Psoriasis

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.

Continued use of tumor necrosis factor inhibitors or methotrexate is acceptable in most patients who acquire COVID-19, results of a recent cohort study suggest.

Among patients on tumor necrosis factor inhibitors (TNFi) or methotrexate who developed COVID-19, death and hospitalization rates were similar to matched COVID-19 patients not on those medications, according to authors of the multicenter research network study.

Reassuringly, likelihood of hospitalization and mortality were not significantly different between 214 patients with COVID-19 taking TNFi or methotrexate and 31,862 matched COVID-19 patients not on those medications, according to the investigators, whose findings were published recently in the Journal of the American Academy of Dermatology.

Zachary Zinn, MD, corresponding author on the study, said in an interview that the findings suggest these medicines can be safely continued in the majority of patients taking them during the COVID-19 pandemic.

“If you’re a prescribing physician who’s giving patients TNF inhibitors or methotrexate or both, I think you can comfortably tell your patients there is good data that these do not lead to worse outcomes if you get COVID-19,” said Dr. Zinn, associate professor in the department of dermatology at West Virginia University, Morgantown.

The findings from these researchers corroborate a growing body of evidence suggesting that immunosuppressive treatments can be continued in patients with dermatologic and rheumatic conditions.

In recent guidance from the National Psoriasis Foundation, released Sept. 4, an expert consensus panel cited 15 studies that they said suggested that treatments for psoriasis or psoriatic arthritis “do not meaningfully alter the risk of acquiring SARS-CoV-2 infection or having worse COVID-19 outcomes.”

That said, the data to date are mainly from small case series and registry studies based on spontaneously reported COVID-19 cases, which suggests a continued need for shared decision making. In addition, chronic systemic corticosteroids should be avoided for management of psoriatic arthritis, the guidance states, based on rheumatology and gastroenterology literature suggesting this treatment is linked to worse COVID-19 outcomes.

In the interview, Dr. Zinn noted that some previous studies of immunosuppressive treatments in patients who acquire COVID-19 have aggregated data on numerous classes of biologic medications, lessening the strength of data for each specific medication.

“By focusing specifically on TNF inhibitors and methotrexate, this study gives better guidance to prescribers of these medications,” he said.

To see whether TNFi or methotrexate increased risk of worsened COVID-19 outcomes, Dr. Zinn and coinvestigators evaluated data from TriNetX, a research network that includes approximately 53 million unique patient records, predominantly in the United States.

They identified 32,076 adult patients with COVID-19, of whom 214 had recent exposure to TNFi or methotrexate. The patients in the TNFi/methotrexate group were similar in age to those without exposure to those drugs, at 55.1 versus 53.2 years, respectively. However, patients in the drug exposure group were more frequently White, female, and had substantially more comorbidities, including diabetes and obesity, according to the investigators.

Nevertheless, the likelihood of hospitalization was not statistically different in the TNFi/methotrexate group versus the non-TNFi/methotrexate group, with a risk ratio of 0.91 (95% confidence interval, 0.68-1.22; P = .5260).

Likewise, the likelihood of death was not different between groups, with a RR of 0.87 (95% CI, 0.42-1.78; P = .6958). Looking at subgroups of patients exposed to TNFi or methotrexate only didn’t change the results, the investigators added.

Taken together, the findings argue against interruption of these treatments because of the fear of the possibly worse COVID-19 outcomes, the investigators concluded, although they emphasized the need for more research.

“Because the COVID-19 pandemic is ongoing, there is a desperate need for evidence-based data on biologic and immunomodulator exposure in the setting of COVID-19 infection,” they wrote.

Dr. Zinn and coauthors reported no conflicts of interest and no funding sources related to the study.

SOURCE: Zinn Z et al. J Am Acad Dermatol. 2020 Sep 11. doi: 10.1016/j.jaad.2020.09.009.

Continued use of tumor necrosis factor inhibitors or methotrexate is acceptable in most patients who acquire COVID-19, results of a recent cohort study suggest.

Among patients on tumor necrosis factor inhibitors (TNFi) or methotrexate who developed COVID-19, death and hospitalization rates were similar to matched COVID-19 patients not on those medications, according to authors of the multicenter research network study.

Reassuringly, likelihood of hospitalization and mortality were not significantly different between 214 patients with COVID-19 taking TNFi or methotrexate and 31,862 matched COVID-19 patients not on those medications, according to the investigators, whose findings were published recently in the Journal of the American Academy of Dermatology.

Zachary Zinn, MD, corresponding author on the study, said in an interview that the findings suggest these medicines can be safely continued in the majority of patients taking them during the COVID-19 pandemic.

“If you’re a prescribing physician who’s giving patients TNF inhibitors or methotrexate or both, I think you can comfortably tell your patients there is good data that these do not lead to worse outcomes if you get COVID-19,” said Dr. Zinn, associate professor in the department of dermatology at West Virginia University, Morgantown.

The findings from these researchers corroborate a growing body of evidence suggesting that immunosuppressive treatments can be continued in patients with dermatologic and rheumatic conditions.

