and issues with using educational platforms).¹

The COVID-19 pandemic forced an abrupt cessation of traditional in-person education, forcing educational institutions and medical organizations to transition to telelearning. Solutions in the education field appeared during the pandemic, such as videoconferencing, social media, and telemedicine, that effectively addressed the sudden cessation of in-person medical education.¹⁵

Graduate medical education in neurology residency programs served as an experimental set up for tele-education during the pandemic. Residents from neurology training programs outlined the benefits of a volunteer lecturer-based online didactic program that was established to meet this need, which included exposure to subspeciality topics, access to subspecialist experts not available within the department, exposure to different pedagogic methods, interaction with members of other educational institutions and training programs, career development opportunities, and the potential for forming a community of learning.¹⁶

Not all recent educational developments are technology-based. For example, instruction focused on specific patient experiences, and learning processes that emphasize problem solving and personal responsibility over specific knowledge have been successful in neurology.^17,18 Departments and institutions must be creative in finding ways to fund continuing education, especially when budgets are limited.¹⁹

ANNUAL NEUROLOGY SEMINAR

An annual Veterans Health Administration (VHA) neurology seminar began in 2019 as a 1-day in-person event. Neurologists at the Michael E. DeBakey VA Medical Center in Houston presented in 50-minute sessions. Nonspecialist clinical personnel and neurology clinicians attended the event. Attendees requested making the presentations widely available and regularly repeating the seminar.

The second neurology seminar took place during the COVID-19 pandemic. It was conducted online and advertised across the Veterans Integrated Services Network (VISN) 16. The 1-day program had 204 participants who were primarily nurses (59%) and physicians (21%); 94% agreed with the program objectives (Table 1). Participants could earn CME credits for the 7 presentations primarily by VHA experts.

Based on feedback and a needs assessment, the program expanded in 2021 and 2022. With support from the national VHA neurology office and VHA Employee Education System (EES), the Institute for Learning, Education, and Development (ILEAD), the feedback identified topics that resonate with VHA clinicians. Neurological disorders in the fields of stroke, dementia, and headache were included since veterans with these disorders regularly visit primary care, geriatrics, mental health, and other clinical offices. Updates provided in the diagnosis and treatment of common neurological disorders were well received. Almost all speakers were VHA clinicians, which allowed them to focus on topics relevant to clinical practice at the VHA.

Attendance has increased annually. In 2021, 550 clinicians registered (52% nurses) and 433 completed the postseminar survey (Table 2). In 2022, 635 participants registered and 342 completed evaluations, including attendees from other federal agencies who were invited to participate via EES TRAIN (Training Finder Real-time Affiliate Integrated Network). Forty-seven participants from other federal agencies, including the US Department of Defense, National Institute of Health, and Centers for Disease Control and Prevention, completed the feedback evaluation via TRAIN (Table 3). Participants report high levels of satisfaction each year (mean of 4.5 on a 5-point scale). Respondents preferred conventional lecture presentation and case-based discussions for the teaching format and dementia was the most requested topic for future seminars (Table 4).

The content of each seminar was designed to include . 1 topic relevant to current clinical practice. The 2020 seminar covered topics of cerebrovascular complications of COVID- 19 and living well with neurodegenerative disease in the COVID-19 era. In 2021, the seminar included COVID-19 and neurologic manifestations. In 2022, topics included trends in stroke rehabilitation. In addition, ≥ 1 session addressed neurologic issues within the VHA. In 2020, the VA Deputy National Director of Neurology presented on the VHA stroke systems of care. In 2021, there was a presentation on traumatic brain injury (TBI) in the military. In 2022, sessions covered long term neurologic consequences of TBI and use of telemedicine for neurologic disorders. Feedback on the sessions were positive (eAppendix, available at doi:10.12788/fp.0545).

At the request of the participants, individual presentations were shared via email by the course director and speakers. In collaboration with the EES, each session was recorded and the 2022 seminar was made available to registrants in TMS and EES TRAIN and via the VHA Neurology SharePoint.

