Psoriasis

Non-White patient participation in phase 3 therapeutic trials for plaque psoriasis is less than 15%, according to a recently published analysis of data from the ClinicalTrials.gov database.

The exact figure drawn from the survey of 82 trials was 14.2%, but 20 (24%) of the trials did not include ethnoracial data at all, and only 65% of those with data had complete data, according to a report in the British Journal of Dermatology by a team of investigators from the department of dermatology at the University of California, San Francisco.

“The remaining studies reported the percentage of white participants only or white participants and one additional ethnoracial group,” reported the investigators, led by Vidhatha D. Reddy, a medical student at UCSF.

The investigators broke down participation by race in all phase 3 plaque psoriasis trials that enrolled adults and had posted results by May 2020. Data from trials of medications yet to be approved were excluded.

Most trials were multinational. The medications evaluated included 11 biologics, 10 topicals, 2 oral systemic agents, and a phosphodiesterase type-4 inhibitor. The 82 trials included in this analysis enrolled 48,846 collectively.

From trials that identified race, 85.8% of 39,161 participants were White, 3.09% of 25,565 patients were Black, 19.55% of 11,364 patients were Hispanic or Latino, and 9.21% of 30,009 patients were Asian. Of trials that included Native Americans or Pacific Islanders, fewer than 2% of participants represented this category.

Non-White patients remain underrepresented even when recognizing differences in the prevalence of psoriasis. For example, one recent survey found the U.S, prevalence of psoriasis to be about half as great in Blacks as it is in Whites (1.9% vs. 3.9%), but the representation of Blacks in the phase 3 trials evaluated by Mr. Reddy and colleagues was more than 20 times lower.

There are many reasons to suspect that lack of diversification in psoriasis trials is impeding optimal care in those underrepresented. Of several examples offered by the authors, one involved differential responses to adalimumab among patients with hidradenitis suppurativa with genetic variants in the BCL2 gene, but the authors reported racially associated genetic differences are not uncommon.

“Estimates have shown that approximately one-fifth of newly developed medications demonstrate interracial/ethnic variability in regard to various factors, such as pharmacokinetics, safety and efficacy profiles, dosing, and pharmacogenetics,” Mr. Reddy and his coinvestigators stated.

Although racial diversity in the design and recruitment for clinical trials has not been a priority in trials involving psoriasis, other skin diseases, or most diseases in general, the authors cited some evidence that this is changing.

“Since 2017, research funded by the National Institutes of Health has been required to report race and ethnicity of participants following an amendment to the Health Revitalization Act,” according to the authors, who suggested that other such initiatives are needed. They advocated “explicit goals to increase recruitment of people of color” as a standard step in clinical trial conduct.

Hypertension trials were cited as an example in which diversity has made a difference.

“Although Black patients are at an elevated risk of developing hypertension, it was not until the enrollment of a substantial proportion of black participants in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) that enough data on Black patients were available to make specific treatment recommendations in this population,” they noted.
 

Impossible to know treatment benefits without ethnoracial data

Penn Medicine

Another investigator who has considered this issue, Junko Takeshita, MD, PhD, an assistant professor of dermatology at the University of Pennsylvania, Philadelphia, agreed.

“Lack of diversity among participants in phase 3 clinical trials for psoriasis is a problem,” said Dr. Takeshita, who led a study of racial differences in perceptions of psoriasis therapies that was published last year.

In that study, “my research group not only found differences in perceptions about biologics between Black and White patients with psoriasis, but we have also shown that Black patients with psoriasis are less likely to receive biologic treatment,” she reported. There are many explanations. For example, she found in another study that Black patients are underrepresented in direct-to-consumer advertisements for biologics.

This problem is not unique to psoriasis. Underrepresentation of Blacks and other ethnoracial groups is true of other skin diseases and many diseases in general, according to Dr. Takeshita. However, she cautioned that the 3% figure for Black participation in psoriasis trials reported by Mr. Reddy and colleagues is not necessarily reflective of trials in the United States.

“This study included international study sites that are recruiting patients from populations with different demographics than the U.S.,” she noted. By including sites with only Asian patients or countries with few Blacks in the population, it dilutes Black representation. She would expect the exact proportion of Black participants to be somewhat higher even if they are “still likely to be underrepresented” if the analysis has been limited to U.S. data.

The research had no funding source. Three of the nine authors reported financial relationships with pharmaceutical companies.

SOURCE: Reddy VD et al. Br J Dermatol. 2020 Sep 17. doi: 10.1111/bjd.19468.

Non-White patient participation in phase 3 therapeutic trials for plaque psoriasis is less than 15%, according to a recently published analysis of data from the ClinicalTrials.gov database.

The exact figure drawn from the survey of 82 trials was 14.2%, but 20 (24%) of the trials did not include ethnoracial data at all, and only 65% of those with data had complete data, according to a report in the British Journal of Dermatology by a team of investigators from the department of dermatology at the University of California, San Francisco.

“The remaining studies reported the percentage of white participants only or white participants and one additional ethnoracial group,” reported the investigators, led by Vidhatha D. Reddy, a medical student at UCSF.

The investigators broke down participation by race in all phase 3 plaque psoriasis trials that enrolled adults and had posted results by May 2020. Data from trials of medications yet to be approved were excluded.

Most trials were multinational. The medications evaluated included 11 biologics, 10 topicals, 2 oral systemic agents, and a phosphodiesterase type-4 inhibitor. The 82 trials included in this analysis enrolled 48,846 collectively.

From trials that identified race, 85.8% of 39,161 participants were White, 3.09% of 25,565 patients were Black, 19.55% of 11,364 patients were Hispanic or Latino, and 9.21% of 30,009 patients were Asian. Of trials that included Native Americans or Pacific Islanders, fewer than 2% of participants represented this category.

Non-White patients remain underrepresented even when recognizing differences in the prevalence of psoriasis. For example, one recent survey found the U.S, prevalence of psoriasis to be about half as great in Blacks as it is in Whites (1.9% vs. 3.9%), but the representation of Blacks in the phase 3 trials evaluated by Mr. Reddy and colleagues was more than 20 times lower.

There are many reasons to suspect that lack of diversification in psoriasis trials is impeding optimal care in those underrepresented. Of several examples offered by the authors, one involved differential responses to adalimumab among patients with hidradenitis suppurativa with genetic variants in the BCL2 gene, but the authors reported racially associated genetic differences are not uncommon.

“Estimates have shown that approximately one-fifth of newly developed medications demonstrate interracial/ethnic variability in regard to various factors, such as pharmacokinetics, safety and efficacy profiles, dosing, and pharmacogenetics,” Mr. Reddy and his coinvestigators stated.

Although racial diversity in the design and recruitment for clinical trials has not been a priority in trials involving psoriasis, other skin diseases, or most diseases in general, the authors cited some evidence that this is changing.

“Since 2017, research funded by the National Institutes of Health has been required to report race and ethnicity of participants following an amendment to the Health Revitalization Act,” according to the authors, who suggested that other such initiatives are needed. They advocated “explicit goals to increase recruitment of people of color” as a standard step in clinical trial conduct.

Hypertension trials were cited as an example in which diversity has made a difference.

“Although Black patients are at an elevated risk of developing hypertension, it was not until the enrollment of a substantial proportion of black participants in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) that enough data on Black patients were available to make specific treatment recommendations in this population,” they noted.
 

Impossible to know treatment benefits without ethnoracial data

Penn Medicine

Another investigator who has considered this issue, Junko Takeshita, MD, PhD, an assistant professor of dermatology at the University of Pennsylvania, Philadelphia, agreed.

“Lack of diversity among participants in phase 3 clinical trials for psoriasis is a problem,” said Dr. Takeshita, who led a study of racial differences in perceptions of psoriasis therapies that was published last year.

In that study, “my research group not only found differences in perceptions about biologics between Black and White patients with psoriasis, but we have also shown that Black patients with psoriasis are less likely to receive biologic treatment,” she reported. There are many explanations. For example, she found in another study that Black patients are underrepresented in direct-to-consumer advertisements for biologics.

This problem is not unique to psoriasis. Underrepresentation of Blacks and other ethnoracial groups is true of other skin diseases and many diseases in general, according to Dr. Takeshita. However, she cautioned that the 3% figure for Black participation in psoriasis trials reported by Mr. Reddy and colleagues is not necessarily reflective of trials in the United States.

“This study included international study sites that are recruiting patients from populations with different demographics than the U.S.,” she noted. By including sites with only Asian patients or countries with few Blacks in the population, it dilutes Black representation. She would expect the exact proportion of Black participants to be somewhat higher even if they are “still likely to be underrepresented” if the analysis has been limited to U.S. data.

The research had no funding source. Three of the nine authors reported financial relationships with pharmaceutical companies.

SOURCE: Reddy VD et al. Br J Dermatol. 2020 Sep 17. doi: 10.1111/bjd.19468.

Non-White patient participation in phase 3 therapeutic trials for plaque psoriasis is less than 15%, according to a recently published analysis of data from the ClinicalTrials.gov database.

The exact figure drawn from the survey of 82 trials was 14.2%, but 20 (24%) of the trials did not include ethnoracial data at all, and only 65% of those with data had complete data, according to a report in the British Journal of Dermatology by a team of investigators from the department of dermatology at the University of California, San Francisco.

“The remaining studies reported the percentage of white participants only or white participants and one additional ethnoracial group,” reported the investigators, led by Vidhatha D. Reddy, a medical student at UCSF.

The investigators broke down participation by race in all phase 3 plaque psoriasis trials that enrolled adults and had posted results by May 2020. Data from trials of medications yet to be approved were excluded.

Most trials were multinational. The medications evaluated included 11 biologics, 10 topicals, 2 oral systemic agents, and a phosphodiesterase type-4 inhibitor. The 82 trials included in this analysis enrolled 48,846 collectively.

From trials that identified race, 85.8% of 39,161 participants were White, 3.09% of 25,565 patients were Black, 19.55% of 11,364 patients were Hispanic or Latino, and 9.21% of 30,009 patients were Asian. Of trials that included Native Americans or Pacific Islanders, fewer than 2% of participants represented this category.

Non-White patients remain underrepresented even when recognizing differences in the prevalence of psoriasis. For example, one recent survey found the U.S, prevalence of psoriasis to be about half as great in Blacks as it is in Whites (1.9% vs. 3.9%), but the representation of Blacks in the phase 3 trials evaluated by Mr. Reddy and colleagues was more than 20 times lower.

There are many reasons to suspect that lack of diversification in psoriasis trials is impeding optimal care in those underrepresented. Of several examples offered by the authors, one involved differential responses to adalimumab among patients with hidradenitis suppurativa with genetic variants in the BCL2 gene, but the authors reported racially associated genetic differences are not uncommon.

“Estimates have shown that approximately one-fifth of newly developed medications demonstrate interracial/ethnic variability in regard to various factors, such as pharmacokinetics, safety and efficacy profiles, dosing, and pharmacogenetics,” Mr. Reddy and his coinvestigators stated.

Although racial diversity in the design and recruitment for clinical trials has not been a priority in trials involving psoriasis, other skin diseases, or most diseases in general, the authors cited some evidence that this is changing.

“Since 2017, research funded by the National Institutes of Health has been required to report race and ethnicity of participants following an amendment to the Health Revitalization Act,” according to the authors, who suggested that other such initiatives are needed. They advocated “explicit goals to increase recruitment of people of color” as a standard step in clinical trial conduct.

Hypertension trials were cited as an example in which diversity has made a difference.

“Although Black patients are at an elevated risk of developing hypertension, it was not until the enrollment of a substantial proportion of black participants in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) that enough data on Black patients were available to make specific treatment recommendations in this population,” they noted.
 

Impossible to know treatment benefits without ethnoracial data

Penn Medicine

Another investigator who has considered this issue, Junko Takeshita, MD, PhD, an assistant professor of dermatology at the University of Pennsylvania, Philadelphia, agreed.

“Lack of diversity among participants in phase 3 clinical trials for psoriasis is a problem,” said Dr. Takeshita, who led a study of racial differences in perceptions of psoriasis therapies that was published last year.

In that study, “my research group not only found differences in perceptions about biologics between Black and White patients with psoriasis, but we have also shown that Black patients with psoriasis are less likely to receive biologic treatment,” she reported. There are many explanations. For example, she found in another study that Black patients are underrepresented in direct-to-consumer advertisements for biologics.

This problem is not unique to psoriasis. Underrepresentation of Blacks and other ethnoracial groups is true of other skin diseases and many diseases in general, according to Dr. Takeshita. However, she cautioned that the 3% figure for Black participation in psoriasis trials reported by Mr. Reddy and colleagues is not necessarily reflective of trials in the United States.

“This study included international study sites that are recruiting patients from populations with different demographics than the U.S.,” she noted. By including sites with only Asian patients or countries with few Blacks in the population, it dilutes Black representation. She would expect the exact proportion of Black participants to be somewhat higher even if they are “still likely to be underrepresented” if the analysis has been limited to U.S. data.

The research had no funding source. Three of the nine authors reported financial relationships with pharmaceutical companies.

SOURCE: Reddy VD et al. Br J Dermatol. 2020 Sep 17. doi: 10.1111/bjd.19468.

A 42-year-old woman with psoriasis presents for a checkup at the dermatology clinic. Her psoriasis has been fairly stable on methotrexate with no recent flares. She presents her concern of the coronavirus pandemic continuing into the flu season and mentions she would like to minimize her chances of having a respiratory illness. The influenza vaccine has just become available, and she inquires when she can get the vaccine and whether it will interfere with her treatment. What are your recommendations for the patient?

Psoriasis is an immune-mediated, inflammatory skin condition stemming from hyperproliferation of keratinocytes that classically involves erythematous skin plaques with overlying scale. Treatment options vary widely and include topical modalities, phototherapy, immunosuppressants, and biologic agents. Selection of treatment largely depends on the severity and extent of body surface area involvement; systemic therapy generally is indicated when the affected body surface area is greater than 5% to 10%. In patients on systemic therapy, increased susceptibility to infection is a priority concern for prescribing physicians. In the context of continuing immunosuppressive medications, vaccines that reduce susceptibility to infectious diseases can play an important role in reducing morbidity and mortality for these patients; however, an important consideration is that in patients with chronic conditions and frequent hospital visits, vaccines may be administered by various clinicians who may not be familiar with the management of immunosuppressive treatments. It is pivotal for prescribing dermatologists to provide appropriate vaccination instructions for the patient and any future clinicians to ensure vaccine efficacy in these patients.

The intramuscular influenza vaccine is a killed vaccine that is administered annually and has been shown to be safe for use in both immunocompetent and immunocompromised patients.^1,2 Despite its safety, questions remain regarding the efficacy of vaccines while a patient is unable to mount a normal immune response and whether the treatment must be altered to maximize immunogenicity. The common systemic treatment options for psoriasis and any recommendations that can be made regarding administration of the influenza vaccine in that context are outlined in the Table. Given the sparsity of clinical data measuring vaccine immunogenicity in patients with psoriasis, vaccine guidelines are drawn from patients with various conditions who are receiving the same dose of medication as indicated for psoriasis.

A 42-year-old woman with psoriasis presents for a checkup at the dermatology clinic. Her psoriasis has been fairly stable on methotrexate with no recent flares. She presents her concern of the coronavirus pandemic continuing into the flu season and mentions she would like to minimize her chances of having a respiratory illness. The influenza vaccine has just become available, and she inquires when she can get the vaccine and whether it will interfere with her treatment. What are your recommendations for the patient?

Psoriasis is an immune-mediated, inflammatory skin condition stemming from hyperproliferation of keratinocytes that classically involves erythematous skin plaques with overlying scale. Treatment options vary widely and include topical modalities, phototherapy, immunosuppressants, and biologic agents. Selection of treatment largely depends on the severity and extent of body surface area involvement; systemic therapy generally is indicated when the affected body surface area is greater than 5% to 10%. In patients on systemic therapy, increased susceptibility to infection is a priority concern for prescribing physicians. In the context of continuing immunosuppressive medications, vaccines that reduce susceptibility to infectious diseases can play an important role in reducing morbidity and mortality for these patients; however, an important consideration is that in patients with chronic conditions and frequent hospital visits, vaccines may be administered by various clinicians who may not be familiar with the management of immunosuppressive treatments. It is pivotal for prescribing dermatologists to provide appropriate vaccination instructions for the patient and any future clinicians to ensure vaccine efficacy in these patients.

The intramuscular influenza vaccine is a killed vaccine that is administered annually and has been shown to be safe for use in both immunocompetent and immunocompromised patients.^1,2 Despite its safety, questions remain regarding the efficacy of vaccines while a patient is unable to mount a normal immune response and whether the treatment must be altered to maximize immunogenicity. The common systemic treatment options for psoriasis and any recommendations that can be made regarding administration of the influenza vaccine in that context are outlined in the Table. Given the sparsity of clinical data measuring vaccine immunogenicity in patients with psoriasis, vaccine guidelines are drawn from patients with various conditions who are receiving the same dose of medication as indicated for psoriasis.

A 42-year-old woman with psoriasis presents for a checkup at the dermatology clinic. Her psoriasis has been fairly stable on methotrexate with no recent flares. She presents her concern of the coronavirus pandemic continuing into the flu season and mentions she would like to minimize her chances of having a respiratory illness. The influenza vaccine has just become available, and she inquires when she can get the vaccine and whether it will interfere with her treatment. What are your recommendations for the patient?

Psoriasis is an immune-mediated, inflammatory skin condition stemming from hyperproliferation of keratinocytes that classically involves erythematous skin plaques with overlying scale. Treatment options vary widely and include topical modalities, phototherapy, immunosuppressants, and biologic agents. Selection of treatment largely depends on the severity and extent of body surface area involvement; systemic therapy generally is indicated when the affected body surface area is greater than 5% to 10%. In patients on systemic therapy, increased susceptibility to infection is a priority concern for prescribing physicians. In the context of continuing immunosuppressive medications, vaccines that reduce susceptibility to infectious diseases can play an important role in reducing morbidity and mortality for these patients; however, an important consideration is that in patients with chronic conditions and frequent hospital visits, vaccines may be administered by various clinicians who may not be familiar with the management of immunosuppressive treatments. It is pivotal for prescribing dermatologists to provide appropriate vaccination instructions for the patient and any future clinicians to ensure vaccine efficacy in these patients.

The intramuscular influenza vaccine is a killed vaccine that is administered annually and has been shown to be safe for use in both immunocompetent and immunocompromised patients.^1,2 Despite its safety, questions remain regarding the efficacy of vaccines while a patient is unable to mount a normal immune response and whether the treatment must be altered to maximize immunogenicity. The common systemic treatment options for psoriasis and any recommendations that can be made regarding administration of the influenza vaccine in that context are outlined in the Table. Given the sparsity of clinical data measuring vaccine immunogenicity in patients with psoriasis, vaccine guidelines are drawn from patients with various conditions who are receiving the same dose of medication as indicated for psoriasis.

Psoriasis is a common chronic, multisystem, inflammatory disease with predominantly skin and joint manifestations that affects approximately 2% of the world’s population.¹ It occurs in a variety of clinical forms, from a few well-demarcated, erythematous plaques with a silvery scale to involvement of almost the entire body surface area. Beyond the debilitating physical ailments of the disease, psoriasis also may have psychosocial effects on quality of life.² The pathogenesis of psoriasis is not fully understood but represents a complex multifactorial disease with both immune-mediated and genetic components. Characterized by hyperplasia of epidermal keratinocytes, psoriasis is shown to be mediated by infiltration of T-cell lymphocytes with an increase of various inflammatory cytokines, including tumor necrosis factor (TNF) α.³ More recently, interactions of helper T cells (T_H17) via IL-17 and IL-23 have been supported to play a major role in the pathogenesis of psoriasis.^4,5

With the growing understanding of the pathophysiology of psoriasis, focused biologics have been developed to target specific cytokines implicated in the disease process and have been increasingly utilized. Tumor necrosis factor α inhibitors, including adalimumab, infliximab, and etanercept, along with the IL-12/IL-23 inhibitor ustekinumab, have been revolutionary in psoriasis treatment by providing safe and effective long-term therapy; however, there is concern of life-threatening infections with biologics because of the immunosuppressive effects and mechanisms of action.⁶ Specifically, there have been reported cases of deep fungal infections associated with TNF-α inhibitor use.⁷

Recently, the advent of IL-17 and IL-23 inhibitors has garnered notable interest in these biologics as promising treatments for psoriasis. With IL-17 and IL-23 supported to have a major role in the pathogenesis of psoriasis, targeting the cytokine is not only logical but also has proven to be effacacious.^8-10 Secukinumab, ixekizumab, and brodalumab are IL-17 inhibitors that have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis. Secukinumab and ixekizumab are anti–IL-17A monoclonal antibodies, whereas brodalumab is an anti–IL-17 receptor antibody. Risankizumab, guselkumab, and tildrakizumab are IL-23 inhibitors that also have been approved by the FDA for the treatment of psoriasis. As with older biologics, there is concern over the safety of these inhibitors because of the central role of IL-17 and IL-23 in both innate and adaptive immune responses, particularly against fungi.¹¹ Therefore, use of biologics targeting IL-17 and IL-23 may increase susceptibility to deep fungal infections.

Safety data and discussion of the risk for deep fungal infections from IL-17, IL-12/IL-23, and IL-23 inhibitor use for psoriasis treatment currently are lacking. Given the knowledge gap, we sought to synthesize and review the current evidence on risks for deep fungal infections during biologic therapy in patients with psoriasis, with a focus on IL-17 inhibitor therapies.