In recent guidance from the National Psoriasis Foundation, released Sept. 4, an expert consensus panel cited 15 studies that they said suggested that treatments for psoriasis or psoriatic arthritis “do not meaningfully alter the risk of acquiring SARS-CoV-2 infection or having worse COVID-19 outcomes.”

That said, the data to date are mainly from small case series and registry studies based on spontaneously reported COVID-19 cases, which suggests a continued need for shared decision making. In addition, chronic systemic corticosteroids should be avoided for management of psoriatic arthritis, the guidance states, based on rheumatology and gastroenterology literature suggesting this treatment is linked to worse COVID-19 outcomes.

In the interview, Dr. Zinn noted that some previous studies of immunosuppressive treatments in patients who acquire COVID-19 have aggregated data on numerous classes of biologic medications, lessening the strength of data for each specific medication.

“By focusing specifically on TNF inhibitors and methotrexate, this study gives better guidance to prescribers of these medications,” he said.

To see whether TNFi or methotrexate increased risk of worsened COVID-19 outcomes, Dr. Zinn and coinvestigators evaluated data from TriNetX, a research network that includes approximately 53 million unique patient records, predominantly in the United States.

They identified 32,076 adult patients with COVID-19, of whom 214 had recent exposure to TNFi or methotrexate. The patients in the TNFi/methotrexate group were similar in age to those without exposure to those drugs, at 55.1 versus 53.2 years, respectively. However, patients in the drug exposure group were more frequently White, female, and had substantially more comorbidities, including diabetes and obesity, according to the investigators.

Nevertheless, the likelihood of hospitalization was not statistically different in the TNFi/methotrexate group versus the non-TNFi/methotrexate group, with a risk ratio of 0.91 (95% confidence interval, 0.68-1.22; P = .5260).

Likewise, the likelihood of death was not different between groups, with a RR of 0.87 (95% CI, 0.42-1.78; P = .6958). Looking at subgroups of patients exposed to TNFi or methotrexate only didn’t change the results, the investigators added.

Taken together, the findings argue against interruption of these treatments because of the fear of the possibly worse COVID-19 outcomes, the investigators concluded, although they emphasized the need for more research.

“Because the COVID-19 pandemic is ongoing, there is a desperate need for evidence-based data on biologic and immunomodulator exposure in the setting of COVID-19 infection,” they wrote.

Dr. Zinn and coauthors reported no conflicts of interest and no funding sources related to the study.

SOURCE: Zinn Z et al. J Am Acad Dermatol. 2020 Sep 11. doi: 10.1016/j.jaad.2020.09.009.

Continued use of tumor necrosis factor inhibitors or methotrexate is acceptable in most patients who acquire COVID-19, results of a recent cohort study suggest.

Among patients on tumor necrosis factor inhibitors (TNFi) or methotrexate who developed COVID-19, death and hospitalization rates were similar to matched COVID-19 patients not on those medications, according to authors of the multicenter research network study.

Reassuringly, likelihood of hospitalization and mortality were not significantly different between 214 patients with COVID-19 taking TNFi or methotrexate and 31,862 matched COVID-19 patients not on those medications, according to the investigators, whose findings were published recently in the Journal of the American Academy of Dermatology.

Zachary Zinn, MD, corresponding author on the study, said in an interview that the findings suggest these medicines can be safely continued in the majority of patients taking them during the COVID-19 pandemic.

“If you’re a prescribing physician who’s giving patients TNF inhibitors or methotrexate or both, I think you can comfortably tell your patients there is good data that these do not lead to worse outcomes if you get COVID-19,” said Dr. Zinn, associate professor in the department of dermatology at West Virginia University, Morgantown.

The findings from these researchers corroborate a growing body of evidence suggesting that immunosuppressive treatments can be continued in patients with dermatologic and rheumatic conditions.

In recent guidance from the National Psoriasis Foundation, released Sept. 4, an expert consensus panel cited 15 studies that they said suggested that treatments for psoriasis or psoriatic arthritis “do not meaningfully alter the risk of acquiring SARS-CoV-2 infection or having worse COVID-19 outcomes.”

That said, the data to date are mainly from small case series and registry studies based on spontaneously reported COVID-19 cases, which suggests a continued need for shared decision making. In addition, chronic systemic corticosteroids should be avoided for management of psoriatic arthritis, the guidance states, based on rheumatology and gastroenterology literature suggesting this treatment is linked to worse COVID-19 outcomes.

In the interview, Dr. Zinn noted that some previous studies of immunosuppressive treatments in patients who acquire COVID-19 have aggregated data on numerous classes of biologic medications, lessening the strength of data for each specific medication.

“By focusing specifically on TNF inhibitors and methotrexate, this study gives better guidance to prescribers of these medications,” he said.

To see whether TNFi or methotrexate increased risk of worsened COVID-19 outcomes, Dr. Zinn and coinvestigators evaluated data from TriNetX, a research network that includes approximately 53 million unique patient records, predominantly in the United States.

They identified 32,076 adult patients with COVID-19, of whom 214 had recent exposure to TNFi or methotrexate. The patients in the TNFi/methotrexate group were similar in age to those without exposure to those drugs, at 55.1 versus 53.2 years, respectively. However, patients in the drug exposure group were more frequently White, female, and had substantially more comorbidities, including diabetes and obesity, according to the investigators.