DISCUSSION

The annual VHA neurology seminar is a 1-day neurology conference that provides education to general neurologists and other clinicians caring for patients with neurologic disorders. It is the first of its kind neurology education program in the VHA covering most subspecialties in neurology and aims at improving neurologic patient care and access through education. Sessions have covered stroke, epilepsy, sleep, amyotrophic lateral sclerosis, neuropathy, dementia, movement disorders and Parkinson disease, headaches, multiple sclerosis, neurorehabilitation, and telehealth.

The seminar has transitioned from an inperson meeting to a virtual format, making neurology education more convenient and accessible. The virtual format provides the means to increase educational collaborations and share lecture platforms with other federal agencies. The program offers CME credits at no cost to government employees. Recorded lectures can also be asynchronously viewed from the Neurology SharePoint without the ability to earn CME credits. These recordings may be used to educate trainees as well.

The seminar aims to educate all health care professionals caring for patients with neurologic disorders. It aims to eliminate neurophobia, the fear of neural sciences and clinical neurology, and help general practitioners, especially in rural areas, take care of patients with neurologic disorders. The seminars introduce general practitioners to VHA neurology experts; the epilepsy, headache multiple sclerosis, and Parkinson disease centers of excellence; and the national programs for telestroke and teleneurology.

Education Support in the VHA

The EES/ILEAD provides a wide variety of learning opportunities to VHA employees on a broad range of topics, making it one of the largest medical education programs in the country. Pharmacists, social workers, psychologists, therapists, nurses, physician assistants, and physicians have access to certified training opportunities to gain knowledge and skills needed to provide high-quality, veteran-centered care.

A review of geriatrics learning activities through the EES found > 15,000 lectures from 1999 to 2009 for > 300,000 attendees.²⁰ To our knowledge, a review of neurology-related learning activities offered by the EES/ILEAD has not been completed, but the study on geriatrics shows that a similar review would be feasible, given the integrated education system, and helpful in identifying what topics are covered, formats are used, and participants are engaged in neurology education at the VHA. This is a future project planned by the neurology education workgroup.

The EES/ILEAD arranged CME credit for the VHA Neurology Seminar and assisted in organizing an online event with > 500 attendees. Technology support and tools provided by EES during the virtual seminar, such as polling and chat features, kept the audience engaged. Other specialties may similarly value a virtual, all-day seminar format that is efficient and can encourage increased participation from practitioners, nurses, and clinicians.

Future Growth

We plan to increase future participation in the annual neurology seminar with primary care, geriatrics, neurology, and other specialties by instituting an improved and earlier marketing strategy. This includes working with the VHA neurology office to inform neurology practitioners as well as other program offices in the VHA. We intend to host the seminar the same day every year to make it easy for attendees to plan accordingly. In the future we may consider hybrid in-person and virtual modalities if feasible. We plan to focus on reaching out to other government agencies through platforms like TRAIN and the American Academy of Neurology government sections. Securing funding, administrative staff, and protected time in the future may help expand the program further.

Limitations

While a virtual format offers several advantages, using it removes the feel of an in-person meeting, which could be viewed by some attendees as a limitation. The other challenges and drawbacks of transitioning to the virtual platform for a national meeting are similar to those reported in the literature: time zone differences, internet issues, and participants having difficulty using certain online platforms. Attendance could also be limited by scheduling conflicts.¹⁶ Despite a large audience attending the seminar, many clinicians do not get protected time from their institutions. Institutional and leadership support at national and local levels will likely improve participation and help participants earn CME credits. While we are still doing a preliminary needs assessment, a formal needs assessment across federal governmental organizations will be helpful.

CONCLUSIONS

The annual VHA neurology seminar promotes interprofessional education, introduces neurology subspecialty centers of excellence, improves access to renowned neurology experts, and provides neurology-related updates through a VHA lens. The program not only provides educational updates to neurology clinicians, but also increases the confidence of non-neurology clinicians called to care for veterans with neurological disorders in their respective clinics.