METHODS

A PubMed search of articles indexed for MEDLINE from database inception to 2019 (1946-2019) was performed to find randomized controlled trials (RCTs), including extended trials and clinical trials, for IL-17, IL-12/IL-23, and IL-23 inhibitors approved by the FDA for psoriasis treatment. The following keywords were used: psoriasis or inflammatory disease and secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Studies were restricted to the English-language literature, and those that did not provide adequate safety data on the specific types of infections that occurred were excluded.

RESULTSIL-17 Inhibitors

Our search yielded RCTs, some including extension trials, and clinical trials of IL-17 inhibitors used for psoriatic disease and other nonpsoriatic conditions (Table).

Risk for Deep Fungal Infection With Secukinumab
The queried studies included 20 RCTs or clinical trials along with extension trials of 3746 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In a 3-year extension study of SCULPTURE, Bissonnette et al¹² reported no new safety concerns for the 340 patients with moderate to severe psoriasis treated with secukinumab. Common adverse events (AEs) included nasopharyngitis, upper respiratory tract infections, and headache, but there were no reports of deep fungal infections.¹² In a subsequent 5-year analysis of 168 patients that focused on the 300-mg fixed interval treatment with secukinumab, the safety profile remained favorable, with 0 reports of invasive fungal infections.¹³ A study (FEATURE) of 118 patients with psoriasis treated with a prefilled syringe of 300 or 150 mg of secukinumab also described an acceptable safety profile and reported no deep fungal infections.¹⁴ JUNCTURE, another study utilizing autoinjectors, also found that treatment with 300 or 150 mg of secukinumab was well tolerated in 121 patients, with no deep fungal infections.¹⁵ Common AEs for both studies included nasopharyngitis and headache.^14,15 A 24-week phase 3 study for scalp psoriasis treated with secukinumab also reported 0 deep fungal infections in 51 patients.¹⁶ In an RCT comparing secukinumab and ustekinumab for moderate to severe plaque psoriasis, Blauvelt et al¹⁷ demonstrated that the incidence of serious AEs was comparable between the 2 groups, with no reports of invasive fungal infections in the 334 patients exposed to secukinumab. The CLEAR study, which compared secukinumab and ustekinumab, also found no reported deep fungal disease in the 335 patients exposed to secukinumab.¹⁸ Secukinumab exhibited a similar safety profile to ustekinumab in both studies, with common AEs being headache and nasopharyngitis.^17,18 The GESTURE study investigated the efficacy of secukinumab in 137 patients with palmoplantar psoriasis and reported a favorable profile with no reports of deep fungal disease.¹⁹ In a subanalysis of the phase 3 study ERASURE, secukinumab was shown to have a robust and sustainable efficacy in 58 Japanese patients with moderate to severe plaque psoriasis, and there were no reports of invasive fungal infections.²⁰ Another subanalysis of 36 Taiwanese patients from the ERASURE study also had similar findings, with no dose relationship observed for AEs.²¹ In a phase 2 study of 103 patients with psoriasis, Papp et al²² demonstrated AE rates that were similar across different doses of secukinumab—3×150 mg, 3×75 mg, 3×25 mg, and 1×25 mg—and described no incidences of invasive fungal disease. In a phase 2 regimen-finding study of 337 patients conducted by Rich et al,²³ the most commonly reported AEs included nasopharyngitis, worsening psoriasis, and upper respiratory tract infections, but there were no reported deep fungal infections.

Our search also resulted in studies specific to the treatment of psoriatic arthritis (PsA) with secukinumab. McInnes et al⁹ conducted a phase 2 proof-of-concept trial for patients with PsA and reported no deep fungal infections in 28 patients exposed to 10 mg/kg of secukinumab. A 2-year follow-up with the cohort from FUTURE 1, a phase 3 clinical trial, also showed no new or unexpected safety signals in 404 patients exposed to 150 or 75 mg of secukinumab, including no reports of invasive fungal disease.²⁴ FUTURE 2, a phase 3 clinical trial, demonstrated that the most common AE was upper respiratory tract infection in the 299 patients treatedwith secukinumab, but there were no recorded invasive fungal infections.²⁵ In FUTURE 3, 277 patients were treated with secukinumab, with 14 nonserious candida infections but no observed deep fungal infections.²⁶ A study comparing secukinumab to fumaric acid esters reported that 6 of 105 patients treated with secukinumab also experienced superficial candidiasis, but there were no reports of deep fungal disease.²⁷

Secukinumab also has been used in the treatment of ankylosing spondylitis in a phase 3 RCT (MEASURE 1) in which 4 cases of superficial candidiasis were reported (0.7 cases per 100 patient-years of secukinumab) that were all resolved with standard antifungal therapy.²⁸ In MEASURE 2, a 5-year phase 3 RCT, 145 patients were treated with secukinumab for ankylosing spondylitis, with common AEs including nasopharyngitis, diarrhea, and upper respiratory tract infection, but there were no reports of any invasive fungal infections.²⁹ MEASURE 3 also demonstrated similar results in which no invasive fungal infections were observed.³⁰

Risk for Deep Fungal Infection With Ixekizumab
The queried studies included 7 RCTs or clinical trials of 3523 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In UNCOVER-A, a phase 3 RCT of the pharmacokinetics and safety of ixekizumab, 204 patients were randomized to a prefilled syringe or autoinjector; 48% of patients experienced AEs, but no invasive fungal infections were observed.³¹ In an analysis of 3 phase 3 trials of ixekizumab including a total 2334 patients treated with ixekizumab from UNCOVER-1, UNCOVER-2, and UNCOVER-3, oral candidiasis frequently was reported, but no candidal infections met criteria for serious invasive infection.³² In UNCOVER-J, a 52-week phase 3 open-label trial of Japanese patients, 91 patients were treated for plaque psoriasis, erythrodermic psoriasis, or generalized pustular psoriasis using ixekizumab; the most common AEs included allergic reactions and injection-site reactions. One case of oral candidiasis was reported, but there were no reported cases of invasive fungal infections.³³ A comparison of ixekizumab vs ustekinumab from the IXORA-S trial demonstrated no substantial differences in AEs between the two, and no cases of deep fungal infections were reported. The most common AE between the 2 groups was nasopharyngitis.³⁴ An open-label extension over 4 years of a phase 2 RCT treated 211 patients with either 120 or 80 mg of ixekizumab; 87% of patients had experienced at least 1 AE, and all AEs were considered mild or moderate in severity, with no invasive fungal disease.³⁵

Our search also resulted in 1 study specific to the treatment of PsA with ixekizumab. A phase 3, 52-week study of patients treated with ixekizumab for PsA observed 2 incidences of oral candidiasis and nail candida infections, but no invasive fungal infections were reported.³⁶

We also found 1 study of ixekizumab used in the treatment of ankylosing spondylitis. COAST-V was a phase 3 RCT of patients treated for ankylosing spondylitis in which 164 patients were treated with ixekizumab; no serious AEs were recorded, including 0 deep fungal infections. The most common AEs observed were nasopharyngitis and upper respiratory tract infections.³⁷

Risk for Deep Fungal Infection With Brodalumab
The queried studies included 9 RCTs and 3 clinical trials along with extension trials of 1599 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 120 weeks. In a phase 2 RCT of Japanese patients with moderate to severe plaque psoriasis, 113 patients were treated with 70, 140, or 210 mg of brodalumab, and the most common AEs were nasopharyngitis, diarrhea, and upper respiratory tract inflammation. There were no reported cases of fungal infections in the study.³⁸ In an open-label extension study of Japanese patients that evaluated the long-term clinical safety of brodalumab, 145 patients were enrolled and observed similar AEs to the RCT, with 7 patients experiencing oral candidiasis and 1 patient having skin candidiasis, but there were no observed deep fungal infections.³⁹ In AMG 827, which evaluated the efficacy and safety of brodalumab, 320 patients were treated, and only 2 serious AEs were reported, neither of which were deep fungal disease.¹⁰ A phase 3 RCT conducted by Papp et al⁴⁰ (AMAGINE-1) also treated 441 patients with moderate to severe plaque psoriasis with brodalumab and observed candida infections in 9 patients that were mild to moderate and responsive to treatment, with no patients discontinuing the study. In a 120-week open-label extension study of 181 patients, Papp et al⁴¹ reported 8% of patients experienced serious AEs, with 1 case of latent tuberculosis that led to withdrawal of treatment. A study also investigated the efficacy and safety of brodalumab in 30 patients with generalized pustular psoriasis or psoriatic erythroderma and observed 2 cases of mild candida infections that resolved with treatment. There were no reports of invasive fungal disease.⁴²

Our search also resulted in studies of brodalumab used in the treatment of PsA and nonpsoriatic diseases. In one phase 2 RCT, 113 patients with PsA were treated with 140 mg, 280 mg, or combined doses of brodalumab, with the most common AEs being nasopharyngitis, upper respiratory tract infection, and diarrhea, but there were no reports of deep fungal infection.⁴³ In a phase 1b trial of patients with methotrexate-resistant rheumatoid arthritis treated with brodalumab, common AEs reported included headache, cough, and abdominal pain, with only 1 case of oral candidiasis that was determined not to be drug related.⁴⁴ Finally, an RCT of patients with moderate to severe asthma treated 226 patients with brodalumab and reported a greater incidence of oral candidiasis in treatment groups compared with placebo (3.5% vs 0%) but saw no instances of invasive fungal infection.⁴⁵

IL-12/IL-23 Inhibitor

Risk for Deep Fungal Infection With Ustekinumab
The queried studies included 4 RCTs of 954 patients with psoriasis treated with ustekinumab (eTable).^46-49 Within these trials, there were no reported cases of serious infections involving deep fungal organisms during the stated follow-up period. The literature search also found long-term safety data from the ACCEPT and PHOENIX trials that included 5437 patients with psoriasis treated with ustekinumab.^66,67 There also were no demonstrated incidences of invasive fungal disease in these studies, with most cases of infection being common bacterial or viral infections.

IL-23 Inhibitors

Risk for Deep Fungal Infection With Risankizumab, Guselkumab, and Tildrakizumab
The queried studies included 16 RCTs or clinical trials for psoriatic patients treated with IL-23 inhibitors, including 5 with risankizumab,^50-54 9 with guselkumab,^55-63 and 2 with tildrakizumab.^64,65 Within these trials there were no observed cases of serious infections with deep fungal disease.

COMMENT

Our literature review has demonstrated that there does not appear to be an increased incidence of deep fungal infections for patients treated with IL-17, IL-12/IL-23, or IL-23 inhibitors for psoriatic disease. All of the reviewed studies found no cases of invasive fungal infections for patients with psoriasis treated with secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Patients with other inflammatory conditions, such as ankylosing spondylitis, rheumatoid arthritis, and asthma, also did not appear to show an increased incidence of deep fungal disease.

Although these results show promising safety data for the use of these biologic therapies in treating inflammatory conditions, caution still is warranted, as these medications still are relatively new, with FDA approvals within the last 5 years. Safety data among different study populations also cannot be derived without further investigation, and much of the available literature is limited in long-term data. More extended trials or registry data from a large, broadly representative cohort are necessary to establish the long-term safety and risk for deep fungal infections with IL-17 and especially the newer IL-23 inhibitors.

A small percentage of patients from the reviewed literature did develop superficial candidiasis. This outcome can be expected, as the central role of IL-17 and IL-23 has been recognized in immunologic protection against infections, specifically against fungi.¹¹ Because all of the fungal infections reported for patients on IL-17 inhibitors were superficial candidiasis, guides for practical management and treatment should be implemented to standardize future research and care. A proposed screening algorithm for patients on these biologic therapies involves safety monitoring, including inspection of the oral cavity, folds, and genitals, along with inquiring about symptoms such as burning, dysgeusia, and dysuria.⁶⁸ If infection is suspected, confirmation by culture, molecular method, or optimally with esophagoscopy can be performed, and appropriate treatment may be initiated.⁶⁸ Patients with candida infections of the oral cavity, folds, or genitals can be placed on topical therapy such as nystatin, amphotericin B, ciclopirox, or other azoles, while those with infections of the esophagus can be started on oral fluconazole.⁶⁸

Although there were no reported cases of deep fungal infections, the theoretical risk for developing one while on IL-17 and IL-23 inhibitors may warrant further screening prior to beginning therapy. The TNF inhibitors approved for the treatment of psoriasis currently contain a black box warning for risk for disseminated and extrapulmonary histoplasmosis, coccidioidomycosis, blastomycosis, and other invasive fungal infections, which may highlight the importance of thorough evaluation and awareness of endemic areas for patients on biologics. Prior to initiating treatment with TNF inhibitors, current suggestions involve performing a thorough examination along with keeping a high index of suspicion for invasive fungal infections in patients who live in or have traveled to endemic regions.⁶⁹

Screening for invasive fungal infections for patients on TNF inhibitors involves questioning about potential exposures, such as demolition of old buildings, bird roosts, or spelunking.⁷⁰ Serologies or antigen testing can be used routinely, but as these tests are insensitive, empiric antifungal therapy should be initiated if there is high enough clinical suspicion.⁷¹ Currently, there are no clinical guidelines regarding fungal screening and initiation of IL-17 and IL-23 inhibitors for treatment of psoriasis and other inflammatory conditions, but careful stewardship over using these effective medications should still be practiced.

Upon review of the available safety data on the use of IL-17 and IL-23 inhibitors for the treatment of psoriasis and other inflammatory conditions, there does not appear to be an increased incidence of deep fungal infections. Physicians, however, should still be cautiously optimistic in prescribing these medications, as there is a theoretical risk for infection for all patients on biologics. A high index of suspicion for patients presenting with symptoms of fungal infections should be maintained, and appropriate diagnosis and management should be initiated if they do occur.

Psoriasis is a common chronic, multisystem, inflammatory disease with predominantly skin and joint manifestations that affects approximately 2% of the world’s population.¹ It occurs in a variety of clinical forms, from a few well-demarcated, erythematous plaques with a silvery scale to involvement of almost the entire body surface area. Beyond the debilitating physical ailments of the disease, psoriasis also may have psychosocial effects on quality of life.² The pathogenesis of psoriasis is not fully understood but represents a complex multifactorial disease with both immune-mediated and genetic components. Characterized by hyperplasia of epidermal keratinocytes, psoriasis is shown to be mediated by infiltration of T-cell lymphocytes with an increase of various inflammatory cytokines, including tumor necrosis factor (TNF) α.³ More recently, interactions of helper T cells (T_H17) via IL-17 and IL-23 have been supported to play a major role in the pathogenesis of psoriasis.^4,5

With the growing understanding of the pathophysiology of psoriasis, focused biologics have been developed to target specific cytokines implicated in the disease process and have been increasingly utilized. Tumor necrosis factor α inhibitors, including adalimumab, infliximab, and etanercept, along with the IL-12/IL-23 inhibitor ustekinumab, have been revolutionary in psoriasis treatment by providing safe and effective long-term therapy; however, there is concern of life-threatening infections with biologics because of the immunosuppressive effects and mechanisms of action.⁶ Specifically, there have been reported cases of deep fungal infections associated with TNF-α inhibitor use.⁷

Recently, the advent of IL-17 and IL-23 inhibitors has garnered notable interest in these biologics as promising treatments for psoriasis. With IL-17 and IL-23 supported to have a major role in the pathogenesis of psoriasis, targeting the cytokine is not only logical but also has proven to be effacacious.^8-10 Secukinumab, ixekizumab, and brodalumab are IL-17 inhibitors that have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis. Secukinumab and ixekizumab are anti–IL-17A monoclonal antibodies, whereas brodalumab is an anti–IL-17 receptor antibody. Risankizumab, guselkumab, and tildrakizumab are IL-23 inhibitors that also have been approved by the FDA for the treatment of psoriasis. As with older biologics, there is concern over the safety of these inhibitors because of the central role of IL-17 and IL-23 in both innate and adaptive immune responses, particularly against fungi.¹¹ Therefore, use of biologics targeting IL-17 and IL-23 may increase susceptibility to deep fungal infections.

Safety data and discussion of the risk for deep fungal infections from IL-17, IL-12/IL-23, and IL-23 inhibitor use for psoriasis treatment currently are lacking. Given the knowledge gap, we sought to synthesize and review the current evidence on risks for deep fungal infections during biologic therapy in patients with psoriasis, with a focus on IL-17 inhibitor therapies.

METHODS

A PubMed search of articles indexed for MEDLINE from database inception to 2019 (1946-2019) was performed to find randomized controlled trials (RCTs), including extended trials and clinical trials, for IL-17, IL-12/IL-23, and IL-23 inhibitors approved by the FDA for psoriasis treatment. The following keywords were used: psoriasis or inflammatory disease and secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Studies were restricted to the English-language literature, and those that did not provide adequate safety data on the specific types of infections that occurred were excluded.

RESULTSIL-17 Inhibitors

Our search yielded RCTs, some including extension trials, and clinical trials of IL-17 inhibitors used for psoriatic disease and other nonpsoriatic conditions (Table).

Risk for Deep Fungal Infection With Secukinumab
The queried studies included 20 RCTs or clinical trials along with extension trials of 3746 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In a 3-year extension study of SCULPTURE, Bissonnette et al¹² reported no new safety concerns for the 340 patients with moderate to severe psoriasis treated with secukinumab. Common adverse events (AEs) included nasopharyngitis, upper respiratory tract infections, and headache, but there were no reports of deep fungal infections.¹² In a subsequent 5-year analysis of 168 patients that focused on the 300-mg fixed interval treatment with secukinumab, the safety profile remained favorable, with 0 reports of invasive fungal infections.¹³ A study (FEATURE) of 118 patients with psoriasis treated with a prefilled syringe of 300 or 150 mg of secukinumab also described an acceptable safety profile and reported no deep fungal infections.¹⁴ JUNCTURE, another study utilizing autoinjectors, also found that treatment with 300 or 150 mg of secukinumab was well tolerated in 121 patients, with no deep fungal infections.¹⁵ Common AEs for both studies included nasopharyngitis and headache.^14,15 A 24-week phase 3 study for scalp psoriasis treated with secukinumab also reported 0 deep fungal infections in 51 patients.¹⁶ In an RCT comparing secukinumab and ustekinumab for moderate to severe plaque psoriasis, Blauvelt et al¹⁷ demonstrated that the incidence of serious AEs was comparable between the 2 groups, with no reports of invasive fungal infections in the 334 patients exposed to secukinumab. The CLEAR study, which compared secukinumab and ustekinumab, also found no reported deep fungal disease in the 335 patients exposed to secukinumab.¹⁸ Secukinumab exhibited a similar safety profile to ustekinumab in both studies, with common AEs being headache and nasopharyngitis.^17,18 The GESTURE study investigated the efficacy of secukinumab in 137 patients with palmoplantar psoriasis and reported a favorable profile with no reports of deep fungal disease.¹⁹ In a subanalysis of the phase 3 study ERASURE, secukinumab was shown to have a robust and sustainable efficacy in 58 Japanese patients with moderate to severe plaque psoriasis, and there were no reports of invasive fungal infections.²⁰ Another subanalysis of 36 Taiwanese patients from the ERASURE study also had similar findings, with no dose relationship observed for AEs.²¹ In a phase 2 study of 103 patients with psoriasis, Papp et al²² demonstrated AE rates that were similar across different doses of secukinumab—3×150 mg, 3×75 mg, 3×25 mg, and 1×25 mg—and described no incidences of invasive fungal disease. In a phase 2 regimen-finding study of 337 patients conducted by Rich et al,²³ the most commonly reported AEs included nasopharyngitis, worsening psoriasis, and upper respiratory tract infections, but there were no reported deep fungal infections.