Nevertheless, the likelihood of hospitalization was not statistically different in the TNFi/methotrexate group versus the non-TNFi/methotrexate group, with a risk ratio of 0.91 (95% confidence interval, 0.68-1.22; P = .5260).

Likewise, the likelihood of death was not different between groups, with a RR of 0.87 (95% CI, 0.42-1.78; P = .6958). Looking at subgroups of patients exposed to TNFi or methotrexate only didn’t change the results, the investigators added.

Taken together, the findings argue against interruption of these treatments because of the fear of the possibly worse COVID-19 outcomes, the investigators concluded, although they emphasized the need for more research.

“Because the COVID-19 pandemic is ongoing, there is a desperate need for evidence-based data on biologic and immunomodulator exposure in the setting of COVID-19 infection,” they wrote.

Dr. Zinn and coauthors reported no conflicts of interest and no funding sources related to the study.

SOURCE: Zinn Z et al. J Am Acad Dermatol. 2020 Sep 11. doi: 10.1016/j.jaad.2020.09.009.

Direct-to-consumer (DTC) advertisements are an important and influential source of health-related information for Americans. In 1997, the US Food and Drug Administration (FDA) relaxed regulations and permitted DTC drug advertisements to be televised. Now, via television alone, the average American is exposed to more than 30 hours annually of DTC advertisements for drugs,¹ which exceeds, by far, the amount of time the average American spends with his/her physician.² The United States spends $9.6 billion on DTC advertisements per year, of which $605 million is spent exclusively on DTC advertisements for dermatologic conditions—one of the highest amounts of spending for DTC advertisements, second only to diabetes.³

The increase in advertising for dermatologic conditions is reflective of the rapid growth in the number of treatment options available for chronic skin diseases, especially psoriasis. Since 2004, 11 biologics and 1 oral medication were FDA approved for the treatment of moderate to severe psoriasis. Despite the expansion of treatment options for psoriasis, knowledge and understanding of psoriasis and its treatments generally are poor,^4,5 and undertreatment of psoriasis continues to be common.⁶ Data also suggest existing age and racial disparities in psoriasis treatment in the United States, whereby patients who are older or Black are less likely to receive biologic therapies.^7-9 Although the exact causes of these disparities remain unclear, one study found that Black patients with psoriasis were less familiar with biologics compared to White patients,¹⁰ which suggests that the racial disparity in biologic treatment of psoriasis could be due to less exposure to and thus recognition of biologics as treatments of psoriasis among Black patients.

Some data suggest that DTC advertisements may affect drug uptake by encouraging patients to request advertised medications from their medical providers.^11,12 As such, DTC advertisements are a potentially important source of exposure and information for patients. However, is it possible that DTC advertisements also may contribute to widening knowledge gaps among certain populations, and thus treatment disparities, by neglecting certain groups and targeting others with their content? In an effort to answer this question, we performed an analysis of DTC advertisements for psoriasis and eczema with special attention to advertisement placement, character representation, and disease-related content. We specifically targeted advertisements for psoriasis and eczema, as advertisements for the former are rampant and advertisements for the latter are on the rise because of emerging therapies. We hypothesized that age and racial/ethnic diversity among advertisement characters is poor, and disease-related content is lacking.

Materials and Methods

Study Design and Sample
We performed a cross-sectional analysis of televised DTC advertisements for psoriasis and eczema over 14 consecutive days (July 1, 2018, to July 14, 2018). We accessed Nielsen’s top 10 lists, specifically Prime Broadcast Network TV-United States and Prime Broadcast Programs Among African-American, from June 2018 and identified the networks with the greatest potential exposure to American consumers: ABC, CBS, FOX, and NBC.^13,14 Each day, programming aired from 5 pm to 11 pm EST was recorded on a random selection of 2 of 4 listed networks. No pair of networks was recorded for 2 consecutive days, and each day of the week was represented for each network.

The FDA identifies DTC advertisement types as product-claim, reminder, and help-seeking advertisements. Product-claim advertisements are required to include the following information for the drug of interest: name; at least 1 FDA-approved indication; the most notable risks; and reference to a toll-free telephone number, website, or print advertisement by which a detailed summary of risks and benefits can be accessed. Reminder advertisements include the name of the drug but no information about the drug’s use.¹⁵ Help-seeking advertisements describe a disease or condition without referencing a specific drug treatment. Product-claim, reminder, and help-seeking advertisements for psoriasis or eczema that aired during the recorded time frame were included for analysis; advertisements that aired during sporting events and special programming were excluded.

DTC Advertisement Coding
Advertisement placement (ie, network, day of the week, time, associated television program), type, and target disease were documented for all advertisements included in the study. The content of each unique advertisement for psoriasis and eczema also was documented electronically in REDCap (Research Electronic Data Capture) as follows: characteristics of affected individuals and disease-related content. Advertisement coding was performed independently by 2 graduate students (A.H. and C.W.). First, one-third of the advertisements were randomly selected to be coded by both students. Intercoder agreement between the 2 students was 95.3%. Coding disagreements were primarily due to misunderstanding of definitions and were resolved through consensus. Subsequently, the remaining advertisements were randomly distributed between the 2 students, and each advertisement was coded by 1 student.