Neurologic disorders are major causes of death and disability. Globally, the burden of neurologic disorders continues to increase. The prevalence of disabling neurologic disorders significantly increases with age. As people live longer, health care systems will face increasing demands for treatment, rehabilitation, and support services for neurologic disorders. The scarcity of established modifiable risks for most of the neurologic burden demonstrates how new knowledge is required to develop effective prevention and treatment strategies.¹

A single-center study for chronic headache at a rural institution found that, when combined with public education, clinician education not only can increase access to care but also reduce specialist overuse, hospitalizations, polypharmacy, and emergency department visits.² A predicted shortage of neurologists has sparked increased interest in the field and individual neurology educators are helping fuel its popularity.^3-5

TELE-EDUCATION

Educating the next generation of health professionals is 1 of 4 statutory missions of the US Department of Veterans Affairs (VA).⁶ Tele-education (also known as telelearning and distance learning) deviates from traditional in-person classroom settings, in which the lecture has been a core pedagogic method.⁷ Audio, video, and online technologies provide health education and can overcome geographic barriers for rural and remote clinicians.⁸ Recent technological improvements have allowed for inexpensive and efficient dissemination of educational materials, including video lectures, podcasts, online modules, assessment materials, and even entire curricula.⁹

There has been an increase in the awareness of the parallel curriculum involving self-directed and asynchronous learning opportunities. ¹⁰ Several studies report knowledge gained via tele-education is comparable to conventional classroom learning.^11-13 A systematic review of e-learning perceptions among health care students suggested benefits (eg, learning flexibility, pedagogical design, online interactions, basic computer skills, and access to technology) and drawbacks (eg, limited acquisition of clinical skills, internet connection problems, and issues with using educational platforms).¹

The COVID-19 pandemic forced an abrupt cessation of traditional in-person education, forcing educational institutions and medical organizations to transition to telelearning. Solutions in the education field appeared during the pandemic, such as videoconferencing, social media, and telemedicine, that effectively addressed the sudden cessation of in-person medical education.¹⁵

Graduate medical education in neurology residency programs served as an experimental set up for tele-education during the pandemic. Residents from neurology training programs outlined the benefits of a volunteer lecturer-based online didactic program that was established to meet this need, which included exposure to subspeciality topics, access to subspecialist experts not available within the department, exposure to different pedagogic methods, interaction with members of other educational institutions and training programs, career development opportunities, and the potential for forming a community of learning.¹⁶

Not all recent educational developments are technology-based. For example, instruction focused on specific patient experiences, and learning processes that emphasize problem solving and personal responsibility over specific knowledge have been successful in neurology.^17,18 Departments and institutions must be creative in finding ways to fund continuing education, especially when budgets are limited.¹⁹

ANNUAL NEUROLOGY SEMINAR

An annual Veterans Health Administration (VHA) neurology seminar began in 2019 as a 1-day in-person event. Neurologists at the Michael E. DeBakey VA Medical Center in Houston presented in 50-minute sessions. Nonspecialist clinical personnel and neurology clinicians attended the event. Attendees requested making the presentations widely available and regularly repeating the seminar.

The second neurology seminar took place during the COVID-19 pandemic. It was conducted online and advertised across the Veterans Integrated Services Network (VISN) 16. The 1-day program had 204 participants who were primarily nurses (59%) and physicians (21%); 94% agreed with the program objectives (Table 1). Participants could earn CME credits for the 7 presentations primarily by VHA experts.