Our search also resulted in studies specific to the treatment of psoriatic arthritis (PsA) with secukinumab. McInnes et al⁹ conducted a phase 2 proof-of-concept trial for patients with PsA and reported no deep fungal infections in 28 patients exposed to 10 mg/kg of secukinumab. A 2-year follow-up with the cohort from FUTURE 1, a phase 3 clinical trial, also showed no new or unexpected safety signals in 404 patients exposed to 150 or 75 mg of secukinumab, including no reports of invasive fungal disease.²⁴ FUTURE 2, a phase 3 clinical trial, demonstrated that the most common AE was upper respiratory tract infection in the 299 patients treatedwith secukinumab, but there were no recorded invasive fungal infections.²⁵ In FUTURE 3, 277 patients were treated with secukinumab, with 14 nonserious candida infections but no observed deep fungal infections.²⁶ A study comparing secukinumab to fumaric acid esters reported that 6 of 105 patients treated with secukinumab also experienced superficial candidiasis, but there were no reports of deep fungal disease.²⁷

Secukinumab also has been used in the treatment of ankylosing spondylitis in a phase 3 RCT (MEASURE 1) in which 4 cases of superficial candidiasis were reported (0.7 cases per 100 patient-years of secukinumab) that were all resolved with standard antifungal therapy.²⁸ In MEASURE 2, a 5-year phase 3 RCT, 145 patients were treated with secukinumab for ankylosing spondylitis, with common AEs including nasopharyngitis, diarrhea, and upper respiratory tract infection, but there were no reports of any invasive fungal infections.²⁹ MEASURE 3 also demonstrated similar results in which no invasive fungal infections were observed.³⁰

Risk for Deep Fungal Infection With Ixekizumab
The queried studies included 7 RCTs or clinical trials of 3523 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In UNCOVER-A, a phase 3 RCT of the pharmacokinetics and safety of ixekizumab, 204 patients were randomized to a prefilled syringe or autoinjector; 48% of patients experienced AEs, but no invasive fungal infections were observed.³¹ In an analysis of 3 phase 3 trials of ixekizumab including a total 2334 patients treated with ixekizumab from UNCOVER-1, UNCOVER-2, and UNCOVER-3, oral candidiasis frequently was reported, but no candidal infections met criteria for serious invasive infection.³² In UNCOVER-J, a 52-week phase 3 open-label trial of Japanese patients, 91 patients were treated for plaque psoriasis, erythrodermic psoriasis, or generalized pustular psoriasis using ixekizumab; the most common AEs included allergic reactions and injection-site reactions. One case of oral candidiasis was reported, but there were no reported cases of invasive fungal infections.³³ A comparison of ixekizumab vs ustekinumab from the IXORA-S trial demonstrated no substantial differences in AEs between the two, and no cases of deep fungal infections were reported. The most common AE between the 2 groups was nasopharyngitis.³⁴ An open-label extension over 4 years of a phase 2 RCT treated 211 patients with either 120 or 80 mg of ixekizumab; 87% of patients had experienced at least 1 AE, and all AEs were considered mild or moderate in severity, with no invasive fungal disease.³⁵

Our search also resulted in 1 study specific to the treatment of PsA with ixekizumab. A phase 3, 52-week study of patients treated with ixekizumab for PsA observed 2 incidences of oral candidiasis and nail candida infections, but no invasive fungal infections were reported.³⁶

We also found 1 study of ixekizumab used in the treatment of ankylosing spondylitis. COAST-V was a phase 3 RCT of patients treated for ankylosing spondylitis in which 164 patients were treated with ixekizumab; no serious AEs were recorded, including 0 deep fungal infections. The most common AEs observed were nasopharyngitis and upper respiratory tract infections.³⁷

Risk for Deep Fungal Infection With Brodalumab
The queried studies included 9 RCTs and 3 clinical trials along with extension trials of 1599 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 120 weeks. In a phase 2 RCT of Japanese patients with moderate to severe plaque psoriasis, 113 patients were treated with 70, 140, or 210 mg of brodalumab, and the most common AEs were nasopharyngitis, diarrhea, and upper respiratory tract inflammation. There were no reported cases of fungal infections in the study.³⁸ In an open-label extension study of Japanese patients that evaluated the long-term clinical safety of brodalumab, 145 patients were enrolled and observed similar AEs to the RCT, with 7 patients experiencing oral candidiasis and 1 patient having skin candidiasis, but there were no observed deep fungal infections.³⁹ In AMG 827, which evaluated the efficacy and safety of brodalumab, 320 patients were treated, and only 2 serious AEs were reported, neither of which were deep fungal disease.¹⁰ A phase 3 RCT conducted by Papp et al⁴⁰ (AMAGINE-1) also treated 441 patients with moderate to severe plaque psoriasis with brodalumab and observed candida infections in 9 patients that were mild to moderate and responsive to treatment, with no patients discontinuing the study. In a 120-week open-label extension study of 181 patients, Papp et al⁴¹ reported 8% of patients experienced serious AEs, with 1 case of latent tuberculosis that led to withdrawal of treatment. A study also investigated the efficacy and safety of brodalumab in 30 patients with generalized pustular psoriasis or psoriatic erythroderma and observed 2 cases of mild candida infections that resolved with treatment. There were no reports of invasive fungal disease.⁴²

Our search also resulted in studies of brodalumab used in the treatment of PsA and nonpsoriatic diseases. In one phase 2 RCT, 113 patients with PsA were treated with 140 mg, 280 mg, or combined doses of brodalumab, with the most common AEs being nasopharyngitis, upper respiratory tract infection, and diarrhea, but there were no reports of deep fungal infection.⁴³ In a phase 1b trial of patients with methotrexate-resistant rheumatoid arthritis treated with brodalumab, common AEs reported included headache, cough, and abdominal pain, with only 1 case of oral candidiasis that was determined not to be drug related.⁴⁴ Finally, an RCT of patients with moderate to severe asthma treated 226 patients with brodalumab and reported a greater incidence of oral candidiasis in treatment groups compared with placebo (3.5% vs 0%) but saw no instances of invasive fungal infection.⁴⁵

IL-12/IL-23 Inhibitor

Risk for Deep Fungal Infection With Ustekinumab
The queried studies included 4 RCTs of 954 patients with psoriasis treated with ustekinumab (eTable).^46-49 Within these trials, there were no reported cases of serious infections involving deep fungal organisms during the stated follow-up period. The literature search also found long-term safety data from the ACCEPT and PHOENIX trials that included 5437 patients with psoriasis treated with ustekinumab.^66,67 There also were no demonstrated incidences of invasive fungal disease in these studies, with most cases of infection being common bacterial or viral infections.

IL-23 Inhibitors

Risk for Deep Fungal Infection With Risankizumab, Guselkumab, and Tildrakizumab
The queried studies included 16 RCTs or clinical trials for psoriatic patients treated with IL-23 inhibitors, including 5 with risankizumab,^50-54 9 with guselkumab,^55-63 and 2 with tildrakizumab.^64,65 Within these trials there were no observed cases of serious infections with deep fungal disease.

COMMENT

Our literature review has demonstrated that there does not appear to be an increased incidence of deep fungal infections for patients treated with IL-17, IL-12/IL-23, or IL-23 inhibitors for psoriatic disease. All of the reviewed studies found no cases of invasive fungal infections for patients with psoriasis treated with secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Patients with other inflammatory conditions, such as ankylosing spondylitis, rheumatoid arthritis, and asthma, also did not appear to show an increased incidence of deep fungal disease.

Although these results show promising safety data for the use of these biologic therapies in treating inflammatory conditions, caution still is warranted, as these medications still are relatively new, with FDA approvals within the last 5 years. Safety data among different study populations also cannot be derived without further investigation, and much of the available literature is limited in long-term data. More extended trials or registry data from a large, broadly representative cohort are necessary to establish the long-term safety and risk for deep fungal infections with IL-17 and especially the newer IL-23 inhibitors.

A small percentage of patients from the reviewed literature did develop superficial candidiasis. This outcome can be expected, as the central role of IL-17 and IL-23 has been recognized in immunologic protection against infections, specifically against fungi.¹¹ Because all of the fungal infections reported for patients on IL-17 inhibitors were superficial candidiasis, guides for practical management and treatment should be implemented to standardize future research and care. A proposed screening algorithm for patients on these biologic therapies involves safety monitoring, including inspection of the oral cavity, folds, and genitals, along with inquiring about symptoms such as burning, dysgeusia, and dysuria.⁶⁸ If infection is suspected, confirmation by culture, molecular method, or optimally with esophagoscopy can be performed, and appropriate treatment may be initiated.⁶⁸ Patients with candida infections of the oral cavity, folds, or genitals can be placed on topical therapy such as nystatin, amphotericin B, ciclopirox, or other azoles, while those with infections of the esophagus can be started on oral fluconazole.⁶⁸

Although there were no reported cases of deep fungal infections, the theoretical risk for developing one while on IL-17 and IL-23 inhibitors may warrant further screening prior to beginning therapy. The TNF inhibitors approved for the treatment of psoriasis currently contain a black box warning for risk for disseminated and extrapulmonary histoplasmosis, coccidioidomycosis, blastomycosis, and other invasive fungal infections, which may highlight the importance of thorough evaluation and awareness of endemic areas for patients on biologics. Prior to initiating treatment with TNF inhibitors, current suggestions involve performing a thorough examination along with keeping a high index of suspicion for invasive fungal infections in patients who live in or have traveled to endemic regions.⁶⁹

Screening for invasive fungal infections for patients on TNF inhibitors involves questioning about potential exposures, such as demolition of old buildings, bird roosts, or spelunking.⁷⁰ Serologies or antigen testing can be used routinely, but as these tests are insensitive, empiric antifungal therapy should be initiated if there is high enough clinical suspicion.⁷¹ Currently, there are no clinical guidelines regarding fungal screening and initiation of IL-17 and IL-23 inhibitors for treatment of psoriasis and other inflammatory conditions, but careful stewardship over using these effective medications should still be practiced.

Upon review of the available safety data on the use of IL-17 and IL-23 inhibitors for the treatment of psoriasis and other inflammatory conditions, there does not appear to be an increased incidence of deep fungal infections. Physicians, however, should still be cautiously optimistic in prescribing these medications, as there is a theoretical risk for infection for all patients on biologics. A high index of suspicion for patients presenting with symptoms of fungal infections should be maintained, and appropriate diagnosis and management should be initiated if they do occur.

Psoriasis is a common chronic, multisystem, inflammatory disease with predominantly skin and joint manifestations that affects approximately 2% of the world’s population.¹ It occurs in a variety of clinical forms, from a few well-demarcated, erythematous plaques with a silvery scale to involvement of almost the entire body surface area. Beyond the debilitating physical ailments of the disease, psoriasis also may have psychosocial effects on quality of life.² The pathogenesis of psoriasis is not fully understood but represents a complex multifactorial disease with both immune-mediated and genetic components. Characterized by hyperplasia of epidermal keratinocytes, psoriasis is shown to be mediated by infiltration of T-cell lymphocytes with an increase of various inflammatory cytokines, including tumor necrosis factor (TNF) α.³ More recently, interactions of helper T cells (T_H17) via IL-17 and IL-23 have been supported to play a major role in the pathogenesis of psoriasis.^4,5

With the growing understanding of the pathophysiology of psoriasis, focused biologics have been developed to target specific cytokines implicated in the disease process and have been increasingly utilized. Tumor necrosis factor α inhibitors, including adalimumab, infliximab, and etanercept, along with the IL-12/IL-23 inhibitor ustekinumab, have been revolutionary in psoriasis treatment by providing safe and effective long-term therapy; however, there is concern of life-threatening infections with biologics because of the immunosuppressive effects and mechanisms of action.⁶ Specifically, there have been reported cases of deep fungal infections associated with TNF-α inhibitor use.⁷

Recently, the advent of IL-17 and IL-23 inhibitors has garnered notable interest in these biologics as promising treatments for psoriasis. With IL-17 and IL-23 supported to have a major role in the pathogenesis of psoriasis, targeting the cytokine is not only logical but also has proven to be effacacious.^8-10 Secukinumab, ixekizumab, and brodalumab are IL-17 inhibitors that have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis. Secukinumab and ixekizumab are anti–IL-17A monoclonal antibodies, whereas brodalumab is an anti–IL-17 receptor antibody. Risankizumab, guselkumab, and tildrakizumab are IL-23 inhibitors that also have been approved by the FDA for the treatment of psoriasis. As with older biologics, there is concern over the safety of these inhibitors because of the central role of IL-17 and IL-23 in both innate and adaptive immune responses, particularly against fungi.¹¹ Therefore, use of biologics targeting IL-17 and IL-23 may increase susceptibility to deep fungal infections.

Safety data and discussion of the risk for deep fungal infections from IL-17, IL-12/IL-23, and IL-23 inhibitor use for psoriasis treatment currently are lacking. Given the knowledge gap, we sought to synthesize and review the current evidence on risks for deep fungal infections during biologic therapy in patients with psoriasis, with a focus on IL-17 inhibitor therapies.

METHODS

A PubMed search of articles indexed for MEDLINE from database inception to 2019 (1946-2019) was performed to find randomized controlled trials (RCTs), including extended trials and clinical trials, for IL-17, IL-12/IL-23, and IL-23 inhibitors approved by the FDA for psoriasis treatment. The following keywords were used: psoriasis or inflammatory disease and secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Studies were restricted to the English-language literature, and those that did not provide adequate safety data on the specific types of infections that occurred were excluded.

RESULTSIL-17 Inhibitors

Our search yielded RCTs, some including extension trials, and clinical trials of IL-17 inhibitors used for psoriatic disease and other nonpsoriatic conditions (Table).

Risk for Deep Fungal Infection With Secukinumab
The queried studies included 20 RCTs or clinical trials along with extension trials of 3746 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In a 3-year extension study of SCULPTURE, Bissonnette et al¹² reported no new safety concerns for the 340 patients with moderate to severe psoriasis treated with secukinumab. Common adverse events (AEs) included nasopharyngitis, upper respiratory tract infections, and headache, but there were no reports of deep fungal infections.¹² In a subsequent 5-year analysis of 168 patients that focused on the 300-mg fixed interval treatment with secukinumab, the safety profile remained favorable, with 0 reports of invasive fungal infections.¹³ A study (FEATURE) of 118 patients with psoriasis treated with a prefilled syringe of 300 or 150 mg of secukinumab also described an acceptable safety profile and reported no deep fungal infections.¹⁴ JUNCTURE, another study utilizing autoinjectors, also found that treatment with 300 or 150 mg of secukinumab was well tolerated in 121 patients, with no deep fungal infections.¹⁵ Common AEs for both studies included nasopharyngitis and headache.^14,15 A 24-week phase 3 study for scalp psoriasis treated with secukinumab also reported 0 deep fungal infections in 51 patients.¹⁶ In an RCT comparing secukinumab and ustekinumab for moderate to severe plaque psoriasis, Blauvelt et al¹⁷ demonstrated that the incidence of serious AEs was comparable between the 2 groups, with no reports of invasive fungal infections in the 334 patients exposed to secukinumab. The CLEAR study, which compared secukinumab and ustekinumab, also found no reported deep fungal disease in the 335 patients exposed to secukinumab.¹⁸ Secukinumab exhibited a similar safety profile to ustekinumab in both studies, with common AEs being headache and nasopharyngitis.^17,18 The GESTURE study investigated the efficacy of secukinumab in 137 patients with palmoplantar psoriasis and reported a favorable profile with no reports of deep fungal disease.¹⁹ In a subanalysis of the phase 3 study ERASURE, secukinumab was shown to have a robust and sustainable efficacy in 58 Japanese patients with moderate to severe plaque psoriasis, and there were no reports of invasive fungal infections.²⁰ Another subanalysis of 36 Taiwanese patients from the ERASURE study also had similar findings, with no dose relationship observed for AEs.²¹ In a phase 2 study of 103 patients with psoriasis, Papp et al²² demonstrated AE rates that were similar across different doses of secukinumab—3×150 mg, 3×75 mg, 3×25 mg, and 1×25 mg—and described no incidences of invasive fungal disease. In a phase 2 regimen-finding study of 337 patients conducted by Rich et al,²³ the most commonly reported AEs included nasopharyngitis, worsening psoriasis, and upper respiratory tract infections, but there were no reported deep fungal infections.

Our search also resulted in studies specific to the treatment of psoriatic arthritis (PsA) with secukinumab. McInnes et al⁹ conducted a phase 2 proof-of-concept trial for patients with PsA and reported no deep fungal infections in 28 patients exposed to 10 mg/kg of secukinumab. A 2-year follow-up with the cohort from FUTURE 1, a phase 3 clinical trial, also showed no new or unexpected safety signals in 404 patients exposed to 150 or 75 mg of secukinumab, including no reports of invasive fungal disease.²⁴ FUTURE 2, a phase 3 clinical trial, demonstrated that the most common AE was upper respiratory tract infection in the 299 patients treatedwith secukinumab, but there were no recorded invasive fungal infections.²⁵ In FUTURE 3, 277 patients were treated with secukinumab, with 14 nonserious candida infections but no observed deep fungal infections.²⁶ A study comparing secukinumab to fumaric acid esters reported that 6 of 105 patients treated with secukinumab also experienced superficial candidiasis, but there were no reports of deep fungal disease.²⁷

Secukinumab also has been used in the treatment of ankylosing spondylitis in a phase 3 RCT (MEASURE 1) in which 4 cases of superficial candidiasis were reported (0.7 cases per 100 patient-years of secukinumab) that were all resolved with standard antifungal therapy.²⁸ In MEASURE 2, a 5-year phase 3 RCT, 145 patients were treated with secukinumab for ankylosing spondylitis, with common AEs including nasopharyngitis, diarrhea, and upper respiratory tract infection, but there were no reports of any invasive fungal infections.²⁹ MEASURE 3 also demonstrated similar results in which no invasive fungal infections were observed.³⁰

Risk for Deep Fungal Infection With Ixekizumab
The queried studies included 7 RCTs or clinical trials of 3523 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In UNCOVER-A, a phase 3 RCT of the pharmacokinetics and safety of ixekizumab, 204 patients were randomized to a prefilled syringe or autoinjector; 48% of patients experienced AEs, but no invasive fungal infections were observed.³¹ In an analysis of 3 phase 3 trials of ixekizumab including a total 2334 patients treated with ixekizumab from UNCOVER-1, UNCOVER-2, and UNCOVER-3, oral candidiasis frequently was reported, but no candidal infections met criteria for serious invasive infection.³² In UNCOVER-J, a 52-week phase 3 open-label trial of Japanese patients, 91 patients were treated for plaque psoriasis, erythrodermic psoriasis, or generalized pustular psoriasis using ixekizumab; the most common AEs included allergic reactions and injection-site reactions. One case of oral candidiasis was reported, but there were no reported cases of invasive fungal infections.³³ A comparison of ixekizumab vs ustekinumab from the IXORA-S trial demonstrated no substantial differences in AEs between the two, and no cases of deep fungal infections were reported. The most common AE between the 2 groups was nasopharyngitis.³⁴ An open-label extension over 4 years of a phase 2 RCT treated 211 patients with either 120 or 80 mg of ixekizumab; 87% of patients had experienced at least 1 AE, and all AEs were considered mild or moderate in severity, with no invasive fungal disease.³⁵

Our search also resulted in 1 study specific to the treatment of PsA with ixekizumab. A phase 3, 52-week study of patients treated with ixekizumab for PsA observed 2 incidences of oral candidiasis and nail candida infections, but no invasive fungal infections were reported.³⁶

We also found 1 study of ixekizumab used in the treatment of ankylosing spondylitis. COAST-V was a phase 3 RCT of patients treated for ankylosing spondylitis in which 164 patients were treated with ixekizumab; no serious AEs were recorded, including 0 deep fungal infections. The most common AEs observed were nasopharyngitis and upper respiratory tract infections.³⁷

Risk for Deep Fungal Infection With Brodalumab
The queried studies included 9 RCTs and 3 clinical trials along with extension trials of 1599 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 120 weeks. In a phase 2 RCT of Japanese patients with moderate to severe plaque psoriasis, 113 patients were treated with 70, 140, or 210 mg of brodalumab, and the most common AEs were nasopharyngitis, diarrhea, and upper respiratory tract inflammation. There were no reported cases of fungal infections in the study.³⁸ In an open-label extension study of Japanese patients that evaluated the long-term clinical safety of brodalumab, 145 patients were enrolled and observed similar AEs to the RCT, with 7 patients experiencing oral candidiasis and 1 patient having skin candidiasis, but there were no observed deep fungal infections.³⁹ In AMG 827, which evaluated the efficacy and safety of brodalumab, 320 patients were treated, and only 2 serious AEs were reported, neither of which were deep fungal disease.¹⁰ A phase 3 RCT conducted by Papp et al⁴⁰ (AMAGINE-1) also treated 441 patients with moderate to severe plaque psoriasis with brodalumab and observed candida infections in 9 patients that were mild to moderate and responsive to treatment, with no patients discontinuing the study. In a 120-week open-label extension study of 181 patients, Papp et al⁴¹ reported 8% of patients experienced serious AEs, with 1 case of latent tuberculosis that led to withdrawal of treatment. A study also investigated the efficacy and safety of brodalumab in 30 patients with generalized pustular psoriasis or psoriatic erythroderma and observed 2 cases of mild candida infections that resolved with treatment. There were no reports of invasive fungal disease.⁴²

Our search also resulted in studies of brodalumab used in the treatment of PsA and nonpsoriatic diseases. In one phase 2 RCT, 113 patients with PsA were treated with 140 mg, 280 mg, or combined doses of brodalumab, with the most common AEs being nasopharyngitis, upper respiratory tract infection, and diarrhea, but there were no reports of deep fungal infection.⁴³ In a phase 1b trial of patients with methotrexate-resistant rheumatoid arthritis treated with brodalumab, common AEs reported included headache, cough, and abdominal pain, with only 1 case of oral candidiasis that was determined not to be drug related.⁴⁴ Finally, an RCT of patients with moderate to severe asthma treated 226 patients with brodalumab and reported a greater incidence of oral candidiasis in treatment groups compared with placebo (3.5% vs 0%) but saw no instances of invasive fungal infection.⁴⁵

IL-12/IL-23 Inhibitor

Risk for Deep Fungal Infection With Ustekinumab
The queried studies included 4 RCTs of 954 patients with psoriasis treated with ustekinumab (eTable).^46-49 Within these trials, there were no reported cases of serious infections involving deep fungal organisms during the stated follow-up period. The literature search also found long-term safety data from the ACCEPT and PHOENIX trials that included 5437 patients with psoriasis treated with ustekinumab.^66,67 There also were no demonstrated incidences of invasive fungal disease in these studies, with most cases of infection being common bacterial or viral infections.

IL-23 Inhibitors

Risk for Deep Fungal Infection With Risankizumab, Guselkumab, and Tildrakizumab
The queried studies included 16 RCTs or clinical trials for psoriatic patients treated with IL-23 inhibitors, including 5 with risankizumab,^50-54 9 with guselkumab,^55-63 and 2 with tildrakizumab.^64,65 Within these trials there were no observed cases of serious infections with deep fungal disease.

COMMENT

Our literature review has demonstrated that there does not appear to be an increased incidence of deep fungal infections for patients treated with IL-17, IL-12/IL-23, or IL-23 inhibitors for psoriatic disease. All of the reviewed studies found no cases of invasive fungal infections for patients with psoriasis treated with secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Patients with other inflammatory conditions, such as ankylosing spondylitis, rheumatoid arthritis, and asthma, also did not appear to show an increased incidence of deep fungal disease.