Statistical Analysis
All data were summarized descriptively with counts and frequencies using Stata 15 (StataCorp).

Results

We identified 297 DTC advertisements addressing 25 different conditions during our study period. CBS, ABC, NBC, and FOX aired 44.4%, 26.3%, 24.4%, and 5.1% of advertisements, respectively. Overall, DTC advertisements were least likely to air on Saturdays and between the hours of 5 pm and 6 pm on any day. Product-claim advertisements accounted for 83.2% of DTC advertisements, 15.8% were help-seeking advertisements, and the remaining 1.0% were reminder advertisements. Advertisements for skin conditions represented 16.5% (n=49) of all DTC advertisements, of which 81.6% (n=40) were for psoriasis or eczema, while the other 18.4% (n=9) were for hyperhidrosis. In total, 13 advertisements for psoriasis and 27 advertisements for eczema were aired during the study period.

Psoriasis DTC Advertisements
There were 5 unique psoriasis DTC advertisements, all of which were product-claim advertisements, with 1 each for secukinumab (Cosentyx [Novartis]), ixekizumab (Taltz [Eli Lilly and Company]), and guselkumab (Tremfya [Janssen Biotech, Inc]), and 2 for adalimumab (Humira [AbbVie Inc]). The advertisements aired on ABC (n=5 [38.5%]), CBS (n=5 [38.5%]), and NBC (n=3 [23.1%]). Most advertisements aired on weekdays (61.5%) between 6 pm and 7 pm (69.2%) and during news programming (69.2%).

Psoriasis Character Portrayal and Disease-Related Content
We identified 81 main characters who were depicted as having psoriasis among all advertisements. Characteristics of the affected characters are summarized in the Table. All affected characters were perceived to be younger adults, and there was a slight female predominance (58.0% [47/81]). Most characters were perceived to be White (92.6% [75/81]). Black and Asian characters only represented 6.2% (5/81) and 1.2% (1/81) of all affected individuals, respectively. Notably, the advertisements that featured only White main characters were aired 2.75 times more frequently than the advertisements that included non-White characters.

Skin manifestations of eczema were portrayed on at least 1 character in all of the advertisements; 77.8% (21/27) of the advertisements had at least 1 obvious depiction. Symptoms of eczema and the mechanism of disease (pathophysiology) were each included in 44.4% (12/27) of advertisements. This information was included exclusively in the single help-seeking advertisement, which also referenced a website for additional disease-related information. No advertisements included information on the epidemiology of, risk factors for, or comorbid diseases associated with eczema.

Comment

In our study of televised DTC advertisements for psoriasis and eczema in the United States, we identified underrepresentation of racial/ethnic minorities and specific age groups (older adults for psoriasis and all adults for eczema) across all advertisements. Although psoriasis is suggested to be less prevalent among minority patients (1.3%–1.9% among Black patients and 1.6% among Hispanic patients) compared to White patients (2%–4%),^16,17 minority vs White representation in psoriasis DTC advertisements was disproportionately lower than population-based prevalence estimates. Direct-to-consumer advertisements for eczema included more minority characters than psoriasis advertisements; however, minority representation remained inadequate considering that childhood eczema is more prevalent among Black vs White children,¹⁸ and adult eczema is at least as prevalent among minority patients compared to White patients.¹⁹ Not only was minority representation in all advertisements poor, but advertisement placement also was suboptimal, particularly for reaching Black viewers. FOX network was home to 2 of the top 3 primetime broadcast programs among Black viewers around the study period,¹³ yet no DTC advertisements were aired on FOX. Together, our findings suggest inadequate patient reach of psoriasis and eczema DTC advertisements that, particularly in the case of psoriasis, mirror and may reinforce existing age and racial disparities in treatment^5-7 and poor familiarity with biologics.¹⁰ A similar impact of eczema DTC advertisements on emerging eczema treatment patterns and potential treatment disparities also might be anticipated and is of concern.

The current literature regarding minority representation in DTC advertisements is mixed. Some studies report underrepresentation of Black and other minority patients across a variety of diseases.²⁰ Other studies suggest that representation of Black patients, in particular, generally is adequate, except among select serious health conditions, and that advertisements depict tokenism or stereotypical roles for minorities.²¹ Our study provides new and specific insight about the state of racial/ethnic and age diversity, or lack thereof, in DTC advertisements for the skin conditions that currently are most commonly targeted—psoriasis and eczema. Although it remains unclear whether DTC advertisements are good or bad, existing data suggest that potential benefits of DTC advertisements include strengthening of patient-provider relationships, reduction of underdiagnosis and undertreatment of disease, and reduction of disease stigma.²² However, in our analyses, we found disease-specific factual content among all DTC advertisements to be sparse and obvious depictions of skin disease and symptoms to be uncommon, especially for psoriasis. As such, it seems unlikely that existing DTC advertisements for psoriasis and eczema can be expected to contribute to meaningful disease education, reduce underdiagnosis, and reduce the stigmatizing attitudes that have been documented for both skin diseases.^23-25

Furthermore, it is important to consider our findings in light of the role that social identity theory plays in marketing. Social identity theory supports the idea that a person’s social identity (eg, age, gender, race/ethnicity) influences his/her behavior, perceptions, and performance.²⁶ The principle of homophily—the tendency for individuals to have positive ties to those who are similar to themselves—is a critical concept in social identity theory and suggests that consumers are more likely to pay attention to and be influenced by sources perceived as similar to themselves.²⁰ Thus, even if the potential benefits of DTC advertisements were to be realized for psoriasis and eczema, the lack of adequate minority and older adult representation raises concerns about whether these benefits would reach a diverse population and if the advertisements might further potentiate existing knowledge and treatment disparities.