Based on feedback and a needs assessment, the program expanded in 2021 and 2022. With support from the national VHA neurology office and VHA Employee Education System (EES), the Institute for Learning, Education, and Development (ILEAD), the feedback identified topics that resonate with VHA clinicians. Neurological disorders in the fields of stroke, dementia, and headache were included since veterans with these disorders regularly visit primary care, geriatrics, mental health, and other clinical offices. Updates provided in the diagnosis and treatment of common neurological disorders were well received. Almost all speakers were VHA clinicians, which allowed them to focus on topics relevant to clinical practice at the VHA.

Attendance has increased annually. In 2021, 550 clinicians registered (52% nurses) and 433 completed the postseminar survey (Table 2). In 2022, 635 participants registered and 342 completed evaluations, including attendees from other federal agencies who were invited to participate via EES TRAIN (Training Finder Real-time Affiliate Integrated Network). Forty-seven participants from other federal agencies, including the US Department of Defense, National Institute of Health, and Centers for Disease Control and Prevention, completed the feedback evaluation via TRAIN (Table 3). Participants report high levels of satisfaction each year (mean of 4.5 on a 5-point scale). Respondents preferred conventional lecture presentation and case-based discussions for the teaching format and dementia was the most requested topic for future seminars (Table 4).

The content of each seminar was designed to include . 1 topic relevant to current clinical practice. The 2020 seminar covered topics of cerebrovascular complications of COVID- 19 and living well with neurodegenerative disease in the COVID-19 era. In 2021, the seminar included COVID-19 and neurologic manifestations. In 2022, topics included trends in stroke rehabilitation. In addition, ≥ 1 session addressed neurologic issues within the VHA. In 2020, the VA Deputy National Director of Neurology presented on the VHA stroke systems of care. In 2021, there was a presentation on traumatic brain injury (TBI) in the military. In 2022, sessions covered long term neurologic consequences of TBI and use of telemedicine for neurologic disorders. Feedback on the sessions were positive (eAppendix, available at doi:10.12788/fp.0545).

At the request of the participants, individual presentations were shared via email by the course director and speakers. In collaboration with the EES, each session was recorded and the 2022 seminar was made available to registrants in TMS and EES TRAIN and via the VHA Neurology SharePoint.

DISCUSSION

The annual VHA neurology seminar is a 1-day neurology conference that provides education to general neurologists and other clinicians caring for patients with neurologic disorders. It is the first of its kind neurology education program in the VHA covering most subspecialties in neurology and aims at improving neurologic patient care and access through education. Sessions have covered stroke, epilepsy, sleep, amyotrophic lateral sclerosis, neuropathy, dementia, movement disorders and Parkinson disease, headaches, multiple sclerosis, neurorehabilitation, and telehealth.

The seminar has transitioned from an inperson meeting to a virtual format, making neurology education more convenient and accessible. The virtual format provides the means to increase educational collaborations and share lecture platforms with other federal agencies. The program offers CME credits at no cost to government employees. Recorded lectures can also be asynchronously viewed from the Neurology SharePoint without the ability to earn CME credits. These recordings may be used to educate trainees as well.

The seminar aims to educate all health care professionals caring for patients with neurologic disorders. It aims to eliminate neurophobia, the fear of neural sciences and clinical neurology, and help general practitioners, especially in rural areas, take care of patients with neurologic disorders. The seminars introduce general practitioners to VHA neurology experts; the epilepsy, headache multiple sclerosis, and Parkinson disease centers of excellence; and the national programs for telestroke and teleneurology.

Education Support in the VHA

The EES/ILEAD provides a wide variety of learning opportunities to VHA employees on a broad range of topics, making it one of the largest medical education programs in the country. Pharmacists, social workers, psychologists, therapists, nurses, physician assistants, and physicians have access to certified training opportunities to gain knowledge and skills needed to provide high-quality, veteran-centered care.

A review of geriatrics learning activities through the EES found > 15,000 lectures from 1999 to 2009 for > 300,000 attendees.²⁰ To our knowledge, a review of neurology-related learning activities offered by the EES/ILEAD has not been completed, but the study on geriatrics shows that a similar review would be feasible, given the integrated education system, and helpful in identifying what topics are covered, formats are used, and participants are engaged in neurology education at the VHA. This is a future project planned by the neurology education workgroup.