Although these results show promising safety data for the use of these biologic therapies in treating inflammatory conditions, caution still is warranted, as these medications still are relatively new, with FDA approvals within the last 5 years. Safety data among different study populations also cannot be derived without further investigation, and much of the available literature is limited in long-term data. More extended trials or registry data from a large, broadly representative cohort are necessary to establish the long-term safety and risk for deep fungal infections with IL-17 and especially the newer IL-23 inhibitors.

A small percentage of patients from the reviewed literature did develop superficial candidiasis. This outcome can be expected, as the central role of IL-17 and IL-23 has been recognized in immunologic protection against infections, specifically against fungi.¹¹ Because all of the fungal infections reported for patients on IL-17 inhibitors were superficial candidiasis, guides for practical management and treatment should be implemented to standardize future research and care. A proposed screening algorithm for patients on these biologic therapies involves safety monitoring, including inspection of the oral cavity, folds, and genitals, along with inquiring about symptoms such as burning, dysgeusia, and dysuria.⁶⁸ If infection is suspected, confirmation by culture, molecular method, or optimally with esophagoscopy can be performed, and appropriate treatment may be initiated.⁶⁸ Patients with candida infections of the oral cavity, folds, or genitals can be placed on topical therapy such as nystatin, amphotericin B, ciclopirox, or other azoles, while those with infections of the esophagus can be started on oral fluconazole.⁶⁸

Although there were no reported cases of deep fungal infections, the theoretical risk for developing one while on IL-17 and IL-23 inhibitors may warrant further screening prior to beginning therapy. The TNF inhibitors approved for the treatment of psoriasis currently contain a black box warning for risk for disseminated and extrapulmonary histoplasmosis, coccidioidomycosis, blastomycosis, and other invasive fungal infections, which may highlight the importance of thorough evaluation and awareness of endemic areas for patients on biologics. Prior to initiating treatment with TNF inhibitors, current suggestions involve performing a thorough examination along with keeping a high index of suspicion for invasive fungal infections in patients who live in or have traveled to endemic regions.⁶⁹

Screening for invasive fungal infections for patients on TNF inhibitors involves questioning about potential exposures, such as demolition of old buildings, bird roosts, or spelunking.⁷⁰ Serologies or antigen testing can be used routinely, but as these tests are insensitive, empiric antifungal therapy should be initiated if there is high enough clinical suspicion.⁷¹ Currently, there are no clinical guidelines regarding fungal screening and initiation of IL-17 and IL-23 inhibitors for treatment of psoriasis and other inflammatory conditions, but careful stewardship over using these effective medications should still be practiced.

Upon review of the available safety data on the use of IL-17 and IL-23 inhibitors for the treatment of psoriasis and other inflammatory conditions, there does not appear to be an increased incidence of deep fungal infections. Physicians, however, should still be cautiously optimistic in prescribing these medications, as there is a theoretical risk for infection for all patients on biologics. A high index of suspicion for patients presenting with symptoms of fungal infections should be maintained, and appropriate diagnosis and management should be initiated if they do occur.

Latino patients participating in clinical trials of psoriasis treatments were found to have different patterns of disease and a lower level of quality of life, compared with White participants in the same studies, according to new data presented at the virtual Skin of Color Update 2020.

“Our findings demonstrate that, though White psoriasis patients may have higher severity in certain body regions such as the trunk, axilla, and groin areas, Latino psoriasis patients have a greater distribution of involvement, particularly in their upper limbs,” reported Alyssa G. Ashbaugh, a third-year medical student at the University of California, Irvine.

The study also found that psoriasis had a greater adverse impact on well-being, as measured with the Dermatology Life Quality Index (DLQI). At entry into the trials from which these patients were drawn, the higher DLQI score, significantly lower quality of life, was nearly two times higher (13.78 vs. 7.31; P = .01) among the Latino patients, compared with White patients.

This is not the first study to show a greater negative impact from psoriasis on Latinos than Whites, according to Ms. Ashbaugh. For example, Latinos had the worse quality of life at baseline by DLQI score than White, Asians, or Black participants in a trial of etanercept that enrolled more than 2000 patients.

In this retrospective chart review, patient characteristics were evaluated in all 21 Latino patients enrolled in psoriasis clinical trials at the University of California, Irvine, in a recent period. They were matched by age and gender to an equal number of White patients participating in the same trials.

The mean age at diagnosis of psoriasis was older in the Latino group than in the White population (42.4 vs. 35.6 years; P = .20), but the difference did not reach statistical significance. The proportion of patients with severe disease on investigator global assessment was also greater but not significantly different in the Latino group, compared with the White group, respectively (42.9% vs. 28.6%; P = .10).

However, differences in the patterns of disease did reach significance. This included a lower mean Psoriasis Assessment Severity Index score of the trunk, axilla, and groin in Latinos (4.74 vs. 9.73; P = .02). But compared with White participants, Latinos had a higher mean percentage of body surface area involvement in the upper limbs (4.78 vs. 1.85; P = .004) and a higher percentage of total body surface area involvement (20.50 vs. 10.03; P = .02).

“While White patients were found to have lived many more years with psoriasis, it is important for future studies to examine whether this is due to earlier onset or delayed diagnosis, given the fact that minorities are less likely to have access to a dermatologist,” reported Ms. Ashbaugh, who performed this work under the guidance of the senior author, Natasha Mesinkovska, MD, PhD, with the department of dermatology, University of California, Irvine.

Overall, the study suggested that body surface coverage and severity is not similarly distributed in Latinos relative to Whites. Although Ms. Ashbaugh conceded that the small sample size and retrospective design of this study are important limitations, she believes that her study, along with previously published studies that suggest psoriasis characteristics may differ meaningfully by race or ethnicity, raises issues that should be explored in future studies designed to confirm differences and whether those differences should affect management.

Other studies have suggested “there are notable differences in the presentation of psoriasis between racial and ethnic groups with the Latino population often presenting to physicians with more severe psoriasis and increased body surface area involvement,” Ms. Ashbaugh noted. Although this appears to be one of the first studies to examine psoriasis characteristics in Latinos relative to Whites, she believes this is an area ripe for further analysis.

Psoriasis “is not a rare occurrence” in non-White populations even if U.S. data suggest that the prevalence in “people of color is lower than that of psoriasis in the U.S. white population,” Amy McMichael, MD, chair of the department of dermatology, Wake Forest Baptist Medical Center, Winston-Salem, N.C., commented in an interview after the meeting. She agreed that it cannot be assumed that psoriasis in skin of color has the same manifestations or responds to treatment in the same way as in White patients.

“Studies have suggested that lesion thickness and, often, extent of disease can be worse in patients of color. Few studies to date have examined the efficacy of treatments and impact of disease in these populations,” she said.

One exception was a study Dr. McMichael and colleagues published last year on the efficacy and safety of the interleukin-17 receptor A antagonist brodalumab for psoriasis in patients of color. The study showed that Black, Latino, and Asian patients participating in the AMAGINE-2 and AMAGINE-3 trials achieved similar outcomes as White participants.

“We published this study because this is one of the first, if not the first, to have enough patients of color to actually draw conclusions about the efficacy of the biologic as well as the patient-reported outcomes,” she explained.

Like the author of the evaluation of Latino patients undertaken at the University of California, Irvine, Dr. McMichael said studies of psoriasis specific to patients of color are needed.

“We cannot assume all patients of color will have the same outcomes as their Caucasian counterparts. It is imperative to include those of color in future psoriasis treatment trials in order to determine the efficacy of new medications,” she added, specifically calling for collection of data on patient-reported outcomes.

Ms. Ashbaugh has no relevant financial relationships to disclose. Dr. McMichael’s disclosures included serving as an investigator and/or consultant for companies that included Allergan, Procter & Gamble, Johnson & Johnson, and Aclaris.

Latino patients participating in clinical trials of psoriasis treatments were found to have different patterns of disease and a lower level of quality of life, compared with White participants in the same studies, according to new data presented at the virtual Skin of Color Update 2020.

“Our findings demonstrate that, though White psoriasis patients may have higher severity in certain body regions such as the trunk, axilla, and groin areas, Latino psoriasis patients have a greater distribution of involvement, particularly in their upper limbs,” reported Alyssa G. Ashbaugh, a third-year medical student at the University of California, Irvine.

The study also found that psoriasis had a greater adverse impact on well-being, as measured with the Dermatology Life Quality Index (DLQI). At entry into the trials from which these patients were drawn, the higher DLQI score, significantly lower quality of life, was nearly two times higher (13.78 vs. 7.31; P = .01) among the Latino patients, compared with White patients.

This is not the first study to show a greater negative impact from psoriasis on Latinos than Whites, according to Ms. Ashbaugh. For example, Latinos had the worse quality of life at baseline by DLQI score than White, Asians, or Black participants in a trial of etanercept that enrolled more than 2000 patients.

In this retrospective chart review, patient characteristics were evaluated in all 21 Latino patients enrolled in psoriasis clinical trials at the University of California, Irvine, in a recent period. They were matched by age and gender to an equal number of White patients participating in the same trials.

The mean age at diagnosis of psoriasis was older in the Latino group than in the White population (42.4 vs. 35.6 years; P = .20), but the difference did not reach statistical significance. The proportion of patients with severe disease on investigator global assessment was also greater but not significantly different in the Latino group, compared with the White group, respectively (42.9% vs. 28.6%; P = .10).

However, differences in the patterns of disease did reach significance. This included a lower mean Psoriasis Assessment Severity Index score of the trunk, axilla, and groin in Latinos (4.74 vs. 9.73; P = .02). But compared with White participants, Latinos had a higher mean percentage of body surface area involvement in the upper limbs (4.78 vs. 1.85; P = .004) and a higher percentage of total body surface area involvement (20.50 vs. 10.03; P = .02).

“While White patients were found to have lived many more years with psoriasis, it is important for future studies to examine whether this is due to earlier onset or delayed diagnosis, given the fact that minorities are less likely to have access to a dermatologist,” reported Ms. Ashbaugh, who performed this work under the guidance of the senior author, Natasha Mesinkovska, MD, PhD, with the department of dermatology, University of California, Irvine.

Overall, the study suggested that body surface coverage and severity is not similarly distributed in Latinos relative to Whites. Although Ms. Ashbaugh conceded that the small sample size and retrospective design of this study are important limitations, she believes that her study, along with previously published studies that suggest psoriasis characteristics may differ meaningfully by race or ethnicity, raises issues that should be explored in future studies designed to confirm differences and whether those differences should affect management.

Other studies have suggested “there are notable differences in the presentation of psoriasis between racial and ethnic groups with the Latino population often presenting to physicians with more severe psoriasis and increased body surface area involvement,” Ms. Ashbaugh noted. Although this appears to be one of the first studies to examine psoriasis characteristics in Latinos relative to Whites, she believes this is an area ripe for further analysis.

Psoriasis “is not a rare occurrence” in non-White populations even if U.S. data suggest that the prevalence in “people of color is lower than that of psoriasis in the U.S. white population,” Amy McMichael, MD, chair of the department of dermatology, Wake Forest Baptist Medical Center, Winston-Salem, N.C., commented in an interview after the meeting. She agreed that it cannot be assumed that psoriasis in skin of color has the same manifestations or responds to treatment in the same way as in White patients.

“Studies have suggested that lesion thickness and, often, extent of disease can be worse in patients of color. Few studies to date have examined the efficacy of treatments and impact of disease in these populations,” she said.

One exception was a study Dr. McMichael and colleagues published last year on the efficacy and safety of the interleukin-17 receptor A antagonist brodalumab for psoriasis in patients of color. The study showed that Black, Latino, and Asian patients participating in the AMAGINE-2 and AMAGINE-3 trials achieved similar outcomes as White participants.

“We published this study because this is one of the first, if not the first, to have enough patients of color to actually draw conclusions about the efficacy of the biologic as well as the patient-reported outcomes,” she explained.

Like the author of the evaluation of Latino patients undertaken at the University of California, Irvine, Dr. McMichael said studies of psoriasis specific to patients of color are needed.

“We cannot assume all patients of color will have the same outcomes as their Caucasian counterparts. It is imperative to include those of color in future psoriasis treatment trials in order to determine the efficacy of new medications,” she added, specifically calling for collection of data on patient-reported outcomes.

Ms. Ashbaugh has no relevant financial relationships to disclose. Dr. McMichael’s disclosures included serving as an investigator and/or consultant for companies that included Allergan, Procter & Gamble, Johnson & Johnson, and Aclaris.

Latino patients participating in clinical trials of psoriasis treatments were found to have different patterns of disease and a lower level of quality of life, compared with White participants in the same studies, according to new data presented at the virtual Skin of Color Update 2020.

“Our findings demonstrate that, though White psoriasis patients may have higher severity in certain body regions such as the trunk, axilla, and groin areas, Latino psoriasis patients have a greater distribution of involvement, particularly in their upper limbs,” reported Alyssa G. Ashbaugh, a third-year medical student at the University of California, Irvine.

The study also found that psoriasis had a greater adverse impact on well-being, as measured with the Dermatology Life Quality Index (DLQI). At entry into the trials from which these patients were drawn, the higher DLQI score, significantly lower quality of life, was nearly two times higher (13.78 vs. 7.31; P = .01) among the Latino patients, compared with White patients.

This is not the first study to show a greater negative impact from psoriasis on Latinos than Whites, according to Ms. Ashbaugh. For example, Latinos had the worse quality of life at baseline by DLQI score than White, Asians, or Black participants in a trial of etanercept that enrolled more than 2000 patients.

In this retrospective chart review, patient characteristics were evaluated in all 21 Latino patients enrolled in psoriasis clinical trials at the University of California, Irvine, in a recent period. They were matched by age and gender to an equal number of White patients participating in the same trials.

The mean age at diagnosis of psoriasis was older in the Latino group than in the White population (42.4 vs. 35.6 years; P = .20), but the difference did not reach statistical significance. The proportion of patients with severe disease on investigator global assessment was also greater but not significantly different in the Latino group, compared with the White group, respectively (42.9% vs. 28.6%; P = .10).

However, differences in the patterns of disease did reach significance. This included a lower mean Psoriasis Assessment Severity Index score of the trunk, axilla, and groin in Latinos (4.74 vs. 9.73; P = .02). But compared with White participants, Latinos had a higher mean percentage of body surface area involvement in the upper limbs (4.78 vs. 1.85; P = .004) and a higher percentage of total body surface area involvement (20.50 vs. 10.03; P = .02).

“While White patients were found to have lived many more years with psoriasis, it is important for future studies to examine whether this is due to earlier onset or delayed diagnosis, given the fact that minorities are less likely to have access to a dermatologist,” reported Ms. Ashbaugh, who performed this work under the guidance of the senior author, Natasha Mesinkovska, MD, PhD, with the department of dermatology, University of California, Irvine.

Overall, the study suggested that body surface coverage and severity is not similarly distributed in Latinos relative to Whites. Although Ms. Ashbaugh conceded that the small sample size and retrospective design of this study are important limitations, she believes that her study, along with previously published studies that suggest psoriasis characteristics may differ meaningfully by race or ethnicity, raises issues that should be explored in future studies designed to confirm differences and whether those differences should affect management.

Other studies have suggested “there are notable differences in the presentation of psoriasis between racial and ethnic groups with the Latino population often presenting to physicians with more severe psoriasis and increased body surface area involvement,” Ms. Ashbaugh noted. Although this appears to be one of the first studies to examine psoriasis characteristics in Latinos relative to Whites, she believes this is an area ripe for further analysis.

Psoriasis “is not a rare occurrence” in non-White populations even if U.S. data suggest that the prevalence in “people of color is lower than that of psoriasis in the U.S. white population,” Amy McMichael, MD, chair of the department of dermatology, Wake Forest Baptist Medical Center, Winston-Salem, N.C., commented in an interview after the meeting. She agreed that it cannot be assumed that psoriasis in skin of color has the same manifestations or responds to treatment in the same way as in White patients.

“Studies have suggested that lesion thickness and, often, extent of disease can be worse in patients of color. Few studies to date have examined the efficacy of treatments and impact of disease in these populations,” she said.

One exception was a study Dr. McMichael and colleagues published last year on the efficacy and safety of the interleukin-17 receptor A antagonist brodalumab for psoriasis in patients of color. The study showed that Black, Latino, and Asian patients participating in the AMAGINE-2 and AMAGINE-3 trials achieved similar outcomes as White participants.

“We published this study because this is one of the first, if not the first, to have enough patients of color to actually draw conclusions about the efficacy of the biologic as well as the patient-reported outcomes,” she explained.

Like the author of the evaluation of Latino patients undertaken at the University of California, Irvine, Dr. McMichael said studies of psoriasis specific to patients of color are needed.

“We cannot assume all patients of color will have the same outcomes as their Caucasian counterparts. It is imperative to include those of color in future psoriasis treatment trials in order to determine the efficacy of new medications,” she added, specifically calling for collection of data on patient-reported outcomes.

Ms. Ashbaugh has no relevant financial relationships to disclose. Dr. McMichael’s disclosures included serving as an investigator and/or consultant for companies that included Allergan, Procter & Gamble, Johnson & Johnson, and Aclaris.

The adjuvanted recombinant zoster vaccine Shingrix appears to be effective in older adults with autoimmune diseases who are not receiving treatment regimens that suppress the immune system, according to a post hoc analysis of patients in two clinical trials.

jarun011/thinkstock

A two-dose regimen of Shingrix was effective in 90.5% of a subset of patients in two phase 3 clinical trials of adults who were aged at least 50 years, according to Alemnew F. Dagnew, MD, of GlaxoSmithKline and colleagues. The lowest rates of effectiveness with Shingrix, for patients aged between 70-79 years, was 84.4%, the researchers reported in Rheumatology.

The CDC recommends adults aged at least 50 years receive two doses of Shingrix to help prevent reoccurrence of herpes zoster, or Zostavax (zoster vaccine live) if adults are allergic to components of the Shingrix vaccine or have tested negative for varicella zoster virus immunity.

Dr. Dagnew and colleagues evaluated Shingrix in 983 patients who received two doses of Shingrix and 960 patients who received placebo from the ZOE-50 and ZOE-70 trials, where each dose was administered at least 2 months apart. The mean age of patients in both groups was 68.8 years in the Shingrix group and 69.4 years in the placebo group, and more than half of patients in both Shingrix (59.9%) and placebo groups (60.8%) were women. About 7% of the patients in two clinical trial had a pIMD.

At enrollment, the most common preexisting immune-mediated disorders (pIMDs) were psoriasis (215 patients taking Shingrix vs. 239 patients on placebo), spondyloarthropathy (109 patients taking Shingrix vs. 89 patients on placebo), rheumatoid arthritis (96 patients taking Shingrix vs. 94 patients on placebo), and celiac disease (41 patients taking Shingrix vs. 34 patients on placebo). Dr. Dagnew and colleagues examined the subgroup of patients with pIMDs for safety and vaccine efficacy, which was defined as not developing herpes zoster before the second dose.

Overall, the efficacy of Shingrix was 90.5% across all age groups (95% confidence interval, 73.5%-97.5%), with the group aged between 70-79 years having the lowest rate of effectiveness (95% CI, 30.8%-98.3%). The rate of severe adverse events was 14.6% in the Shingrix group and 11.7% in the placebo group between the first Shingrix dose and for up to 1 year after the second dose. The most common adverse events were infections and infestations as well as cardiac disorders. “Our data show a balance between study groups in the frequency and nature of SAEs, confirming the favorable safety profile of [Shingrix] in populations with pIMDs,” Dr. Dagnew and colleagues wrote.

The researchers acknowledged that the ZOE-50/70 studies were underpowered to detect the efficacy and safety of Shingrix in individuals with pIMDs but said that the large number of participants in the studies let them estimate efficacy and adverse events for this subgroup. They also noted there was no randomization of pIMDs at enrollment, even though pIMDs occurred at similar rates between Shingrix and placebo groups.

This study was funded by GlaxoSmithKline; the company helped with conducting and analyzing the study and also provided the costs associated with publishing it. Five authors reported being an employee of GlaxoSmithKline during the time the work was conducted, and four of the five own stock in the company. One author is now an employee of UCB. One author reported having served on the advisory boards for Merck Sharp & Dohme, GlaxoSmithKline, and Curevo.

SOURCE: Dagnew AF et al. Rheumatology. 2020 Sep 10. doi: 10.1093/rheumatology/keaa424.

The adjuvanted recombinant zoster vaccine Shingrix appears to be effective in older adults with autoimmune diseases who are not receiving treatment regimens that suppress the immune system, according to a post hoc analysis of patients in two clinical trials.

jarun011/thinkstock

A two-dose regimen of Shingrix was effective in 90.5% of a subset of patients in two phase 3 clinical trials of adults who were aged at least 50 years, according to Alemnew F. Dagnew, MD, of GlaxoSmithKline and colleagues. The lowest rates of effectiveness with Shingrix, for patients aged between 70-79 years, was 84.4%, the researchers reported in Rheumatology.

The CDC recommends adults aged at least 50 years receive two doses of Shingrix to help prevent reoccurrence of herpes zoster, or Zostavax (zoster vaccine live) if adults are allergic to components of the Shingrix vaccine or have tested negative for varicella zoster virus immunity.

Dr. Dagnew and colleagues evaluated Shingrix in 983 patients who received two doses of Shingrix and 960 patients who received placebo from the ZOE-50 and ZOE-70 trials, where each dose was administered at least 2 months apart. The mean age of patients in both groups was 68.8 years in the Shingrix group and 69.4 years in the placebo group, and more than half of patients in both Shingrix (59.9%) and placebo groups (60.8%) were women. About 7% of the patients in two clinical trial had a pIMD.