Limitations
Our study is not without limitations. The sampling period was short and might not reflect advertisement content over a longer time course. We did not evaluate other potential sources of information, such as the Internet and social media. Nevertheless, televised DTC advertisements remain a major source of medical and drug information for the general public. We did not directly evaluate viewers’ reactions to the DTC advertisements of interest; however, other literature lends support to the significance of social identity theory and its impact on consumer behavior.²⁶

Conclusion

Our study highlights a lost opportunity among psoriasis and eczema DTC advertisements for patient reach and disease education that may encourage existing and emerging knowledge and treatment disparities for both conditions. Our findings should serve as a call to action to pharmaceutical companies and other organizations involved in creating and supporting DTC advertisements for psoriasis and eczema to increase the educational content, diversify the depicted characters, and optimize advertisement placement.

Direct-to-consumer (DTC) advertisements are an important and influential source of health-related information for Americans. In 1997, the US Food and Drug Administration (FDA) relaxed regulations and permitted DTC drug advertisements to be televised. Now, via television alone, the average American is exposed to more than 30 hours annually of DTC advertisements for drugs,¹ which exceeds, by far, the amount of time the average American spends with his/her physician.² The United States spends $9.6 billion on DTC advertisements per year, of which $605 million is spent exclusively on DTC advertisements for dermatologic conditions—one of the highest amounts of spending for DTC advertisements, second only to diabetes.³

The increase in advertising for dermatologic conditions is reflective of the rapid growth in the number of treatment options available for chronic skin diseases, especially psoriasis. Since 2004, 11 biologics and 1 oral medication were FDA approved for the treatment of moderate to severe psoriasis. Despite the expansion of treatment options for psoriasis, knowledge and understanding of psoriasis and its treatments generally are poor,^4,5 and undertreatment of psoriasis continues to be common.⁶ Data also suggest existing age and racial disparities in psoriasis treatment in the United States, whereby patients who are older or Black are less likely to receive biologic therapies.^7-9 Although the exact causes of these disparities remain unclear, one study found that Black patients with psoriasis were less familiar with biologics compared to White patients,¹⁰ which suggests that the racial disparity in biologic treatment of psoriasis could be due to less exposure to and thus recognition of biologics as treatments of psoriasis among Black patients.

Some data suggest that DTC advertisements may affect drug uptake by encouraging patients to request advertised medications from their medical providers.^11,12 As such, DTC advertisements are a potentially important source of exposure and information for patients. However, is it possible that DTC advertisements also may contribute to widening knowledge gaps among certain populations, and thus treatment disparities, by neglecting certain groups and targeting others with their content? In an effort to answer this question, we performed an analysis of DTC advertisements for psoriasis and eczema with special attention to advertisement placement, character representation, and disease-related content. We specifically targeted advertisements for psoriasis and eczema, as advertisements for the former are rampant and advertisements for the latter are on the rise because of emerging therapies. We hypothesized that age and racial/ethnic diversity among advertisement characters is poor, and disease-related content is lacking.

Materials and Methods

Study Design and Sample
We performed a cross-sectional analysis of televised DTC advertisements for psoriasis and eczema over 14 consecutive days (July 1, 2018, to July 14, 2018). We accessed Nielsen’s top 10 lists, specifically Prime Broadcast Network TV-United States and Prime Broadcast Programs Among African-American, from June 2018 and identified the networks with the greatest potential exposure to American consumers: ABC, CBS, FOX, and NBC.^13,14 Each day, programming aired from 5 pm to 11 pm EST was recorded on a random selection of 2 of 4 listed networks. No pair of networks was recorded for 2 consecutive days, and each day of the week was represented for each network.

The FDA identifies DTC advertisement types as product-claim, reminder, and help-seeking advertisements. Product-claim advertisements are required to include the following information for the drug of interest: name; at least 1 FDA-approved indication; the most notable risks; and reference to a toll-free telephone number, website, or print advertisement by which a detailed summary of risks and benefits can be accessed. Reminder advertisements include the name of the drug but no information about the drug’s use.¹⁵ Help-seeking advertisements describe a disease or condition without referencing a specific drug treatment. Product-claim, reminder, and help-seeking advertisements for psoriasis or eczema that aired during the recorded time frame were included for analysis; advertisements that aired during sporting events and special programming were excluded.

DTC Advertisement Coding
Advertisement placement (ie, network, day of the week, time, associated television program), type, and target disease were documented for all advertisements included in the study. The content of each unique advertisement for psoriasis and eczema also was documented electronically in REDCap (Research Electronic Data Capture) as follows: characteristics of affected individuals and disease-related content. Advertisement coding was performed independently by 2 graduate students (A.H. and C.W.). First, one-third of the advertisements were randomly selected to be coded by both students. Intercoder agreement between the 2 students was 95.3%. Coding disagreements were primarily due to misunderstanding of definitions and were resolved through consensus. Subsequently, the remaining advertisements were randomly distributed between the 2 students, and each advertisement was coded by 1 student.