The EES/ILEAD arranged CME credit for the VHA Neurology Seminar and assisted in organizing an online event with > 500 attendees. Technology support and tools provided by EES during the virtual seminar, such as polling and chat features, kept the audience engaged. Other specialties may similarly value a virtual, all-day seminar format that is efficient and can encourage increased participation from practitioners, nurses, and clinicians.

Future Growth

We plan to increase future participation in the annual neurology seminar with primary care, geriatrics, neurology, and other specialties by instituting an improved and earlier marketing strategy. This includes working with the VHA neurology office to inform neurology practitioners as well as other program offices in the VHA. We intend to host the seminar the same day every year to make it easy for attendees to plan accordingly. In the future we may consider hybrid in-person and virtual modalities if feasible. We plan to focus on reaching out to other government agencies through platforms like TRAIN and the American Academy of Neurology government sections. Securing funding, administrative staff, and protected time in the future may help expand the program further.

Limitations

While a virtual format offers several advantages, using it removes the feel of an in-person meeting, which could be viewed by some attendees as a limitation. The other challenges and drawbacks of transitioning to the virtual platform for a national meeting are similar to those reported in the literature: time zone differences, internet issues, and participants having difficulty using certain online platforms. Attendance could also be limited by scheduling conflicts.¹⁶ Despite a large audience attending the seminar, many clinicians do not get protected time from their institutions. Institutional and leadership support at national and local levels will likely improve participation and help participants earn CME credits. While we are still doing a preliminary needs assessment, a formal needs assessment across federal governmental organizations will be helpful.

CONCLUSIONS

The annual VHA neurology seminar promotes interprofessional education, introduces neurology subspecialty centers of excellence, improves access to renowned neurology experts, and provides neurology-related updates through a VHA lens. The program not only provides educational updates to neurology clinicians, but also increases the confidence of non-neurology clinicians called to care for veterans with neurological disorders in their respective clinics.

Neurologic disorders are major causes of death and disability. Globally, the burden of neurologic disorders continues to increase. The prevalence of disabling neurologic disorders significantly increases with age. As people live longer, health care systems will face increasing demands for treatment, rehabilitation, and support services for neurologic disorders. The scarcity of established modifiable risks for most of the neurologic burden demonstrates how new knowledge is required to develop effective prevention and treatment strategies.¹

A single-center study for chronic headache at a rural institution found that, when combined with public education, clinician education not only can increase access to care but also reduce specialist overuse, hospitalizations, polypharmacy, and emergency department visits.² A predicted shortage of neurologists has sparked increased interest in the field and individual neurology educators are helping fuel its popularity.^3-5

TELE-EDUCATION

Educating the next generation of health professionals is 1 of 4 statutory missions of the US Department of Veterans Affairs (VA).⁶ Tele-education (also known as telelearning and distance learning) deviates from traditional in-person classroom settings, in which the lecture has been a core pedagogic method.⁷ Audio, video, and online technologies provide health education and can overcome geographic barriers for rural and remote clinicians.⁸ Recent technological improvements have allowed for inexpensive and efficient dissemination of educational materials, including video lectures, podcasts, online modules, assessment materials, and even entire curricula.⁹

There has been an increase in the awareness of the parallel curriculum involving self-directed and asynchronous learning opportunities. ¹⁰ Several studies report knowledge gained via tele-education is comparable to conventional classroom learning.^11-13 A systematic review of e-learning perceptions among health care students suggested benefits (eg, learning flexibility, pedagogical design, online interactions, basic computer skills, and access to technology) and drawbacks (eg, limited acquisition of clinical skills, internet connection problems, and issues with using educational platforms).¹