At enrollment, the most common preexisting immune-mediated disorders (pIMDs) were psoriasis (215 patients taking Shingrix vs. 239 patients on placebo), spondyloarthropathy (109 patients taking Shingrix vs. 89 patients on placebo), rheumatoid arthritis (96 patients taking Shingrix vs. 94 patients on placebo), and celiac disease (41 patients taking Shingrix vs. 34 patients on placebo). Dr. Dagnew and colleagues examined the subgroup of patients with pIMDs for safety and vaccine efficacy, which was defined as not developing herpes zoster before the second dose.

Overall, the efficacy of Shingrix was 90.5% across all age groups (95% confidence interval, 73.5%-97.5%), with the group aged between 70-79 years having the lowest rate of effectiveness (95% CI, 30.8%-98.3%). The rate of severe adverse events was 14.6% in the Shingrix group and 11.7% in the placebo group between the first Shingrix dose and for up to 1 year after the second dose. The most common adverse events were infections and infestations as well as cardiac disorders. “Our data show a balance between study groups in the frequency and nature of SAEs, confirming the favorable safety profile of [Shingrix] in populations with pIMDs,” Dr. Dagnew and colleagues wrote.

The researchers acknowledged that the ZOE-50/70 studies were underpowered to detect the efficacy and safety of Shingrix in individuals with pIMDs but said that the large number of participants in the studies let them estimate efficacy and adverse events for this subgroup. They also noted there was no randomization of pIMDs at enrollment, even though pIMDs occurred at similar rates between Shingrix and placebo groups.

This study was funded by GlaxoSmithKline; the company helped with conducting and analyzing the study and also provided the costs associated with publishing it. Five authors reported being an employee of GlaxoSmithKline during the time the work was conducted, and four of the five own stock in the company. One author is now an employee of UCB. One author reported having served on the advisory boards for Merck Sharp & Dohme, GlaxoSmithKline, and Curevo.

SOURCE: Dagnew AF et al. Rheumatology. 2020 Sep 10. doi: 10.1093/rheumatology/keaa424.

The adjuvanted recombinant zoster vaccine Shingrix appears to be effective in older adults with autoimmune diseases who are not receiving treatment regimens that suppress the immune system, according to a post hoc analysis of patients in two clinical trials.

jarun011/thinkstock

A two-dose regimen of Shingrix was effective in 90.5% of a subset of patients in two phase 3 clinical trials of adults who were aged at least 50 years, according to Alemnew F. Dagnew, MD, of GlaxoSmithKline and colleagues. The lowest rates of effectiveness with Shingrix, for patients aged between 70-79 years, was 84.4%, the researchers reported in Rheumatology.

The CDC recommends adults aged at least 50 years receive two doses of Shingrix to help prevent reoccurrence of herpes zoster, or Zostavax (zoster vaccine live) if adults are allergic to components of the Shingrix vaccine or have tested negative for varicella zoster virus immunity.

Dr. Dagnew and colleagues evaluated Shingrix in 983 patients who received two doses of Shingrix and 960 patients who received placebo from the ZOE-50 and ZOE-70 trials, where each dose was administered at least 2 months apart. The mean age of patients in both groups was 68.8 years in the Shingrix group and 69.4 years in the placebo group, and more than half of patients in both Shingrix (59.9%) and placebo groups (60.8%) were women. About 7% of the patients in two clinical trial had a pIMD.

At enrollment, the most common preexisting immune-mediated disorders (pIMDs) were psoriasis (215 patients taking Shingrix vs. 239 patients on placebo), spondyloarthropathy (109 patients taking Shingrix vs. 89 patients on placebo), rheumatoid arthritis (96 patients taking Shingrix vs. 94 patients on placebo), and celiac disease (41 patients taking Shingrix vs. 34 patients on placebo). Dr. Dagnew and colleagues examined the subgroup of patients with pIMDs for safety and vaccine efficacy, which was defined as not developing herpes zoster before the second dose.

Overall, the efficacy of Shingrix was 90.5% across all age groups (95% confidence interval, 73.5%-97.5%), with the group aged between 70-79 years having the lowest rate of effectiveness (95% CI, 30.8%-98.3%). The rate of severe adverse events was 14.6% in the Shingrix group and 11.7% in the placebo group between the first Shingrix dose and for up to 1 year after the second dose. The most common adverse events were infections and infestations as well as cardiac disorders. “Our data show a balance between study groups in the frequency and nature of SAEs, confirming the favorable safety profile of [Shingrix] in populations with pIMDs,” Dr. Dagnew and colleagues wrote.

The researchers acknowledged that the ZOE-50/70 studies were underpowered to detect the efficacy and safety of Shingrix in individuals with pIMDs but said that the large number of participants in the studies let them estimate efficacy and adverse events for this subgroup. They also noted there was no randomization of pIMDs at enrollment, even though pIMDs occurred at similar rates between Shingrix and placebo groups.

This study was funded by GlaxoSmithKline; the company helped with conducting and analyzing the study and also provided the costs associated with publishing it. Five authors reported being an employee of GlaxoSmithKline during the time the work was conducted, and four of the five own stock in the company. One author is now an employee of UCB. One author reported having served on the advisory boards for Merck Sharp & Dohme, GlaxoSmithKline, and Curevo.

SOURCE: Dagnew AF et al. Rheumatology. 2020 Sep 10. doi: 10.1093/rheumatology/keaa424.

Psoriasis and Psoriatic Arthritis is a supplement to Dermatology News with commentary from Joel M. Gelfand, MD, MSCE and Alan Menter, MD.

• Exploring new guidelines and scientific advances
• ‘Loss-framed’ approach makes psoriasis patients more agreeable to treatment
• Topical PDE-4 inhibitor for psoriasis effective in phase 2b trial
• Biologics may delay psoriatic arthritis
• AAD-NPF releases guidelines for systemic nonbiologic treatments of psoriasis
• Specific markers detect psoriatic disease inflammation without elevated CRP
• Beyond PASI 100: Striving for molecular clearance
• Ultrasound improves specificity of psoriatic arthritis referrals
• Registry data reveal temporal relationship between psoriasis symptoms and PsA onset
• New psoriasis guidelines focus on topical and alternative treatments, and severity measures
• Psoriasis topical combination maintenance strategy hits mark at 1 year

Read the supplement.

Psoriasis and Psoriatic Arthritis is a supplement to Dermatology News with commentary from Joel M. Gelfand, MD, MSCE and Alan Menter, MD.

• Exploring new guidelines and scientific advances
• ‘Loss-framed’ approach makes psoriasis patients more agreeable to treatment
• Topical PDE-4 inhibitor for psoriasis effective in phase 2b trial
• Biologics may delay psoriatic arthritis
• AAD-NPF releases guidelines for systemic nonbiologic treatments of psoriasis
• Specific markers detect psoriatic disease inflammation without elevated CRP
• Beyond PASI 100: Striving for molecular clearance
• Ultrasound improves specificity of psoriatic arthritis referrals
• Registry data reveal temporal relationship between psoriasis symptoms and PsA onset
• New psoriasis guidelines focus on topical and alternative treatments, and severity measures
• Psoriasis topical combination maintenance strategy hits mark at 1 year

Read the supplement.

Psoriasis and Psoriatic Arthritis is a supplement to Dermatology News with commentary from Joel M. Gelfand, MD, MSCE and Alan Menter, MD.

• Exploring new guidelines and scientific advances
• ‘Loss-framed’ approach makes psoriasis patients more agreeable to treatment
• Topical PDE-4 inhibitor for psoriasis effective in phase 2b trial
• Biologics may delay psoriatic arthritis
• AAD-NPF releases guidelines for systemic nonbiologic treatments of psoriasis
• Specific markers detect psoriatic disease inflammation without elevated CRP
• Beyond PASI 100: Striving for molecular clearance
• Ultrasound improves specificity of psoriatic arthritis referrals
• Registry data reveal temporal relationship between psoriasis symptoms and PsA onset
• New psoriasis guidelines focus on topical and alternative treatments, and severity measures
• Psoriasis topical combination maintenance strategy hits mark at 1 year

Read the supplement.

Christina Chambers, PhD, MPH, who runs the MotherToBaby Pregnancy Studies research center at the University of California, San Diego, has found most pregnant women to be “entirely altruistic” about sharing their experiences with drug treatment during pregnancy.

Christina Chambers

This is good news for the growth of more information about the safety of biologics and other drugs during pregnancy. Pregnancy outcomes data are increasingly emerging – particularly for tumor necrosis factor (TNF) inhibitors – but dermatologists, rheumatologists, and their female patients with psoriasis and psoriatic arthritis (PsA) want much more.

And women’s participation in the MotherToBaby studies conducted by the nonprofit Organization of Teratology Information Specialists (OTIS) is key, say physicians who are treating women of reproductive age. OTIS is now listed in drug labeling as the “pregnancy registry” contact for many of the medications they may be discussing with patients.

Dr. Chambers said that most women appreciate “that participating in a study may not help her with her pregnancy, but it can help her sister or her friend or someone else who has these same questions in planning a pregnancy of ‘Can I stay on my treatment?’ or, in the case of an unplanned pregnancy, ‘Should I be concerned?’ ”

OTIS has enrolled women with psoriasis and/or PsA in studies of nine medications, most of them biologics (both TNF-alpha blockers and newer anti-interleukin agents).

Four of the studies – those evaluating etanercept (Enbrel), adalimumab (Humira), abatacept (Orencia), and ustekinumab (Stelara) – are now closed to enrollment with analyses either underway or completed. The other five are currently enrolling patients and involve treatment with certolizumab pegol (Cimzia), tildrakizumab (Ilumya), apremilast (Otezla), guselkumab (Tremfya), and tofacitinib (Xeljanz).

Lisa R. Sammaritano, MD, a rheumatologist at the Hospital for Special Surgery, New York, who led the development of the American College of Rheumatology’s first guideline for the management of reproductive health in rheumatic and musculoskeletal diseases, recommends to some of her patients that they contact OTIS. “Their pregnancy registry studies have added important information to the field over the years,” she said.

Most recently, a study of the anti–TNF-alpha medication adalimumab that began in 2004 in pregnant patients with RA and Crohn’s disease culminated in a 2019 PLOS ONE paper reporting no associations between exposure to the medication and an increased risk of adverse outcomes. The outcomes studied were major structural birth defects, minor defects, spontaneous abortion, preterm delivery, prenatal and postnatal growth deficiency, serious or opportunistic infections, and malignancies.

An analysis is underway of adalimumab exposure in women with PsA – a patient subset that was added after the study started. But in the meantime, Dr. Chambers said, the 2019 research article is relevant to questions of drug safety across indications.

OTIS’s MothertoBaby studies are structured as prospective cohort studies. Dr. Chambers, a perinatal epidemiologist, is president of OTIS, which recruits women who have an exposure to the medication under study – at least one dose, for any length of time. And in most cases, it also recruits women with the underlying condition but no exposure and healthy women without the condition to represent the general population.

It’s the disease-matched comparison group that makes OTIS’s studies different from traditional pregnancy registries involving “a simple exposure series and outcomes that are described in the context of what you’d expect in the general population,” said Dr. Chambers, professor in the department of pediatrics, as well as family and preventative medicine, at UCSD and codirector of the Center for Better Beginnings at that university. “Many maternal conditions themselves [or their comorbidities] carry some risk of adverse outcomes in pregnancy.”

The OTIS studies typically involve at least 100 exposed pregnancies and a similar number of unexposed pregnancies; some have cohorts of 200-300.

The recently published study of adalimumab, for instance, included 257 women with exposure to the drug and 120 women in a disease comparison group with no exposure. In addition to finding no associations between drug exposure and adverse outcomes, the study found that women with RA or Crohn’s were at increased risk of preterm delivery, irrespective of adalimumab exposure.

“There’s insufficient [power with any of these numbers] to come to the conclusion that a drug is safe,” she said. “But what we have been able to say [through our studies] is that we’ve looked carefully at the whole array of outcomes ... and we don’t see anything unusual. That early view can be reassuring” until large population-based studies or claims analyses become possible.

Dr. Sammaritano, also with Weill Cornell Medicine, New York, said that she does not recommend registry participation for patients who stop biologics at the diagnosis of pregnancy. Since “the start of IgG antibody transfer during pregnancy is about 16 weeks,” she worries that including these patients might lead to falsely reassuring findings. “We are most interested in [knowing the outcomes of] patients who must continue the drugs through pregnancy,” she said.

Dr. Chambers, however, said that in her view, placental transfer is not a requirement for a medication to have some effect on the outcome of pregnancy. “The outcome could be influenced by an effect of the medication that doesn’t require placental transfer or require placental transfer in large amounts,” she said. “So it’s relevant to examine exposures that have occurred only in the first trimester, and this is especially true for the outcome of major birth defects, most of which are initiated in the first trimester.”

The MotherToBaby studies typically include both early, short exposures and longer exposures, she said. “And certainly, duration of use is a factor that we do consider in looking at specific outcomes such as growth, preterm delivery, and risk of serious or opportunistic infections.”

(In the published study of adalimumab, 65.3% of women in the medication-exposed cohort used the medication in all three trimesters, 10.5% in the first and second trimesters, and 22.4% in the first trimester only.)

Women participating in the MotherToBaby studies complete two to four interviews during pregnancy and may be interviewed again after delivery. They are asked for their permission to share a copy of their medical records – and their baby’s medical records – and their babies receive a follow-up pediatric exam by a pediatrician with expertise in dysmorphology/genetics (who is blinded to exposure status), most commonly in the participant’s home. Providers are not asked to enter any data.

Oklahoma Medical Research Foundation

Eliza Chakravarty, MD, a rheumatologist with the Oklahoma Medical Research Foundation in Oklahoma City who treats patients with PsA who are pregnant or considering pregnancy, said that her referrals for research participation “have been mostly to MothertoBaby.”

“Most drug companies [in the autoimmune space] are now contracting with them [for their pregnancy exposure research],” she said. “I really like that it’s become so centralized.”

She tells patients that many questions can be answered through research, that their experience matters, and that “there are benefits” to the extra pediatric examination. “I give them the information and let them decide whether or not they want to call [MotherToBaby],” she said. “I don’t want to impose. I want to make them aware.”

Dr. Chambers emphasizes to patients and physicians that the studies are strictly observational and do not require any changes in personal or medical regimens. “When people hear the word ‘research’ they think of clinical trials. We’re saying, you and your provider do everything you normally would do, just let us observe what happens during your pregnancy.”

Physicians should assure patients, moreover, that “just because the drug is being studied doesn’t mean there’s a known risk or even a suspected risk,” she said.

The MotherToBaby studies receive funding from the pharmaceutical companies, which are required by the Food and Drug Administration to conduct pregnancy exposure registries for medications used during pregnancy or in women of reproductive age. OTIS has an independent advisory board, however, and independently analyzes and publishes its findings. Progress reports are shared with the pharmaceutical companies, and in turn, the FDA, Dr. Chambers said.


To refer patients for MotherToBaby studies, physicians can use an online referral form found on the MothertoBaby web site, a service of OTIS, or call the pregnancy studies team at 877-311-8972 to provide them with the patient’s name or number. Patients may also be given the number and advised to consider calling. MotherToBaby offers medication fact sheets that answer questions about exposures during pregnancy and breastfeeding, and runs a free and confidential teratogen counseling service: 866-626-6847.
 

Christina Chambers, PhD, MPH, who runs the MotherToBaby Pregnancy Studies research center at the University of California, San Diego, has found most pregnant women to be “entirely altruistic” about sharing their experiences with drug treatment during pregnancy.

Christina Chambers

This is good news for the growth of more information about the safety of biologics and other drugs during pregnancy. Pregnancy outcomes data are increasingly emerging – particularly for tumor necrosis factor (TNF) inhibitors – but dermatologists, rheumatologists, and their female patients with psoriasis and psoriatic arthritis (PsA) want much more.

And women’s participation in the MotherToBaby studies conducted by the nonprofit Organization of Teratology Information Specialists (OTIS) is key, say physicians who are treating women of reproductive age. OTIS is now listed in drug labeling as the “pregnancy registry” contact for many of the medications they may be discussing with patients.

Dr. Chambers said that most women appreciate “that participating in a study may not help her with her pregnancy, but it can help her sister or her friend or someone else who has these same questions in planning a pregnancy of ‘Can I stay on my treatment?’ or, in the case of an unplanned pregnancy, ‘Should I be concerned?’ ”

OTIS has enrolled women with psoriasis and/or PsA in studies of nine medications, most of them biologics (both TNF-alpha blockers and newer anti-interleukin agents).

Four of the studies – those evaluating etanercept (Enbrel), adalimumab (Humira), abatacept (Orencia), and ustekinumab (Stelara) – are now closed to enrollment with analyses either underway or completed. The other five are currently enrolling patients and involve treatment with certolizumab pegol (Cimzia), tildrakizumab (Ilumya), apremilast (Otezla), guselkumab (Tremfya), and tofacitinib (Xeljanz).

Lisa R. Sammaritano, MD, a rheumatologist at the Hospital for Special Surgery, New York, who led the development of the American College of Rheumatology’s first guideline for the management of reproductive health in rheumatic and musculoskeletal diseases, recommends to some of her patients that they contact OTIS. “Their pregnancy registry studies have added important information to the field over the years,” she said.

Most recently, a study of the anti–TNF-alpha medication adalimumab that began in 2004 in pregnant patients with RA and Crohn’s disease culminated in a 2019 PLOS ONE paper reporting no associations between exposure to the medication and an increased risk of adverse outcomes. The outcomes studied were major structural birth defects, minor defects, spontaneous abortion, preterm delivery, prenatal and postnatal growth deficiency, serious or opportunistic infections, and malignancies.

An analysis is underway of adalimumab exposure in women with PsA – a patient subset that was added after the study started. But in the meantime, Dr. Chambers said, the 2019 research article is relevant to questions of drug safety across indications.

OTIS’s MothertoBaby studies are structured as prospective cohort studies. Dr. Chambers, a perinatal epidemiologist, is president of OTIS, which recruits women who have an exposure to the medication under study – at least one dose, for any length of time. And in most cases, it also recruits women with the underlying condition but no exposure and healthy women without the condition to represent the general population.

It’s the disease-matched comparison group that makes OTIS’s studies different from traditional pregnancy registries involving “a simple exposure series and outcomes that are described in the context of what you’d expect in the general population,” said Dr. Chambers, professor in the department of pediatrics, as well as family and preventative medicine, at UCSD and codirector of the Center for Better Beginnings at that university. “Many maternal conditions themselves [or their comorbidities] carry some risk of adverse outcomes in pregnancy.”

The OTIS studies typically involve at least 100 exposed pregnancies and a similar number of unexposed pregnancies; some have cohorts of 200-300.

The recently published study of adalimumab, for instance, included 257 women with exposure to the drug and 120 women in a disease comparison group with no exposure. In addition to finding no associations between drug exposure and adverse outcomes, the study found that women with RA or Crohn’s were at increased risk of preterm delivery, irrespective of adalimumab exposure.

“There’s insufficient [power with any of these numbers] to come to the conclusion that a drug is safe,” she said. “But what we have been able to say [through our studies] is that we’ve looked carefully at the whole array of outcomes ... and we don’t see anything unusual. That early view can be reassuring” until large population-based studies or claims analyses become possible.

Dr. Sammaritano, also with Weill Cornell Medicine, New York, said that she does not recommend registry participation for patients who stop biologics at the diagnosis of pregnancy. Since “the start of IgG antibody transfer during pregnancy is about 16 weeks,” she worries that including these patients might lead to falsely reassuring findings. “We are most interested in [knowing the outcomes of] patients who must continue the drugs through pregnancy,” she said.

Dr. Chambers, however, said that in her view, placental transfer is not a requirement for a medication to have some effect on the outcome of pregnancy. “The outcome could be influenced by an effect of the medication that doesn’t require placental transfer or require placental transfer in large amounts,” she said. “So it’s relevant to examine exposures that have occurred only in the first trimester, and this is especially true for the outcome of major birth defects, most of which are initiated in the first trimester.”

The MotherToBaby studies typically include both early, short exposures and longer exposures, she said. “And certainly, duration of use is a factor that we do consider in looking at specific outcomes such as growth, preterm delivery, and risk of serious or opportunistic infections.”

(In the published study of adalimumab, 65.3% of women in the medication-exposed cohort used the medication in all three trimesters, 10.5% in the first and second trimesters, and 22.4% in the first trimester only.)

Women participating in the MotherToBaby studies complete two to four interviews during pregnancy and may be interviewed again after delivery. They are asked for their permission to share a copy of their medical records – and their baby’s medical records – and their babies receive a follow-up pediatric exam by a pediatrician with expertise in dysmorphology/genetics (who is blinded to exposure status), most commonly in the participant’s home. Providers are not asked to enter any data.

Oklahoma Medical Research Foundation

Eliza Chakravarty, MD, a rheumatologist with the Oklahoma Medical Research Foundation in Oklahoma City who treats patients with PsA who are pregnant or considering pregnancy, said that her referrals for research participation “have been mostly to MothertoBaby.”

“Most drug companies [in the autoimmune space] are now contracting with them [for their pregnancy exposure research],” she said. “I really like that it’s become so centralized.”

She tells patients that many questions can be answered through research, that their experience matters, and that “there are benefits” to the extra pediatric examination. “I give them the information and let them decide whether or not they want to call [MotherToBaby],” she said. “I don’t want to impose. I want to make them aware.”

Dr. Chambers emphasizes to patients and physicians that the studies are strictly observational and do not require any changes in personal or medical regimens. “When people hear the word ‘research’ they think of clinical trials. We’re saying, you and your provider do everything you normally would do, just let us observe what happens during your pregnancy.”