Statistical Analysis
All data were summarized descriptively with counts and frequencies using Stata 15 (StataCorp).

Results

We identified 297 DTC advertisements addressing 25 different conditions during our study period. CBS, ABC, NBC, and FOX aired 44.4%, 26.3%, 24.4%, and 5.1% of advertisements, respectively. Overall, DTC advertisements were least likely to air on Saturdays and between the hours of 5 pm and 6 pm on any day. Product-claim advertisements accounted for 83.2% of DTC advertisements, 15.8% were help-seeking advertisements, and the remaining 1.0% were reminder advertisements. Advertisements for skin conditions represented 16.5% (n=49) of all DTC advertisements, of which 81.6% (n=40) were for psoriasis or eczema, while the other 18.4% (n=9) were for hyperhidrosis. In total, 13 advertisements for psoriasis and 27 advertisements for eczema were aired during the study period.

Psoriasis DTC Advertisements
There were 5 unique psoriasis DTC advertisements, all of which were product-claim advertisements, with 1 each for secukinumab (Cosentyx [Novartis]), ixekizumab (Taltz [Eli Lilly and Company]), and guselkumab (Tremfya [Janssen Biotech, Inc]), and 2 for adalimumab (Humira [AbbVie Inc]). The advertisements aired on ABC (n=5 [38.5%]), CBS (n=5 [38.5%]), and NBC (n=3 [23.1%]). Most advertisements aired on weekdays (61.5%) between 6 pm and 7 pm (69.2%) and during news programming (69.2%).

Psoriasis Character Portrayal and Disease-Related Content
We identified 81 main characters who were depicted as having psoriasis among all advertisements. Characteristics of the affected characters are summarized in the Table. All affected characters were perceived to be younger adults, and there was a slight female predominance (58.0% [47/81]). Most characters were perceived to be White (92.6% [75/81]). Black and Asian characters only represented 6.2% (5/81) and 1.2% (1/81) of all affected individuals, respectively. Notably, the advertisements that featured only White main characters were aired 2.75 times more frequently than the advertisements that included non-White characters.

Skin manifestations of eczema were portrayed on at least 1 character in all of the advertisements; 77.8% (21/27) of the advertisements had at least 1 obvious depiction. Symptoms of eczema and the mechanism of disease (pathophysiology) were each included in 44.4% (12/27) of advertisements. This information was included exclusively in the single help-seeking advertisement, which also referenced a website for additional disease-related information. No advertisements included information on the epidemiology of, risk factors for, or comorbid diseases associated with eczema.

Comment

In our study of televised DTC advertisements for psoriasis and eczema in the United States, we identified underrepresentation of racial/ethnic minorities and specific age groups (older adults for psoriasis and all adults for eczema) across all advertisements. Although psoriasis is suggested to be less prevalent among minority patients (1.3%–1.9% among Black patients and 1.6% among Hispanic patients) compared to White patients (2%–4%),^16,17 minority vs White representation in psoriasis DTC advertisements was disproportionately lower than population-based prevalence estimates. Direct-to-consumer advertisements for eczema included more minority characters than psoriasis advertisements; however, minority representation remained inadequate considering that childhood eczema is more prevalent among Black vs White children,¹⁸ and adult eczema is at least as prevalent among minority patients compared to White patients.¹⁹ Not only was minority representation in all advertisements poor, but advertisement placement also was suboptimal, particularly for reaching Black viewers. FOX network was home to 2 of the top 3 primetime broadcast programs among Black viewers around the study period,¹³ yet no DTC advertisements were aired on FOX. Together, our findings suggest inadequate patient reach of psoriasis and eczema DTC advertisements that, particularly in the case of psoriasis, mirror and may reinforce existing age and racial disparities in treatment^5-7 and poor familiarity with biologics.¹⁰ A similar impact of eczema DTC advertisements on emerging eczema treatment patterns and potential treatment disparities also might be anticipated and is of concern.

The current literature regarding minority representation in DTC advertisements is mixed. Some studies report underrepresentation of Black and other minority patients across a variety of diseases.²⁰ Other studies suggest that representation of Black patients, in particular, generally is adequate, except among select serious health conditions, and that advertisements depict tokenism or stereotypical roles for minorities.²¹ Our study provides new and specific insight about the state of racial/ethnic and age diversity, or lack thereof, in DTC advertisements for the skin conditions that currently are most commonly targeted—psoriasis and eczema. Although it remains unclear whether DTC advertisements are good or bad, existing data suggest that potential benefits of DTC advertisements include strengthening of patient-provider relationships, reduction of underdiagnosis and undertreatment of disease, and reduction of disease stigma.²² However, in our analyses, we found disease-specific factual content among all DTC advertisements to be sparse and obvious depictions of skin disease and symptoms to be uncommon, especially for psoriasis. As such, it seems unlikely that existing DTC advertisements for psoriasis and eczema can be expected to contribute to meaningful disease education, reduce underdiagnosis, and reduce the stigmatizing attitudes that have been documented for both skin diseases.^23-25