The COVID-19 pandemic forced an abrupt cessation of traditional in-person education, forcing educational institutions and medical organizations to transition to telelearning. Solutions in the education field appeared during the pandemic, such as videoconferencing, social media, and telemedicine, that effectively addressed the sudden cessation of in-person medical education.¹⁵

Graduate medical education in neurology residency programs served as an experimental set up for tele-education during the pandemic. Residents from neurology training programs outlined the benefits of a volunteer lecturer-based online didactic program that was established to meet this need, which included exposure to subspeciality topics, access to subspecialist experts not available within the department, exposure to different pedagogic methods, interaction with members of other educational institutions and training programs, career development opportunities, and the potential for forming a community of learning.¹⁶

Not all recent educational developments are technology-based. For example, instruction focused on specific patient experiences, and learning processes that emphasize problem solving and personal responsibility over specific knowledge have been successful in neurology.^17,18 Departments and institutions must be creative in finding ways to fund continuing education, especially when budgets are limited.¹⁹

ANNUAL NEUROLOGY SEMINAR

An annual Veterans Health Administration (VHA) neurology seminar began in 2019 as a 1-day in-person event. Neurologists at the Michael E. DeBakey VA Medical Center in Houston presented in 50-minute sessions. Nonspecialist clinical personnel and neurology clinicians attended the event. Attendees requested making the presentations widely available and regularly repeating the seminar.

The second neurology seminar took place during the COVID-19 pandemic. It was conducted online and advertised across the Veterans Integrated Services Network (VISN) 16. The 1-day program had 204 participants who were primarily nurses (59%) and physicians (21%); 94% agreed with the program objectives (Table 1). Participants could earn CME credits for the 7 presentations primarily by VHA experts.

Based on feedback and a needs assessment, the program expanded in 2021 and 2022. With support from the national VHA neurology office and VHA Employee Education System (EES), the Institute for Learning, Education, and Development (ILEAD), the feedback identified topics that resonate with VHA clinicians. Neurological disorders in the fields of stroke, dementia, and headache were included since veterans with these disorders regularly visit primary care, geriatrics, mental health, and other clinical offices. Updates provided in the diagnosis and treatment of common neurological disorders were well received. Almost all speakers were VHA clinicians, which allowed them to focus on topics relevant to clinical practice at the VHA.

Attendance has increased annually. In 2021, 550 clinicians registered (52% nurses) and 433 completed the postseminar survey (Table 2). In 2022, 635 participants registered and 342 completed evaluations, including attendees from other federal agencies who were invited to participate via EES TRAIN (Training Finder Real-time Affiliate Integrated Network). Forty-seven participants from other federal agencies, including the US Department of Defense, National Institute of Health, and Centers for Disease Control and Prevention, completed the feedback evaluation via TRAIN (Table 3). Participants report high levels of satisfaction each year (mean of 4.5 on a 5-point scale). Respondents preferred conventional lecture presentation and case-based discussions for the teaching format and dementia was the most requested topic for future seminars (Table 4).

The content of each seminar was designed to include . 1 topic relevant to current clinical practice. The 2020 seminar covered topics of cerebrovascular complications of COVID- 19 and living well with neurodegenerative disease in the COVID-19 era. In 2021, the seminar included COVID-19 and neurologic manifestations. In 2022, topics included trends in stroke rehabilitation. In addition, ≥ 1 session addressed neurologic issues within the VHA. In 2020, the VA Deputy National Director of Neurology presented on the VHA stroke systems of care. In 2021, there was a presentation on traumatic brain injury (TBI) in the military. In 2022, sessions covered long term neurologic consequences of TBI and use of telemedicine for neurologic disorders. Feedback on the sessions were positive (eAppendix, available at doi:10.12788/fp.0545).

At the request of the participants, individual presentations were shared via email by the course director and speakers. In collaboration with the EES, each session was recorded and the 2022 seminar was made available to registrants in TMS and EES TRAIN and via the VHA Neurology SharePoint.