Physicians should assure patients, moreover, that “just because the drug is being studied doesn’t mean there’s a known risk or even a suspected risk,” she said.

The MotherToBaby studies receive funding from the pharmaceutical companies, which are required by the Food and Drug Administration to conduct pregnancy exposure registries for medications used during pregnancy or in women of reproductive age. OTIS has an independent advisory board, however, and independently analyzes and publishes its findings. Progress reports are shared with the pharmaceutical companies, and in turn, the FDA, Dr. Chambers said.


To refer patients for MotherToBaby studies, physicians can use an online referral form found on the MothertoBaby web site, a service of OTIS, or call the pregnancy studies team at 877-311-8972 to provide them with the patient’s name or number. Patients may also be given the number and advised to consider calling. MotherToBaby offers medication fact sheets that answer questions about exposures during pregnancy and breastfeeding, and runs a free and confidential teratogen counseling service: 866-626-6847.
 

Christina Chambers, PhD, MPH, who runs the MotherToBaby Pregnancy Studies research center at the University of California, San Diego, has found most pregnant women to be “entirely altruistic” about sharing their experiences with drug treatment during pregnancy.

Christina Chambers

This is good news for the growth of more information about the safety of biologics and other drugs during pregnancy. Pregnancy outcomes data are increasingly emerging – particularly for tumor necrosis factor (TNF) inhibitors – but dermatologists, rheumatologists, and their female patients with psoriasis and psoriatic arthritis (PsA) want much more.

And women’s participation in the MotherToBaby studies conducted by the nonprofit Organization of Teratology Information Specialists (OTIS) is key, say physicians who are treating women of reproductive age. OTIS is now listed in drug labeling as the “pregnancy registry” contact for many of the medications they may be discussing with patients.

Dr. Chambers said that most women appreciate “that participating in a study may not help her with her pregnancy, but it can help her sister or her friend or someone else who has these same questions in planning a pregnancy of ‘Can I stay on my treatment?’ or, in the case of an unplanned pregnancy, ‘Should I be concerned?’ ”

OTIS has enrolled women with psoriasis and/or PsA in studies of nine medications, most of them biologics (both TNF-alpha blockers and newer anti-interleukin agents).

Four of the studies – those evaluating etanercept (Enbrel), adalimumab (Humira), abatacept (Orencia), and ustekinumab (Stelara) – are now closed to enrollment with analyses either underway or completed. The other five are currently enrolling patients and involve treatment with certolizumab pegol (Cimzia), tildrakizumab (Ilumya), apremilast (Otezla), guselkumab (Tremfya), and tofacitinib (Xeljanz).

Lisa R. Sammaritano, MD, a rheumatologist at the Hospital for Special Surgery, New York, who led the development of the American College of Rheumatology’s first guideline for the management of reproductive health in rheumatic and musculoskeletal diseases, recommends to some of her patients that they contact OTIS. “Their pregnancy registry studies have added important information to the field over the years,” she said.

Most recently, a study of the anti–TNF-alpha medication adalimumab that began in 2004 in pregnant patients with RA and Crohn’s disease culminated in a 2019 PLOS ONE paper reporting no associations between exposure to the medication and an increased risk of adverse outcomes. The outcomes studied were major structural birth defects, minor defects, spontaneous abortion, preterm delivery, prenatal and postnatal growth deficiency, serious or opportunistic infections, and malignancies.

An analysis is underway of adalimumab exposure in women with PsA – a patient subset that was added after the study started. But in the meantime, Dr. Chambers said, the 2019 research article is relevant to questions of drug safety across indications.

OTIS’s MothertoBaby studies are structured as prospective cohort studies. Dr. Chambers, a perinatal epidemiologist, is president of OTIS, which recruits women who have an exposure to the medication under study – at least one dose, for any length of time. And in most cases, it also recruits women with the underlying condition but no exposure and healthy women without the condition to represent the general population.

It’s the disease-matched comparison group that makes OTIS’s studies different from traditional pregnancy registries involving “a simple exposure series and outcomes that are described in the context of what you’d expect in the general population,” said Dr. Chambers, professor in the department of pediatrics, as well as family and preventative medicine, at UCSD and codirector of the Center for Better Beginnings at that university. “Many maternal conditions themselves [or their comorbidities] carry some risk of adverse outcomes in pregnancy.”

The OTIS studies typically involve at least 100 exposed pregnancies and a similar number of unexposed pregnancies; some have cohorts of 200-300.

The recently published study of adalimumab, for instance, included 257 women with exposure to the drug and 120 women in a disease comparison group with no exposure. In addition to finding no associations between drug exposure and adverse outcomes, the study found that women with RA or Crohn’s were at increased risk of preterm delivery, irrespective of adalimumab exposure.

“There’s insufficient [power with any of these numbers] to come to the conclusion that a drug is safe,” she said. “But what we have been able to say [through our studies] is that we’ve looked carefully at the whole array of outcomes ... and we don’t see anything unusual. That early view can be reassuring” until large population-based studies or claims analyses become possible.

Dr. Sammaritano, also with Weill Cornell Medicine, New York, said that she does not recommend registry participation for patients who stop biologics at the diagnosis of pregnancy. Since “the start of IgG antibody transfer during pregnancy is about 16 weeks,” she worries that including these patients might lead to falsely reassuring findings. “We are most interested in [knowing the outcomes of] patients who must continue the drugs through pregnancy,” she said.

Dr. Chambers, however, said that in her view, placental transfer is not a requirement for a medication to have some effect on the outcome of pregnancy. “The outcome could be influenced by an effect of the medication that doesn’t require placental transfer or require placental transfer in large amounts,” she said. “So it’s relevant to examine exposures that have occurred only in the first trimester, and this is especially true for the outcome of major birth defects, most of which are initiated in the first trimester.”

The MotherToBaby studies typically include both early, short exposures and longer exposures, she said. “And certainly, duration of use is a factor that we do consider in looking at specific outcomes such as growth, preterm delivery, and risk of serious or opportunistic infections.”

(In the published study of adalimumab, 65.3% of women in the medication-exposed cohort used the medication in all three trimesters, 10.5% in the first and second trimesters, and 22.4% in the first trimester only.)

Women participating in the MotherToBaby studies complete two to four interviews during pregnancy and may be interviewed again after delivery. They are asked for their permission to share a copy of their medical records – and their baby’s medical records – and their babies receive a follow-up pediatric exam by a pediatrician with expertise in dysmorphology/genetics (who is blinded to exposure status), most commonly in the participant’s home. Providers are not asked to enter any data.

Oklahoma Medical Research Foundation

Eliza Chakravarty, MD, a rheumatologist with the Oklahoma Medical Research Foundation in Oklahoma City who treats patients with PsA who are pregnant or considering pregnancy, said that her referrals for research participation “have been mostly to MothertoBaby.”

“Most drug companies [in the autoimmune space] are now contracting with them [for their pregnancy exposure research],” she said. “I really like that it’s become so centralized.”

She tells patients that many questions can be answered through research, that their experience matters, and that “there are benefits” to the extra pediatric examination. “I give them the information and let them decide whether or not they want to call [MotherToBaby],” she said. “I don’t want to impose. I want to make them aware.”

Dr. Chambers emphasizes to patients and physicians that the studies are strictly observational and do not require any changes in personal or medical regimens. “When people hear the word ‘research’ they think of clinical trials. We’re saying, you and your provider do everything you normally would do, just let us observe what happens during your pregnancy.”

Physicians should assure patients, moreover, that “just because the drug is being studied doesn’t mean there’s a known risk or even a suspected risk,” she said.

The MotherToBaby studies receive funding from the pharmaceutical companies, which are required by the Food and Drug Administration to conduct pregnancy exposure registries for medications used during pregnancy or in women of reproductive age. OTIS has an independent advisory board, however, and independently analyzes and publishes its findings. Progress reports are shared with the pharmaceutical companies, and in turn, the FDA, Dr. Chambers said.


To refer patients for MotherToBaby studies, physicians can use an online referral form found on the MothertoBaby web site, a service of OTIS, or call the pregnancy studies team at 877-311-8972 to provide them with the patient’s name or number. Patients may also be given the number and advised to consider calling. MotherToBaby offers medication fact sheets that answer questions about exposures during pregnancy and breastfeeding, and runs a free and confidential teratogen counseling service: 866-626-6847.
 

Spending on medications is expected to grow from $344 billion in 2018 to $420 billion in 2023, largely driven by the introduction of new branded drugs.¹ These costs place substantial financial burden on patients, with nearly 30% of patients not taking their prescriptions as directed because of costs. Although many new medications have transformed how we care for patients, others may not offer meaningful benefit over existing less-costly alternatives that are supported by declining effect sizes of conventional placebo-controlled trials.² Most medications are approved based on placebo-controlled trial data that does not include an arm comparing the new drug to standard of care, leaving clinicians and patients unable to make meaningful comparisons when deciding on the most appropriate or cost-effective treatment. We consider ways in which clinicians, patients, payers, and regulators could compel more meaningful trials from industry.

Although we often look to the US Food and Drug Administration (FDA) to ensure rigorous and appropriate testing of new medications, the primary mission of the FDA is to ensure efficacy and safety. As a result, pharmaceutical companies seeking approval in the United States have little incentive to go beyond providing the minimal level of evidence required: placebo-controlled randomized trials. Although these trials provide important data on whether a treatment works and its associated risks, they do not provide data on comparative effectiveness. When relevant inexpensive medications are already on the market for the same indication, these placebo-controlled trials provide inadequate evidence to guide clinical decision-making. This issue is particularly relevant in dermatology given how easily topical medications can be combined or reformulated to pursue additional market exclusivity. The addition of an active comparator arm represents an important opportunity to improve the value of these studies.

In the pivotal trials of clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel for the treatment of acne, the experimental group was not only compared to vehicle but also the active comparator arms of clindamycin alone and benzoyl peroxide alone. The mean percentage change in total lesions was 47.9% with clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel, 41.6% with the active comparator arm of benzoyl peroxide alone, 40.4% with the active comparator arm of clindamycin alone, and 26.2% for vehicle.³ With these data in mind, clinicians and patients can decide whether the additional benefit of this new product over benzoyl peroxide alone is worth the increased cost.

In contrast, the trials of dapsone gel 7.5% for the treatment of acne did not include an active comparator. The mean percentage change in total lesions was 48.9% for dapsone gel and 43.2% for vehicle.⁴ Given these data, it is possible that dapsone gel may be no more effective, or possibly less effective, than alternatives such as benzoyl peroxide or other topical antibiotics. Nevertheless, dapsone annual sales were more than $200 million in 2016,⁵ suggesting that effectively marketed new products can achieve high sales even without convincing evidence of their value compared to standard of care. Although dapsone may be a useful treatment, we cannot effectively make patient-centered clinical decisions given the lack of an active comparator trial design.

This issue is not limited to acne. Phase 3 trials of halobetasol propionate foam 0.05% for psoriasis and crisaborole for atopic dermatitis also did not include an active comparator arm.^6,7 Given that topical steroids—and calcineurin inhibitors for atopic dermatitis—are mainstays of treatment for each condition, it is difficult to determine whether these new treatments offer meaningful advantages over existing options and how to incorporate them into our management strategies.

Unfortunately, expensive new medications that are adopted without convincing evidence of their benefit above standard of care can put patients at risk for financial toxicity, either directly through higher out-of-pocket costs or indirectly through higher premiums. Given the impact of rising medication costs on clinicians, patients, and payers, we propose several approaches these stakeholders could adopt to encourage the use of active comparator trial designs.

Clinicians and patients can encourage these trials by remaining skeptical of new treatments that were only compared to vehicle or placebo. Because new medications often are more expensive, clinicians and patients could avoid using these treatments without evidence of either increased efficacy or improved safety and tolerability. In addition, health care institutions should consider reducing pharmaceutical representatives’ access to clinicians to encourage treatment decisions based on the published literature and comparative effectiveness data rather than marketing.

Payers, such as Medicare, also could play a role by requiring active comparator trials for coverage of new medications, particularly when there are already other effective treatments available or other medications in the same class. Payers also could give preferred coverage tier or step therapy status to medications that demonstrate value over existing options.

Although regulatory approaches to increase use of active comparator designs may be more politically challenging to introduce, these options would be more administratively robust. The FDA or a novel regulatory body could require that new treatments demonstrate value in addition to safety and efficacy. This approach would be similar to the role of The National Institute for Health and Care Excellence in the United Kingdom or the recommendations of the European Medicines Agency. Such a group also could provide independent adjudication to ensure appropriate selection of a relevant active comparator. Another approach would be to give extended market exclusivity to medications that are approved based on trials including an additional active comparator arm, an approach used by the European Medicines Agency.

Any approach that encourages increased use of active comparator trials is not without potential downsides. It will be important to avoid unintended consequences of reduced research for rare diseases with smaller markets that may not be able to support the increased cost of these trials. As a result, it would be reasonable to forgo active comparator designs for mediations indicated for rare and orphan diseases or for medications with novel mechanisms of action.

Another argument against including an active comparator arm is that it may stifle innovation by driving up the cost of conducting trials; however, if a product is so marginally innovative that it cannot demonstrate superior safety or efficacy to an existing product, such a new treatment may not be worth the increased cost. In addition, patients provide a notable contribution by participating in these trials, and it is important to ensure that their efforts result in the highest-quality data possible. Furthermore, given the adverse physical and psychosocial impact of a wide variety of dermatologic diseases, the inclusion of an active comparator arm reduces the likelihood that patients will receive placebo, which will make these trials more ethical when effective treatments are available.⁸ By raising the bar, we can encourage pharmaceutical companies to pursue novel approaches that are more likely to have a revolutionary impact rather than minor modifications or formulations that offer little to no benefit at substantially increased cost.

Although some recent clinical trials in dermatology have included active comparators, many new medications continue to be introduced without any evidence of how they compare to existing standards of care. Until clinicians, patients, payers, and regulators demand that pharmaceutical companies conduct the necessary trials to not only demonstrate whether a treatment is effective and safe but also how it provides value, there will be continued introduction of marginal innovations rather than revolutionary treatments that improve patients’ lives. The next time a new medication is approved, as clinicians, patients, and payers, we must ask ourselves, is this treatment worth it?

Spending on medications is expected to grow from $344 billion in 2018 to $420 billion in 2023, largely driven by the introduction of new branded drugs.¹ These costs place substantial financial burden on patients, with nearly 30% of patients not taking their prescriptions as directed because of costs. Although many new medications have transformed how we care for patients, others may not offer meaningful benefit over existing less-costly alternatives that are supported by declining effect sizes of conventional placebo-controlled trials.² Most medications are approved based on placebo-controlled trial data that does not include an arm comparing the new drug to standard of care, leaving clinicians and patients unable to make meaningful comparisons when deciding on the most appropriate or cost-effective treatment. We consider ways in which clinicians, patients, payers, and regulators could compel more meaningful trials from industry.

Although we often look to the US Food and Drug Administration (FDA) to ensure rigorous and appropriate testing of new medications, the primary mission of the FDA is to ensure efficacy and safety. As a result, pharmaceutical companies seeking approval in the United States have little incentive to go beyond providing the minimal level of evidence required: placebo-controlled randomized trials. Although these trials provide important data on whether a treatment works and its associated risks, they do not provide data on comparative effectiveness. When relevant inexpensive medications are already on the market for the same indication, these placebo-controlled trials provide inadequate evidence to guide clinical decision-making. This issue is particularly relevant in dermatology given how easily topical medications can be combined or reformulated to pursue additional market exclusivity. The addition of an active comparator arm represents an important opportunity to improve the value of these studies.

In the pivotal trials of clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel for the treatment of acne, the experimental group was not only compared to vehicle but also the active comparator arms of clindamycin alone and benzoyl peroxide alone. The mean percentage change in total lesions was 47.9% with clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel, 41.6% with the active comparator arm of benzoyl peroxide alone, 40.4% with the active comparator arm of clindamycin alone, and 26.2% for vehicle.³ With these data in mind, clinicians and patients can decide whether the additional benefit of this new product over benzoyl peroxide alone is worth the increased cost.

In contrast, the trials of dapsone gel 7.5% for the treatment of acne did not include an active comparator. The mean percentage change in total lesions was 48.9% for dapsone gel and 43.2% for vehicle.⁴ Given these data, it is possible that dapsone gel may be no more effective, or possibly less effective, than alternatives such as benzoyl peroxide or other topical antibiotics. Nevertheless, dapsone annual sales were more than $200 million in 2016,⁵ suggesting that effectively marketed new products can achieve high sales even without convincing evidence of their value compared to standard of care. Although dapsone may be a useful treatment, we cannot effectively make patient-centered clinical decisions given the lack of an active comparator trial design.

This issue is not limited to acne. Phase 3 trials of halobetasol propionate foam 0.05% for psoriasis and crisaborole for atopic dermatitis also did not include an active comparator arm.^6,7 Given that topical steroids—and calcineurin inhibitors for atopic dermatitis—are mainstays of treatment for each condition, it is difficult to determine whether these new treatments offer meaningful advantages over existing options and how to incorporate them into our management strategies.

Unfortunately, expensive new medications that are adopted without convincing evidence of their benefit above standard of care can put patients at risk for financial toxicity, either directly through higher out-of-pocket costs or indirectly through higher premiums. Given the impact of rising medication costs on clinicians, patients, and payers, we propose several approaches these stakeholders could adopt to encourage the use of active comparator trial designs.

Clinicians and patients can encourage these trials by remaining skeptical of new treatments that were only compared to vehicle or placebo. Because new medications often are more expensive, clinicians and patients could avoid using these treatments without evidence of either increased efficacy or improved safety and tolerability. In addition, health care institutions should consider reducing pharmaceutical representatives’ access to clinicians to encourage treatment decisions based on the published literature and comparative effectiveness data rather than marketing.

Payers, such as Medicare, also could play a role by requiring active comparator trials for coverage of new medications, particularly when there are already other effective treatments available or other medications in the same class. Payers also could give preferred coverage tier or step therapy status to medications that demonstrate value over existing options.

Although regulatory approaches to increase use of active comparator designs may be more politically challenging to introduce, these options would be more administratively robust. The FDA or a novel regulatory body could require that new treatments demonstrate value in addition to safety and efficacy. This approach would be similar to the role of The National Institute for Health and Care Excellence in the United Kingdom or the recommendations of the European Medicines Agency. Such a group also could provide independent adjudication to ensure appropriate selection of a relevant active comparator. Another approach would be to give extended market exclusivity to medications that are approved based on trials including an additional active comparator arm, an approach used by the European Medicines Agency.

Any approach that encourages increased use of active comparator trials is not without potential downsides. It will be important to avoid unintended consequences of reduced research for rare diseases with smaller markets that may not be able to support the increased cost of these trials. As a result, it would be reasonable to forgo active comparator designs for mediations indicated for rare and orphan diseases or for medications with novel mechanisms of action.

Another argument against including an active comparator arm is that it may stifle innovation by driving up the cost of conducting trials; however, if a product is so marginally innovative that it cannot demonstrate superior safety or efficacy to an existing product, such a new treatment may not be worth the increased cost. In addition, patients provide a notable contribution by participating in these trials, and it is important to ensure that their efforts result in the highest-quality data possible. Furthermore, given the adverse physical and psychosocial impact of a wide variety of dermatologic diseases, the inclusion of an active comparator arm reduces the likelihood that patients will receive placebo, which will make these trials more ethical when effective treatments are available.⁸ By raising the bar, we can encourage pharmaceutical companies to pursue novel approaches that are more likely to have a revolutionary impact rather than minor modifications or formulations that offer little to no benefit at substantially increased cost.

Although some recent clinical trials in dermatology have included active comparators, many new medications continue to be introduced without any evidence of how they compare to existing standards of care. Until clinicians, patients, payers, and regulators demand that pharmaceutical companies conduct the necessary trials to not only demonstrate whether a treatment is effective and safe but also how it provides value, there will be continued introduction of marginal innovations rather than revolutionary treatments that improve patients’ lives. The next time a new medication is approved, as clinicians, patients, and payers, we must ask ourselves, is this treatment worth it?

Spending on medications is expected to grow from $344 billion in 2018 to $420 billion in 2023, largely driven by the introduction of new branded drugs.¹ These costs place substantial financial burden on patients, with nearly 30% of patients not taking their prescriptions as directed because of costs. Although many new medications have transformed how we care for patients, others may not offer meaningful benefit over existing less-costly alternatives that are supported by declining effect sizes of conventional placebo-controlled trials.² Most medications are approved based on placebo-controlled trial data that does not include an arm comparing the new drug to standard of care, leaving clinicians and patients unable to make meaningful comparisons when deciding on the most appropriate or cost-effective treatment. We consider ways in which clinicians, patients, payers, and regulators could compel more meaningful trials from industry.

Although we often look to the US Food and Drug Administration (FDA) to ensure rigorous and appropriate testing of new medications, the primary mission of the FDA is to ensure efficacy and safety. As a result, pharmaceutical companies seeking approval in the United States have little incentive to go beyond providing the minimal level of evidence required: placebo-controlled randomized trials. Although these trials provide important data on whether a treatment works and its associated risks, they do not provide data on comparative effectiveness. When relevant inexpensive medications are already on the market for the same indication, these placebo-controlled trials provide inadequate evidence to guide clinical decision-making. This issue is particularly relevant in dermatology given how easily topical medications can be combined or reformulated to pursue additional market exclusivity. The addition of an active comparator arm represents an important opportunity to improve the value of these studies.