Furthermore, it is important to consider our findings in light of the role that social identity theory plays in marketing. Social identity theory supports the idea that a person’s social identity (eg, age, gender, race/ethnicity) influences his/her behavior, perceptions, and performance.²⁶ The principle of homophily—the tendency for individuals to have positive ties to those who are similar to themselves—is a critical concept in social identity theory and suggests that consumers are more likely to pay attention to and be influenced by sources perceived as similar to themselves.²⁰ Thus, even if the potential benefits of DTC advertisements were to be realized for psoriasis and eczema, the lack of adequate minority and older adult representation raises concerns about whether these benefits would reach a diverse population and if the advertisements might further potentiate existing knowledge and treatment disparities.

Limitations
Our study is not without limitations. The sampling period was short and might not reflect advertisement content over a longer time course. We did not evaluate other potential sources of information, such as the Internet and social media. Nevertheless, televised DTC advertisements remain a major source of medical and drug information for the general public. We did not directly evaluate viewers’ reactions to the DTC advertisements of interest; however, other literature lends support to the significance of social identity theory and its impact on consumer behavior.²⁶

Conclusion

Our study highlights a lost opportunity among psoriasis and eczema DTC advertisements for patient reach and disease education that may encourage existing and emerging knowledge and treatment disparities for both conditions. Our findings should serve as a call to action to pharmaceutical companies and other organizations involved in creating and supporting DTC advertisements for psoriasis and eczema to increase the educational content, diversify the depicted characters, and optimize advertisement placement.

Direct-to-consumer (DTC) advertisements are an important and influential source of health-related information for Americans. In 1997, the US Food and Drug Administration (FDA) relaxed regulations and permitted DTC drug advertisements to be televised. Now, via television alone, the average American is exposed to more than 30 hours annually of DTC advertisements for drugs,¹ which exceeds, by far, the amount of time the average American spends with his/her physician.² The United States spends $9.6 billion on DTC advertisements per year, of which $605 million is spent exclusively on DTC advertisements for dermatologic conditions—one of the highest amounts of spending for DTC advertisements, second only to diabetes.³

The increase in advertising for dermatologic conditions is reflective of the rapid growth in the number of treatment options available for chronic skin diseases, especially psoriasis. Since 2004, 11 biologics and 1 oral medication were FDA approved for the treatment of moderate to severe psoriasis. Despite the expansion of treatment options for psoriasis, knowledge and understanding of psoriasis and its treatments generally are poor,^4,5 and undertreatment of psoriasis continues to be common.⁶ Data also suggest existing age and racial disparities in psoriasis treatment in the United States, whereby patients who are older or Black are less likely to receive biologic therapies.^7-9 Although the exact causes of these disparities remain unclear, one study found that Black patients with psoriasis were less familiar with biologics compared to White patients,¹⁰ which suggests that the racial disparity in biologic treatment of psoriasis could be due to less exposure to and thus recognition of biologics as treatments of psoriasis among Black patients.

Some data suggest that DTC advertisements may affect drug uptake by encouraging patients to request advertised medications from their medical providers.^11,12 As such, DTC advertisements are a potentially important source of exposure and information for patients. However, is it possible that DTC advertisements also may contribute to widening knowledge gaps among certain populations, and thus treatment disparities, by neglecting certain groups and targeting others with their content? In an effort to answer this question, we performed an analysis of DTC advertisements for psoriasis and eczema with special attention to advertisement placement, character representation, and disease-related content. We specifically targeted advertisements for psoriasis and eczema, as advertisements for the former are rampant and advertisements for the latter are on the rise because of emerging therapies. We hypothesized that age and racial/ethnic diversity among advertisement characters is poor, and disease-related content is lacking.

Materials and Methods

Study Design and Sample
We performed a cross-sectional analysis of televised DTC advertisements for psoriasis and eczema over 14 consecutive days (July 1, 2018, to July 14, 2018). We accessed Nielsen’s top 10 lists, specifically Prime Broadcast Network TV-United States and Prime Broadcast Programs Among African-American, from June 2018 and identified the networks with the greatest potential exposure to American consumers: ABC, CBS, FOX, and NBC.^13,14 Each day, programming aired from 5 pm to 11 pm EST was recorded on a random selection of 2 of 4 listed networks. No pair of networks was recorded for 2 consecutive days, and each day of the week was represented for each network.

The FDA identifies DTC advertisement types as product-claim, reminder, and help-seeking advertisements. Product-claim advertisements are required to include the following information for the drug of interest: name; at least 1 FDA-approved indication; the most notable risks; and reference to a toll-free telephone number, website, or print advertisement by which a detailed summary of risks and benefits can be accessed. Reminder advertisements include the name of the drug but no information about the drug’s use.¹⁵ Help-seeking advertisements describe a disease or condition without referencing a specific drug treatment. Product-claim, reminder, and help-seeking advertisements for psoriasis or eczema that aired during the recorded time frame were included for analysis; advertisements that aired during sporting events and special programming were excluded.