DISCUSSION

The annual VHA neurology seminar is a 1-day neurology conference that provides education to general neurologists and other clinicians caring for patients with neurologic disorders. It is the first of its kind neurology education program in the VHA covering most subspecialties in neurology and aims at improving neurologic patient care and access through education. Sessions have covered stroke, epilepsy, sleep, amyotrophic lateral sclerosis, neuropathy, dementia, movement disorders and Parkinson disease, headaches, multiple sclerosis, neurorehabilitation, and telehealth.

The seminar has transitioned from an inperson meeting to a virtual format, making neurology education more convenient and accessible. The virtual format provides the means to increase educational collaborations and share lecture platforms with other federal agencies. The program offers CME credits at no cost to government employees. Recorded lectures can also be asynchronously viewed from the Neurology SharePoint without the ability to earn CME credits. These recordings may be used to educate trainees as well.

The seminar aims to educate all health care professionals caring for patients with neurologic disorders. It aims to eliminate neurophobia, the fear of neural sciences and clinical neurology, and help general practitioners, especially in rural areas, take care of patients with neurologic disorders. The seminars introduce general practitioners to VHA neurology experts; the epilepsy, headache multiple sclerosis, and Parkinson disease centers of excellence; and the national programs for telestroke and teleneurology.

Education Support in the VHA

The EES/ILEAD provides a wide variety of learning opportunities to VHA employees on a broad range of topics, making it one of the largest medical education programs in the country. Pharmacists, social workers, psychologists, therapists, nurses, physician assistants, and physicians have access to certified training opportunities to gain knowledge and skills needed to provide high-quality, veteran-centered care.

A review of geriatrics learning activities through the EES found > 15,000 lectures from 1999 to 2009 for > 300,000 attendees.²⁰ To our knowledge, a review of neurology-related learning activities offered by the EES/ILEAD has not been completed, but the study on geriatrics shows that a similar review would be feasible, given the integrated education system, and helpful in identifying what topics are covered, formats are used, and participants are engaged in neurology education at the VHA. This is a future project planned by the neurology education workgroup.

The EES/ILEAD arranged CME credit for the VHA Neurology Seminar and assisted in organizing an online event with > 500 attendees. Technology support and tools provided by EES during the virtual seminar, such as polling and chat features, kept the audience engaged. Other specialties may similarly value a virtual, all-day seminar format that is efficient and can encourage increased participation from practitioners, nurses, and clinicians.

Future Growth

We plan to increase future participation in the annual neurology seminar with primary care, geriatrics, neurology, and other specialties by instituting an improved and earlier marketing strategy. This includes working with the VHA neurology office to inform neurology practitioners as well as other program offices in the VHA. We intend to host the seminar the same day every year to make it easy for attendees to plan accordingly. In the future we may consider hybrid in-person and virtual modalities if feasible. We plan to focus on reaching out to other government agencies through platforms like TRAIN and the American Academy of Neurology government sections. Securing funding, administrative staff, and protected time in the future may help expand the program further.

Limitations

While a virtual format offers several advantages, using it removes the feel of an in-person meeting, which could be viewed by some attendees as a limitation. The other challenges and drawbacks of transitioning to the virtual platform for a national meeting are similar to those reported in the literature: time zone differences, internet issues, and participants having difficulty using certain online platforms. Attendance could also be limited by scheduling conflicts.¹⁶ Despite a large audience attending the seminar, many clinicians do not get protected time from their institutions. Institutional and leadership support at national and local levels will likely improve participation and help participants earn CME credits. While we are still doing a preliminary needs assessment, a formal needs assessment across federal governmental organizations will be helpful.

CONCLUSIONS

The annual VHA neurology seminar promotes interprofessional education, introduces neurology subspecialty centers of excellence, improves access to renowned neurology experts, and provides neurology-related updates through a VHA lens. The program not only provides educational updates to neurology clinicians, but also increases the confidence of non-neurology clinicians called to care for veterans with neurological disorders in their respective clinics.