In the pivotal trials of clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel for the treatment of acne, the experimental group was not only compared to vehicle but also the active comparator arms of clindamycin alone and benzoyl peroxide alone. The mean percentage change in total lesions was 47.9% with clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel, 41.6% with the active comparator arm of benzoyl peroxide alone, 40.4% with the active comparator arm of clindamycin alone, and 26.2% for vehicle.³ With these data in mind, clinicians and patients can decide whether the additional benefit of this new product over benzoyl peroxide alone is worth the increased cost.

In contrast, the trials of dapsone gel 7.5% for the treatment of acne did not include an active comparator. The mean percentage change in total lesions was 48.9% for dapsone gel and 43.2% for vehicle.⁴ Given these data, it is possible that dapsone gel may be no more effective, or possibly less effective, than alternatives such as benzoyl peroxide or other topical antibiotics. Nevertheless, dapsone annual sales were more than $200 million in 2016,⁵ suggesting that effectively marketed new products can achieve high sales even without convincing evidence of their value compared to standard of care. Although dapsone may be a useful treatment, we cannot effectively make patient-centered clinical decisions given the lack of an active comparator trial design.

This issue is not limited to acne. Phase 3 trials of halobetasol propionate foam 0.05% for psoriasis and crisaborole for atopic dermatitis also did not include an active comparator arm.^6,7 Given that topical steroids—and calcineurin inhibitors for atopic dermatitis—are mainstays of treatment for each condition, it is difficult to determine whether these new treatments offer meaningful advantages over existing options and how to incorporate them into our management strategies.

Unfortunately, expensive new medications that are adopted without convincing evidence of their benefit above standard of care can put patients at risk for financial toxicity, either directly through higher out-of-pocket costs or indirectly through higher premiums. Given the impact of rising medication costs on clinicians, patients, and payers, we propose several approaches these stakeholders could adopt to encourage the use of active comparator trial designs.

Clinicians and patients can encourage these trials by remaining skeptical of new treatments that were only compared to vehicle or placebo. Because new medications often are more expensive, clinicians and patients could avoid using these treatments without evidence of either increased efficacy or improved safety and tolerability. In addition, health care institutions should consider reducing pharmaceutical representatives’ access to clinicians to encourage treatment decisions based on the published literature and comparative effectiveness data rather than marketing.

Payers, such as Medicare, also could play a role by requiring active comparator trials for coverage of new medications, particularly when there are already other effective treatments available or other medications in the same class. Payers also could give preferred coverage tier or step therapy status to medications that demonstrate value over existing options.

Although regulatory approaches to increase use of active comparator designs may be more politically challenging to introduce, these options would be more administratively robust. The FDA or a novel regulatory body could require that new treatments demonstrate value in addition to safety and efficacy. This approach would be similar to the role of The National Institute for Health and Care Excellence in the United Kingdom or the recommendations of the European Medicines Agency. Such a group also could provide independent adjudication to ensure appropriate selection of a relevant active comparator. Another approach would be to give extended market exclusivity to medications that are approved based on trials including an additional active comparator arm, an approach used by the European Medicines Agency.

Any approach that encourages increased use of active comparator trials is not without potential downsides. It will be important to avoid unintended consequences of reduced research for rare diseases with smaller markets that may not be able to support the increased cost of these trials. As a result, it would be reasonable to forgo active comparator designs for mediations indicated for rare and orphan diseases or for medications with novel mechanisms of action.

Another argument against including an active comparator arm is that it may stifle innovation by driving up the cost of conducting trials; however, if a product is so marginally innovative that it cannot demonstrate superior safety or efficacy to an existing product, such a new treatment may not be worth the increased cost. In addition, patients provide a notable contribution by participating in these trials, and it is important to ensure that their efforts result in the highest-quality data possible. Furthermore, given the adverse physical and psychosocial impact of a wide variety of dermatologic diseases, the inclusion of an active comparator arm reduces the likelihood that patients will receive placebo, which will make these trials more ethical when effective treatments are available.⁸ By raising the bar, we can encourage pharmaceutical companies to pursue novel approaches that are more likely to have a revolutionary impact rather than minor modifications or formulations that offer little to no benefit at substantially increased cost.

Although some recent clinical trials in dermatology have included active comparators, many new medications continue to be introduced without any evidence of how they compare to existing standards of care. Until clinicians, patients, payers, and regulators demand that pharmaceutical companies conduct the necessary trials to not only demonstrate whether a treatment is effective and safe but also how it provides value, there will be continued introduction of marginal innovations rather than revolutionary treatments that improve patients’ lives. The next time a new medication is approved, as clinicians, patients, and payers, we must ask ourselves, is this treatment worth it?

Initiating treatment with the interleukin-12/23p40–targeting monoclonal antibody ustekinumab may trigger early severe cardiovascular events (SCEs) in susceptible patients, according to a large French case-time-control analysis.

Investigators led by Florence Poizeau, MD, of the department of dermatology at Rennes (France) University Hospital, found high-risk patients had more than four times the risk of an acute SCE in the 6 months after starting treatment. Although ustekinumab (Stelara) effectively treats moderate to severe psoriasis, psoriatic arthritis (PsA), and Crohn’s disease (indications approved by the Food and Drug Administration), the early months after ustekinumab initiation may be associated with atherosclerotic plaque destabilization via the inhibition of helper T cell subtype 17, the group reported in JAMA Dermatology.

The observational study drew on France’s 66 million–registrant health insurance database to identify all patients exposed to ustekinumab between April 1, 2010, and Dec. 31, 2016. Classified by high or low cardiovascular risk level, ustekinumab recipients served as their own controls, being compared during two time windows: the risk period covered the 6 months after initiating treatment and leading up to the SCE, defined as acute coronary syndrome (ACS) or stroke, while a reference period spanned the 6-12 months leading up to the risk period.

In the statistical analysis of 9,290 ustekinumab-exposed patients (mean age 43 years, 52% male), conducted from September 2017 to July 2018, 7,588 (82%) received ustekinumab for psoriasis or PsA, and 724 (8%) for Crohn’s disease. (The remaining indications were for psoriasis or PsA and Crohn’s disease, or were undetermined.)

Of these patients, 98 experienced SCEs (52 with ACS admitted to the ICU and 46 with strokes). In patients deemed at high cardiovascular risk – those with two risk factors or a personal history of atherosclerotic disease – there was a statistically significant association between starting ustekinumab and SCE occurrence, for an odds ratio of 4.17 (95% confidence interval, 1.19-14.59). In contrast, no such association emerged in ustekinumab users at low cardiovascular risk, for an OR of 0.30 (95% CI, 0.03-3.13). The OR for all was 2.41 (95% CI, 0.83-7.01).

Of the 98 patients included in the final case-time-control analysis, 62 were men (63%), the median age was 57 years, and 76 (78%) were at high cardiovascular risk. A total of 89 patients (91%) had psoriasis, four (4%) had Crohn’s disease, and two (2%) had both.

The investigators also did an analysis including these 98 patients plus 13 patients with ACS who were not hospitalized in an ICU, and 68 with unstable angina, for a total of 179. In this group, the ORs for SCE were 1.75 (95% CI, 0.86-3.56) overall, compared with 3.20 (95% CI, 1.29-7.92) among those at high cardiovascular risk and 0.21 (95% CI, 0.02-1.69) among those at low cardiovascular risk.

The Rennes investigators’ decision to focus on early SCEs stemmed in part from a meta-analysis of randomized clinical trials that reported a possible excess of early SCEs in adults exposed to anti–IL-12/23p40 antibodies, which at that time included the now-discontinued experimental antibody briakinumab. Briakinumab trials were aborted and the drug was never brought to market, leaving ustekinumab as the only antibody of this type.

The finding of “an association between ustekinumab initiation and SCE among patients with cardiovascular risk factors suggests the need for caution regarding the prescription of ustekinumab in this population,” Dr. Poizeau and colleagues wrote. The risk “seems to concern patients with psoriasis” rather than Crohn’s disease, which may be related to the older age and greater cardiovascular risk of the former. “A close collaboration between cardiologists and biologic prescribers could be beneficial to evaluate the risk of SCEs for patients who are receiving ustekinumab,” they added, recommending further research into the physiopathological mechanisms of action.

Offering a U.S. clinician’s perspective on the French study, Anthony Fernandez, MD, PhD, director of medical dermatology at the Cleveland Clinic, called the findings “unique and interesting with very robust odds ratios. These posttreatment associations have actually been a big area of research over the past decade but not with such defined time periods.”

No significant increases in risk have been seen with other biologics, Dr. Fernandez added, with the exception of briakinumab. “But still, the current study does not definitively answer the question whether ustekinumab can trigger acute events within 6 months of treatment. There’s smoke, but we haven’t clearly seen a fire.”

As to ustekinumab’s possible pathogenic mechanism of action, Dr. Fernandez pointed to data suggesting that IL-17A can be stabilizing to atherosclerotic plaques. “So there’s a hypothesis that blocking the 17/23 pathway may destabilize plaques and make patients more prone to acute cardiovascular events.”

In other comments from clinicians not involved in the study, Seoyoung Kim, MD, ScD, MSCE, director of the program in rheumatologic, immunologic, and musculoskeletal pharmacoepidemiology (PRIME) at Brigham and Women’s Hospital, Boston, noted that, while the investigators controlled for the trend over time and their design choice included time-fixed covariates such as age, sex, and family history within individuals, the case-crossover study could not control for time-varying confounders within individuals.

“In other words, it’s possible that some of the patients had a lot more disease activity and systemic inflammation and used more NSAIDs, steroids, and other medications potentially related to cardiovascular risk a few months before they started ustekinumab, compared with 6-12 months prior,“ Dr. Kim said in an interview. “I would be curious to know if they would find the same thing or not if they studied a different type of biologic drug.”

She also pointed out that the number of outcomes overall was small, leading to imprecise estimates and wide confidence intervals.

Last year Dr. Kim and associates published a study comparing ustekinumab with tumor necrosis factor inhibitor therapy in younger psoriasis and psoriatic arthritis patients and found no difference between the two groups in major cardiovascular events or atrial fibrillation.

Joel M. Gelfand, MD, MSCE, professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, has more reservations about the findings. “The Poizeau study was methodologically flawed, making the results unreliable,” he said in an interview. “There is a breadth of data from clinical trials and observational studies that do not demonstrate an increased risk of major acute cardiovascular events with ustekinumab and the results of the Poizeau study should not impact clinical practice.”

In an interview, Mark G. Lebwohl, MD, professor and chairman of the department of dermatology and chief for clinical therapeutics at the Icahn School of Medicine at Mount Sinai, New York, said that, in his view, the investigators used early reports of a small number cardiovascular events to look at the issue from a faulty perspective, and hence their findings would have no impact on his clinical practice.

“This study looked at the issue incorrectly. It looked at people put on drug who already had two risk factors for heart attack. And psoriasis itself is a third risk factor,” he said. “So lo and behold, big surprise, some of them had cardiovascular events.”

Dr. Lebwohl noted that a wealth of carefully compiled data has found no increase over time in cardiovascular events with this drug in psoriasis patients. The risk of cardiovascular events actually goes down with time because of the drug’s anti-inflammatory effects.

Dr. Fernandez takes a more positive view of the French findings. “The data certainly support the need for further research in this area,” he said in an interview, “and in the meantime this paper will probably make me extra cautious in using ustekinumab in those at significant risk.”

The French study was supported by a grant from the French National Agency for Medicines and Health Products Safety. Dr. Poizeau and seven coauthors had no disclosures. The remaining five reported disclosures that included receiving fees from AbbVie, Admiral, Amgen, Baxalta, Cologne, Dermavant, Eli Lilly, Janssen, Kyowa Kirin, Novartis, Mylan, Sun Pharmaceuticals, and UCB, as well as grants and personal fees from Boehringer Ingelheim, Leo Pharma, and Pfizer outside the submitted work, and personal fees from Pfizer, AbbVie, UCB Pharma, and Lilly during the conduct of the study. Dr. Fernandez reported consulting work for AbbVie and research grants from Novartis. Dr. Kim disclosed research grants from Brigham and Women’s Hospital and from Pfizer, Abbvie, Roche, and Bristol-Myers Squibb for unrelated studies. Dr. Gelfand reported varying financial ties to Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Janssen Biologics, Regeneron, UCB, Sanofi, Pfizer, Celgene, OrthoDermatolgics, AbbVie, Novartis, and Eli Lilly. He is copatent holder of a treatment for cutaneous T-cell lymphoma. Dr. Lebwohl reported unpaid consulting for most manufacturers of psoriasis drugs, with all fees going directly to Mount Sinai.

Source: Poizeau F et al. JAMA Dermatol. 2020 Sep 9. doi: 10.1001/jamadermatol.2020.2977.
 

Initiating treatment with the interleukin-12/23p40–targeting monoclonal antibody ustekinumab may trigger early severe cardiovascular events (SCEs) in susceptible patients, according to a large French case-time-control analysis.

Investigators led by Florence Poizeau, MD, of the department of dermatology at Rennes (France) University Hospital, found high-risk patients had more than four times the risk of an acute SCE in the 6 months after starting treatment. Although ustekinumab (Stelara) effectively treats moderate to severe psoriasis, psoriatic arthritis (PsA), and Crohn’s disease (indications approved by the Food and Drug Administration), the early months after ustekinumab initiation may be associated with atherosclerotic plaque destabilization via the inhibition of helper T cell subtype 17, the group reported in JAMA Dermatology.

The observational study drew on France’s 66 million–registrant health insurance database to identify all patients exposed to ustekinumab between April 1, 2010, and Dec. 31, 2016. Classified by high or low cardiovascular risk level, ustekinumab recipients served as their own controls, being compared during two time windows: the risk period covered the 6 months after initiating treatment and leading up to the SCE, defined as acute coronary syndrome (ACS) or stroke, while a reference period spanned the 6-12 months leading up to the risk period.

In the statistical analysis of 9,290 ustekinumab-exposed patients (mean age 43 years, 52% male), conducted from September 2017 to July 2018, 7,588 (82%) received ustekinumab for psoriasis or PsA, and 724 (8%) for Crohn’s disease. (The remaining indications were for psoriasis or PsA and Crohn’s disease, or were undetermined.)

Of these patients, 98 experienced SCEs (52 with ACS admitted to the ICU and 46 with strokes). In patients deemed at high cardiovascular risk – those with two risk factors or a personal history of atherosclerotic disease – there was a statistically significant association between starting ustekinumab and SCE occurrence, for an odds ratio of 4.17 (95% confidence interval, 1.19-14.59). In contrast, no such association emerged in ustekinumab users at low cardiovascular risk, for an OR of 0.30 (95% CI, 0.03-3.13). The OR for all was 2.41 (95% CI, 0.83-7.01).

Of the 98 patients included in the final case-time-control analysis, 62 were men (63%), the median age was 57 years, and 76 (78%) were at high cardiovascular risk. A total of 89 patients (91%) had psoriasis, four (4%) had Crohn’s disease, and two (2%) had both.

The investigators also did an analysis including these 98 patients plus 13 patients with ACS who were not hospitalized in an ICU, and 68 with unstable angina, for a total of 179. In this group, the ORs for SCE were 1.75 (95% CI, 0.86-3.56) overall, compared with 3.20 (95% CI, 1.29-7.92) among those at high cardiovascular risk and 0.21 (95% CI, 0.02-1.69) among those at low cardiovascular risk.

The Rennes investigators’ decision to focus on early SCEs stemmed in part from a meta-analysis of randomized clinical trials that reported a possible excess of early SCEs in adults exposed to anti–IL-12/23p40 antibodies, which at that time included the now-discontinued experimental antibody briakinumab. Briakinumab trials were aborted and the drug was never brought to market, leaving ustekinumab as the only antibody of this type.

The finding of “an association between ustekinumab initiation and SCE among patients with cardiovascular risk factors suggests the need for caution regarding the prescription of ustekinumab in this population,” Dr. Poizeau and colleagues wrote. The risk “seems to concern patients with psoriasis” rather than Crohn’s disease, which may be related to the older age and greater cardiovascular risk of the former. “A close collaboration between cardiologists and biologic prescribers could be beneficial to evaluate the risk of SCEs for patients who are receiving ustekinumab,” they added, recommending further research into the physiopathological mechanisms of action.

Offering a U.S. clinician’s perspective on the French study, Anthony Fernandez, MD, PhD, director of medical dermatology at the Cleveland Clinic, called the findings “unique and interesting with very robust odds ratios. These posttreatment associations have actually been a big area of research over the past decade but not with such defined time periods.”

No significant increases in risk have been seen with other biologics, Dr. Fernandez added, with the exception of briakinumab. “But still, the current study does not definitively answer the question whether ustekinumab can trigger acute events within 6 months of treatment. There’s smoke, but we haven’t clearly seen a fire.”

As to ustekinumab’s possible pathogenic mechanism of action, Dr. Fernandez pointed to data suggesting that IL-17A can be stabilizing to atherosclerotic plaques. “So there’s a hypothesis that blocking the 17/23 pathway may destabilize plaques and make patients more prone to acute cardiovascular events.”

In other comments from clinicians not involved in the study, Seoyoung Kim, MD, ScD, MSCE, director of the program in rheumatologic, immunologic, and musculoskeletal pharmacoepidemiology (PRIME) at Brigham and Women’s Hospital, Boston, noted that, while the investigators controlled for the trend over time and their design choice included time-fixed covariates such as age, sex, and family history within individuals, the case-crossover study could not control for time-varying confounders within individuals.

“In other words, it’s possible that some of the patients had a lot more disease activity and systemic inflammation and used more NSAIDs, steroids, and other medications potentially related to cardiovascular risk a few months before they started ustekinumab, compared with 6-12 months prior,“ Dr. Kim said in an interview. “I would be curious to know if they would find the same thing or not if they studied a different type of biologic drug.”

She also pointed out that the number of outcomes overall was small, leading to imprecise estimates and wide confidence intervals.

Last year Dr. Kim and associates published a study comparing ustekinumab with tumor necrosis factor inhibitor therapy in younger psoriasis and psoriatic arthritis patients and found no difference between the two groups in major cardiovascular events or atrial fibrillation.

Joel M. Gelfand, MD, MSCE, professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, has more reservations about the findings. “The Poizeau study was methodologically flawed, making the results unreliable,” he said in an interview. “There is a breadth of data from clinical trials and observational studies that do not demonstrate an increased risk of major acute cardiovascular events with ustekinumab and the results of the Poizeau study should not impact clinical practice.”

In an interview, Mark G. Lebwohl, MD, professor and chairman of the department of dermatology and chief for clinical therapeutics at the Icahn School of Medicine at Mount Sinai, New York, said that, in his view, the investigators used early reports of a small number cardiovascular events to look at the issue from a faulty perspective, and hence their findings would have no impact on his clinical practice.

“This study looked at the issue incorrectly. It looked at people put on drug who already had two risk factors for heart attack. And psoriasis itself is a third risk factor,” he said. “So lo and behold, big surprise, some of them had cardiovascular events.”

Dr. Lebwohl noted that a wealth of carefully compiled data has found no increase over time in cardiovascular events with this drug in psoriasis patients. The risk of cardiovascular events actually goes down with time because of the drug’s anti-inflammatory effects.

Dr. Fernandez takes a more positive view of the French findings. “The data certainly support the need for further research in this area,” he said in an interview, “and in the meantime this paper will probably make me extra cautious in using ustekinumab in those at significant risk.”

The French study was supported by a grant from the French National Agency for Medicines and Health Products Safety. Dr. Poizeau and seven coauthors had no disclosures. The remaining five reported disclosures that included receiving fees from AbbVie, Admiral, Amgen, Baxalta, Cologne, Dermavant, Eli Lilly, Janssen, Kyowa Kirin, Novartis, Mylan, Sun Pharmaceuticals, and UCB, as well as grants and personal fees from Boehringer Ingelheim, Leo Pharma, and Pfizer outside the submitted work, and personal fees from Pfizer, AbbVie, UCB Pharma, and Lilly during the conduct of the study. Dr. Fernandez reported consulting work for AbbVie and research grants from Novartis. Dr. Kim disclosed research grants from Brigham and Women’s Hospital and from Pfizer, Abbvie, Roche, and Bristol-Myers Squibb for unrelated studies. Dr. Gelfand reported varying financial ties to Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Janssen Biologics, Regeneron, UCB, Sanofi, Pfizer, Celgene, OrthoDermatolgics, AbbVie, Novartis, and Eli Lilly. He is copatent holder of a treatment for cutaneous T-cell lymphoma. Dr. Lebwohl reported unpaid consulting for most manufacturers of psoriasis drugs, with all fees going directly to Mount Sinai.

Source: Poizeau F et al. JAMA Dermatol. 2020 Sep 9. doi: 10.1001/jamadermatol.2020.2977.
 

Initiating treatment with the interleukin-12/23p40–targeting monoclonal antibody ustekinumab may trigger early severe cardiovascular events (SCEs) in susceptible patients, according to a large French case-time-control analysis.

Investigators led by Florence Poizeau, MD, of the department of dermatology at Rennes (France) University Hospital, found high-risk patients had more than four times the risk of an acute SCE in the 6 months after starting treatment. Although ustekinumab (Stelara) effectively treats moderate to severe psoriasis, psoriatic arthritis (PsA), and Crohn’s disease (indications approved by the Food and Drug Administration), the early months after ustekinumab initiation may be associated with atherosclerotic plaque destabilization via the inhibition of helper T cell subtype 17, the group reported in JAMA Dermatology.

The observational study drew on France’s 66 million–registrant health insurance database to identify all patients exposed to ustekinumab between April 1, 2010, and Dec. 31, 2016. Classified by high or low cardiovascular risk level, ustekinumab recipients served as their own controls, being compared during two time windows: the risk period covered the 6 months after initiating treatment and leading up to the SCE, defined as acute coronary syndrome (ACS) or stroke, while a reference period spanned the 6-12 months leading up to the risk period.

In the statistical analysis of 9,290 ustekinumab-exposed patients (mean age 43 years, 52% male), conducted from September 2017 to July 2018, 7,588 (82%) received ustekinumab for psoriasis or PsA, and 724 (8%) for Crohn’s disease. (The remaining indications were for psoriasis or PsA and Crohn’s disease, or were undetermined.)

Of these patients, 98 experienced SCEs (52 with ACS admitted to the ICU and 46 with strokes). In patients deemed at high cardiovascular risk – those with two risk factors or a personal history of atherosclerotic disease – there was a statistically significant association between starting ustekinumab and SCE occurrence, for an odds ratio of 4.17 (95% confidence interval, 1.19-14.59). In contrast, no such association emerged in ustekinumab users at low cardiovascular risk, for an OR of 0.30 (95% CI, 0.03-3.13). The OR for all was 2.41 (95% CI, 0.83-7.01).

Of the 98 patients included in the final case-time-control analysis, 62 were men (63%), the median age was 57 years, and 76 (78%) were at high cardiovascular risk. A total of 89 patients (91%) had psoriasis, four (4%) had Crohn’s disease, and two (2%) had both.

The investigators also did an analysis including these 98 patients plus 13 patients with ACS who were not hospitalized in an ICU, and 68 with unstable angina, for a total of 179. In this group, the ORs for SCE were 1.75 (95% CI, 0.86-3.56) overall, compared with 3.20 (95% CI, 1.29-7.92) among those at high cardiovascular risk and 0.21 (95% CI, 0.02-1.69) among those at low cardiovascular risk.

The Rennes investigators’ decision to focus on early SCEs stemmed in part from a meta-analysis of randomized clinical trials that reported a possible excess of early SCEs in adults exposed to anti–IL-12/23p40 antibodies, which at that time included the now-discontinued experimental antibody briakinumab. Briakinumab trials were aborted and the drug was never brought to market, leaving ustekinumab as the only antibody of this type.

The finding of “an association between ustekinumab initiation and SCE among patients with cardiovascular risk factors suggests the need for caution regarding the prescription of ustekinumab in this population,” Dr. Poizeau and colleagues wrote. The risk “seems to concern patients with psoriasis” rather than Crohn’s disease, which may be related to the older age and greater cardiovascular risk of the former. “A close collaboration between cardiologists and biologic prescribers could be beneficial to evaluate the risk of SCEs for patients who are receiving ustekinumab,” they added, recommending further research into the physiopathological mechanisms of action.

Offering a U.S. clinician’s perspective on the French study, Anthony Fernandez, MD, PhD, director of medical dermatology at the Cleveland Clinic, called the findings “unique and interesting with very robust odds ratios. These posttreatment associations have actually been a big area of research over the past decade but not with such defined time periods.”

No significant increases in risk have been seen with other biologics, Dr. Fernandez added, with the exception of briakinumab. “But still, the current study does not definitively answer the question whether ustekinumab can trigger acute events within 6 months of treatment. There’s smoke, but we haven’t clearly seen a fire.”

As to ustekinumab’s possible pathogenic mechanism of action, Dr. Fernandez pointed to data suggesting that IL-17A can be stabilizing to atherosclerotic plaques. “So there’s a hypothesis that blocking the 17/23 pathway may destabilize plaques and make patients more prone to acute cardiovascular events.”

In other comments from clinicians not involved in the study, Seoyoung Kim, MD, ScD, MSCE, director of the program in rheumatologic, immunologic, and musculoskeletal pharmacoepidemiology (PRIME) at Brigham and Women’s Hospital, Boston, noted that, while the investigators controlled for the trend over time and their design choice included time-fixed covariates such as age, sex, and family history within individuals, the case-crossover study could not control for time-varying confounders within individuals.

“In other words, it’s possible that some of the patients had a lot more disease activity and systemic inflammation and used more NSAIDs, steroids, and other medications potentially related to cardiovascular risk a few months before they started ustekinumab, compared with 6-12 months prior,“ Dr. Kim said in an interview. “I would be curious to know if they would find the same thing or not if they studied a different type of biologic drug.”

She also pointed out that the number of outcomes overall was small, leading to imprecise estimates and wide confidence intervals.

Last year Dr. Kim and associates published a study comparing ustekinumab with tumor necrosis factor inhibitor therapy in younger psoriasis and psoriatic arthritis patients and found no difference between the two groups in major cardiovascular events or atrial fibrillation.

Joel M. Gelfand, MD, MSCE, professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, has more reservations about the findings. “The Poizeau study was methodologically flawed, making the results unreliable,” he said in an interview. “There is a breadth of data from clinical trials and observational studies that do not demonstrate an increased risk of major acute cardiovascular events with ustekinumab and the results of the Poizeau study should not impact clinical practice.”

In an interview, Mark G. Lebwohl, MD, professor and chairman of the department of dermatology and chief for clinical therapeutics at the Icahn School of Medicine at Mount Sinai, New York, said that, in his view, the investigators used early reports of a small number cardiovascular events to look at the issue from a faulty perspective, and hence their findings would have no impact on his clinical practice.

“This study looked at the issue incorrectly. It looked at people put on drug who already had two risk factors for heart attack. And psoriasis itself is a third risk factor,” he said. “So lo and behold, big surprise, some of them had cardiovascular events.”

Dr. Lebwohl noted that a wealth of carefully compiled data has found no increase over time in cardiovascular events with this drug in psoriasis patients. The risk of cardiovascular events actually goes down with time because of the drug’s anti-inflammatory effects.

Dr. Fernandez takes a more positive view of the French findings. “The data certainly support the need for further research in this area,” he said in an interview, “and in the meantime this paper will probably make me extra cautious in using ustekinumab in those at significant risk.”

The French study was supported by a grant from the French National Agency for Medicines and Health Products Safety. Dr. Poizeau and seven coauthors had no disclosures. The remaining five reported disclosures that included receiving fees from AbbVie, Admiral, Amgen, Baxalta, Cologne, Dermavant, Eli Lilly, Janssen, Kyowa Kirin, Novartis, Mylan, Sun Pharmaceuticals, and UCB, as well as grants and personal fees from Boehringer Ingelheim, Leo Pharma, and Pfizer outside the submitted work, and personal fees from Pfizer, AbbVie, UCB Pharma, and Lilly during the conduct of the study. Dr. Fernandez reported consulting work for AbbVie and research grants from Novartis. Dr. Kim disclosed research grants from Brigham and Women’s Hospital and from Pfizer, Abbvie, Roche, and Bristol-Myers Squibb for unrelated studies. Dr. Gelfand reported varying financial ties to Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Janssen Biologics, Regeneron, UCB, Sanofi, Pfizer, Celgene, OrthoDermatolgics, AbbVie, Novartis, and Eli Lilly. He is copatent holder of a treatment for cutaneous T-cell lymphoma. Dr. Lebwohl reported unpaid consulting for most manufacturers of psoriasis drugs, with all fees going directly to Mount Sinai.

Source: Poizeau F et al. JAMA Dermatol. 2020 Sep 9. doi: 10.1001/jamadermatol.2020.2977.
 

Biologics used as treatment for psoriasis may also help reduce lipid-rich necrotic core (LRNC), a high-risk plaque associated with cardiovascular events, recent research from a prospective, observational study suggests.

Waldemarus/Thinkstock

Cardiac CT scans performed on patients with psoriasis 1 year after starting biologic therapy revealed a reduction in LRNC, compared with patients who were not receiving biologics, according to Harry Choi, MD, of the National Heart, Lung, and Blood Institute at the National Institutes of Health and colleagues. The association with reduction in LRNC and biologic therapy remained significant when adjusted for type of biologic. “These findings demonstrate that LRNC may be modulated by the control of systemic inflammation,” the researchers wrote in their study, published Sept. 15 in Circulation: Cardiovascular Imaging.

Dr. Choi and colleagues evaluated 289 patients with psoriasis within the Psoriasis Atherosclerosis and Cardiometabolic Disease Initiative cohort. The patients had a mean age of 50 years and a mean body mass index of 29.4 kg/m², as well as a mean Psoriasis Area and Severity Index (PASI) score of 6.0. At baseline, 29% of patients had hypertension, 41% had hyperlipidemia, their mean Framingham risk score was 1.9, and a three-quarters (212 of 289) had mild to moderate psoriasis.

Changes in LRNC were observed at 1 year, compared with baseline prior to and after receiving biologic therapy (124 patients) in comparison with patients who did not undergo biologic therapy (85 patients). Biologic therapies were grouped by type, which included anti–tumor necrosis factor (anti-TNF), anti–interleukin (IL)–12/23, and anti–IL-17 biologics.

There were a significant associations between LRNC and Framingham risk score (standardized beta coefficient, 0.12; 95% confidence interval, 0.00-0.15; P = .045) and severity of psoriasis (beta, 0.13; 95% CI, 0.01-0.26; P = .029) at baseline.
 

Key findings

The researchers found a significant reduction in LRNC 1 year after patients began biologic therapy (median, 2.97 mm²; interquartile range, 1.99-4.66), compared with baseline (median, 3.12 mm²; IQR, 1.84-4.35) (P = .028), while patients who did not receive biologic therapy had nonsignificantly higher LRNC after 1 year (median, 3.12 mm²; IQR, 1.82-4.60), compared with baseline measurements (median, 3.34 mm²; IQR, 2.04–4.74) (P = .06).

The results remained significant after the researchers adjusted for psoriasis severity, Framingham risk score, BMI, use of statins (beta, −0.09; 95% CI, −0.01 to −0.18; P = .033). Significant reductions in LRNC also remained when analyzing patients receiving anti-TNF, anti–IL-12/23, and anti–IL-17 biologics independently, and there were no significant between-group differences in reduction of LRNC.
 

The potential of biologics for improving vascular health

Discussing the study results in a press release from the American Heart Association, senior author Nehal N. Mehta, MD, MSCE, FAHA, chief of the Lab of Inflammation and Cardiometabolic Diseases at the NHLBI at NIH, compared the effect biologic therapy had on coronary plaque reduction with that of statins.

“There is approximately 6%-8% reduction in coronary plaque following therapy with statins. Similarly, our treatment with biologic therapy reduced coronary plaque by the same amount after one year. These findings suggest that biologic therapy to treat psoriasis may be just as beneficial as statin therapy on heart arteries,” Dr. Mehta said in the release.

In an interview, Nieca Goldberg, MD, medical director of NYU Women’s Heart Program at NYU Langone Health, echoed Dr. Mehta’s commments and said psoriasis carries the “potential to treat two conditions with the same drug.”

“We know conditions such as psoriatic arthritis and rheumatoid arthritis cause chronic inflammation. Chronic inflammation causes injury to blood vessels and high-risk coronary plaque. Individuals with these inflammatory conditions are at high risk for heart attack,” she said. “This study shows that biologic treatment for psoriatic arthritis can reduce the presence of high-risk plaque. It shows the potential to treat chronic inflammation and high-risk coronary plaque.”

While the results show an association between use of biologics and LRNC reduction, the study design was observational and patients had a short follow-up period. Dr. Goldberg noted more studies are needed to evaluate the effect of biologics on reducing cardiovascular events such as a myocardial infarction.

“We have never before been able to show healing of an inflamed plaque like this in humans. Biologic therapy reduces systemic inflammation and immune activation, and it has a favorable impact on improving overall vascular health,” Dr. Mehta said in the press release. “Imagine if we can treat both psoriasis and coronary heart disease with one therapy – that is the question to be asked in future studies.”

This study was funded with support from the NHLBI Intramural Research Program and the NIH Medical Research Scholars Program at the National Institutes of Health. One investigator reports financial relationships with numerous pharmaceutical companies. The other authors report no relevant conflicts of interest. Dr. Mehta also reports numerous such relationships. Dr. Goldberg reports no relevant conflicts of interest.

SOURCE: Choi H et al. Circ Cardiovasc Imaging. 2020 Sep;13(9):e011199.

Biologics used as treatment for psoriasis may also help reduce lipid-rich necrotic core (LRNC), a high-risk plaque associated with cardiovascular events, recent research from a prospective, observational study suggests.

Waldemarus/Thinkstock

Cardiac CT scans performed on patients with psoriasis 1 year after starting biologic therapy revealed a reduction in LRNC, compared with patients who were not receiving biologics, according to Harry Choi, MD, of the National Heart, Lung, and Blood Institute at the National Institutes of Health and colleagues. The association with reduction in LRNC and biologic therapy remained significant when adjusted for type of biologic. “These findings demonstrate that LRNC may be modulated by the control of systemic inflammation,” the researchers wrote in their study, published Sept. 15 in Circulation: Cardiovascular Imaging.

Dr. Choi and colleagues evaluated 289 patients with psoriasis within the Psoriasis Atherosclerosis and Cardiometabolic Disease Initiative cohort. The patients had a mean age of 50 years and a mean body mass index of 29.4 kg/m², as well as a mean Psoriasis Area and Severity Index (PASI) score of 6.0. At baseline, 29% of patients had hypertension, 41% had hyperlipidemia, their mean Framingham risk score was 1.9, and a three-quarters (212 of 289) had mild to moderate psoriasis.

Changes in LRNC were observed at 1 year, compared with baseline prior to and after receiving biologic therapy (124 patients) in comparison with patients who did not undergo biologic therapy (85 patients). Biologic therapies were grouped by type, which included anti–tumor necrosis factor (anti-TNF), anti–interleukin (IL)–12/23, and anti–IL-17 biologics.

There were a significant associations between LRNC and Framingham risk score (standardized beta coefficient, 0.12; 95% confidence interval, 0.00-0.15; P = .045) and severity of psoriasis (beta, 0.13; 95% CI, 0.01-0.26; P = .029) at baseline.
 

Key findings

The researchers found a significant reduction in LRNC 1 year after patients began biologic therapy (median, 2.97 mm²; interquartile range, 1.99-4.66), compared with baseline (median, 3.12 mm²; IQR, 1.84-4.35) (P = .028), while patients who did not receive biologic therapy had nonsignificantly higher LRNC after 1 year (median, 3.12 mm²; IQR, 1.82-4.60), compared with baseline measurements (median, 3.34 mm²; IQR, 2.04–4.74) (P = .06).

The results remained significant after the researchers adjusted for psoriasis severity, Framingham risk score, BMI, use of statins (beta, −0.09; 95% CI, −0.01 to −0.18; P = .033). Significant reductions in LRNC also remained when analyzing patients receiving anti-TNF, anti–IL-12/23, and anti–IL-17 biologics independently, and there were no significant between-group differences in reduction of LRNC.
 

The potential of biologics for improving vascular health

Discussing the study results in a press release from the American Heart Association, senior author Nehal N. Mehta, MD, MSCE, FAHA, chief of the Lab of Inflammation and Cardiometabolic Diseases at the NHLBI at NIH, compared the effect biologic therapy had on coronary plaque reduction with that of statins.

“There is approximately 6%-8% reduction in coronary plaque following therapy with statins. Similarly, our treatment with biologic therapy reduced coronary plaque by the same amount after one year. These findings suggest that biologic therapy to treat psoriasis may be just as beneficial as statin therapy on heart arteries,” Dr. Mehta said in the release.

In an interview, Nieca Goldberg, MD, medical director of NYU Women’s Heart Program at NYU Langone Health, echoed Dr. Mehta’s commments and said psoriasis carries the “potential to treat two conditions with the same drug.”

“We know conditions such as psoriatic arthritis and rheumatoid arthritis cause chronic inflammation. Chronic inflammation causes injury to blood vessels and high-risk coronary plaque. Individuals with these inflammatory conditions are at high risk for heart attack,” she said. “This study shows that biologic treatment for psoriatic arthritis can reduce the presence of high-risk plaque. It shows the potential to treat chronic inflammation and high-risk coronary plaque.”

While the results show an association between use of biologics and LRNC reduction, the study design was observational and patients had a short follow-up period. Dr. Goldberg noted more studies are needed to evaluate the effect of biologics on reducing cardiovascular events such as a myocardial infarction.

“We have never before been able to show healing of an inflamed plaque like this in humans. Biologic therapy reduces systemic inflammation and immune activation, and it has a favorable impact on improving overall vascular health,” Dr. Mehta said in the press release. “Imagine if we can treat both psoriasis and coronary heart disease with one therapy – that is the question to be asked in future studies.”

This study was funded with support from the NHLBI Intramural Research Program and the NIH Medical Research Scholars Program at the National Institutes of Health. One investigator reports financial relationships with numerous pharmaceutical companies. The other authors report no relevant conflicts of interest. Dr. Mehta also reports numerous such relationships. Dr. Goldberg reports no relevant conflicts of interest.

SOURCE: Choi H et al. Circ Cardiovasc Imaging. 2020 Sep;13(9):e011199.

Biologics used as treatment for psoriasis may also help reduce lipid-rich necrotic core (LRNC), a high-risk plaque associated with cardiovascular events, recent research from a prospective, observational study suggests.

Waldemarus/Thinkstock

Cardiac CT scans performed on patients with psoriasis 1 year after starting biologic therapy revealed a reduction in LRNC, compared with patients who were not receiving biologics, according to Harry Choi, MD, of the National Heart, Lung, and Blood Institute at the National Institutes of Health and colleagues. The association with reduction in LRNC and biologic therapy remained significant when adjusted for type of biologic. “These findings demonstrate that LRNC may be modulated by the control of systemic inflammation,” the researchers wrote in their study, published Sept. 15 in Circulation: Cardiovascular Imaging.

Dr. Choi and colleagues evaluated 289 patients with psoriasis within the Psoriasis Atherosclerosis and Cardiometabolic Disease Initiative cohort. The patients had a mean age of 50 years and a mean body mass index of 29.4 kg/m², as well as a mean Psoriasis Area and Severity Index (PASI) score of 6.0. At baseline, 29% of patients had hypertension, 41% had hyperlipidemia, their mean Framingham risk score was 1.9, and a three-quarters (212 of 289) had mild to moderate psoriasis.

Changes in LRNC were observed at 1 year, compared with baseline prior to and after receiving biologic therapy (124 patients) in comparison with patients who did not undergo biologic therapy (85 patients). Biologic therapies were grouped by type, which included anti–tumor necrosis factor (anti-TNF), anti–interleukin (IL)–12/23, and anti–IL-17 biologics.

There were a significant associations between LRNC and Framingham risk score (standardized beta coefficient, 0.12; 95% confidence interval, 0.00-0.15; P = .045) and severity of psoriasis (beta, 0.13; 95% CI, 0.01-0.26; P = .029) at baseline.
 

Key findings

The researchers found a significant reduction in LRNC 1 year after patients began biologic therapy (median, 2.97 mm²; interquartile range, 1.99-4.66), compared with baseline (median, 3.12 mm²; IQR, 1.84-4.35) (P = .028), while patients who did not receive biologic therapy had nonsignificantly higher LRNC after 1 year (median, 3.12 mm²; IQR, 1.82-4.60), compared with baseline measurements (median, 3.34 mm²; IQR, 2.04–4.74) (P = .06).

The results remained significant after the researchers adjusted for psoriasis severity, Framingham risk score, BMI, use of statins (beta, −0.09; 95% CI, −0.01 to −0.18; P = .033). Significant reductions in LRNC also remained when analyzing patients receiving anti-TNF, anti–IL-12/23, and anti–IL-17 biologics independently, and there were no significant between-group differences in reduction of LRNC.
 

The potential of biologics for improving vascular health

Discussing the study results in a press release from the American Heart Association, senior author Nehal N. Mehta, MD, MSCE, FAHA, chief of the Lab of Inflammation and Cardiometabolic Diseases at the NHLBI at NIH, compared the effect biologic therapy had on coronary plaque reduction with that of statins.

“There is approximately 6%-8% reduction in coronary plaque following therapy with statins. Similarly, our treatment with biologic therapy reduced coronary plaque by the same amount after one year. These findings suggest that biologic therapy to treat psoriasis may be just as beneficial as statin therapy on heart arteries,” Dr. Mehta said in the release.

In an interview, Nieca Goldberg, MD, medical director of NYU Women’s Heart Program at NYU Langone Health, echoed Dr. Mehta’s commments and said psoriasis carries the “potential to treat two conditions with the same drug.”

“We know conditions such as psoriatic arthritis and rheumatoid arthritis cause chronic inflammation. Chronic inflammation causes injury to blood vessels and high-risk coronary plaque. Individuals with these inflammatory conditions are at high risk for heart attack,” she said. “This study shows that biologic treatment for psoriatic arthritis can reduce the presence of high-risk plaque. It shows the potential to treat chronic inflammation and high-risk coronary plaque.”

While the results show an association between use of biologics and LRNC reduction, the study design was observational and patients had a short follow-up period. Dr. Goldberg noted more studies are needed to evaluate the effect of biologics on reducing cardiovascular events such as a myocardial infarction.

“We have never before been able to show healing of an inflamed plaque like this in humans. Biologic therapy reduces systemic inflammation and immune activation, and it has a favorable impact on improving overall vascular health,” Dr. Mehta said in the press release. “Imagine if we can treat both psoriasis and coronary heart disease with one therapy – that is the question to be asked in future studies.”

This study was funded with support from the NHLBI Intramural Research Program and the NIH Medical Research Scholars Program at the National Institutes of Health. One investigator reports financial relationships with numerous pharmaceutical companies. The other authors report no relevant conflicts of interest. Dr. Mehta also reports numerous such relationships. Dr. Goldberg reports no relevant conflicts of interest.

SOURCE: Choi H et al. Circ Cardiovasc Imaging. 2020 Sep;13(9):e011199.