DTC Advertisement Coding
Advertisement placement (ie, network, day of the week, time, associated television program), type, and target disease were documented for all advertisements included in the study. The content of each unique advertisement for psoriasis and eczema also was documented electronically in REDCap (Research Electronic Data Capture) as follows: characteristics of affected individuals and disease-related content. Advertisement coding was performed independently by 2 graduate students (A.H. and C.W.). First, one-third of the advertisements were randomly selected to be coded by both students. Intercoder agreement between the 2 students was 95.3%. Coding disagreements were primarily due to misunderstanding of definitions and were resolved through consensus. Subsequently, the remaining advertisements were randomly distributed between the 2 students, and each advertisement was coded by 1 student.

Statistical Analysis
All data were summarized descriptively with counts and frequencies using Stata 15 (StataCorp).

Results

We identified 297 DTC advertisements addressing 25 different conditions during our study period. CBS, ABC, NBC, and FOX aired 44.4%, 26.3%, 24.4%, and 5.1% of advertisements, respectively. Overall, DTC advertisements were least likely to air on Saturdays and between the hours of 5 pm and 6 pm on any day. Product-claim advertisements accounted for 83.2% of DTC advertisements, 15.8% were help-seeking advertisements, and the remaining 1.0% were reminder advertisements. Advertisements for skin conditions represented 16.5% (n=49) of all DTC advertisements, of which 81.6% (n=40) were for psoriasis or eczema, while the other 18.4% (n=9) were for hyperhidrosis. In total, 13 advertisements for psoriasis and 27 advertisements for eczema were aired during the study period.

Psoriasis DTC Advertisements
There were 5 unique psoriasis DTC advertisements, all of which were product-claim advertisements, with 1 each for secukinumab (Cosentyx [Novartis]), ixekizumab (Taltz [Eli Lilly and Company]), and guselkumab (Tremfya [Janssen Biotech, Inc]), and 2 for adalimumab (Humira [AbbVie Inc]). The advertisements aired on ABC (n=5 [38.5%]), CBS (n=5 [38.5%]), and NBC (n=3 [23.1%]). Most advertisements aired on weekdays (61.5%) between 6 pm and 7 pm (69.2%) and during news programming (69.2%).

Psoriasis Character Portrayal and Disease-Related Content
We identified 81 main characters who were depicted as having psoriasis among all advertisements. Characteristics of the affected characters are summarized in the Table. All affected characters were perceived to be younger adults, and there was a slight female predominance (58.0% [47/81]). Most characters were perceived to be White (92.6% [75/81]). Black and Asian characters only represented 6.2% (5/81) and 1.2% (1/81) of all affected individuals, respectively. Notably, the advertisements that featured only White main characters were aired 2.75 times more frequently than the advertisements that included non-White characters.

Skin manifestations of eczema were portrayed on at least 1 character in all of the advertisements; 77.8% (21/27) of the advertisements had at least 1 obvious depiction. Symptoms of eczema and the mechanism of disease (pathophysiology) were each included in 44.4% (12/27) of advertisements. This information was included exclusively in the single help-seeking advertisement, which also referenced a website for additional disease-related information. No advertisements included information on the epidemiology of, risk factors for, or comorbid diseases associated with eczema.

Comment

In our study of televised DTC advertisements for psoriasis and eczema in the United States, we identified underrepresentation of racial/ethnic minorities and specific age groups (older adults for psoriasis and all adults for eczema) across all advertisements. Although psoriasis is suggested to be less prevalent among minority patients (1.3%–1.9% among Black patients and 1.6% among Hispanic patients) compared to White patients (2%–4%),^16,17 minority vs White representation in psoriasis DTC advertisements was disproportionately lower than population-based prevalence estimates. Direct-to-consumer advertisements for eczema included more minority characters than psoriasis advertisements; however, minority representation remained inadequate considering that childhood eczema is more prevalent among Black vs White children,¹⁸ and adult eczema is at least as prevalent among minority patients compared to White patients.¹⁹ Not only was minority representation in all advertisements poor, but advertisement placement also was suboptimal, particularly for reaching Black viewers. FOX network was home to 2 of the top 3 primetime broadcast programs among Black viewers around the study period,¹³ yet no DTC advertisements were aired on FOX. Together, our findings suggest inadequate patient reach of psoriasis and eczema DTC advertisements that, particularly in the case of psoriasis, mirror and may reinforce existing age and racial disparities in treatment^5-7 and poor familiarity with biologics.¹⁰ A similar impact of eczema DTC advertisements on emerging eczema treatment patterns and potential treatment disparities also might be anticipated and is of concern.

The current literature regarding minority representation in DTC advertisements is mixed. Some studies report underrepresentation of Black and other minority patients across a variety of diseases.²⁰ Other studies suggest that representation of Black patients, in particular, generally is adequate, except among select serious health conditions, and that advertisements depict tokenism or stereotypical roles for minorities.²¹ Our study provides new and specific insight about the state of racial/ethnic and age diversity, or lack thereof, in DTC advertisements for the skin conditions that currently are most commonly targeted—psoriasis and eczema. Although it remains unclear whether DTC advertisements are good or bad, existing data suggest that potential benefits of DTC advertisements include strengthening of patient-provider relationships, reduction of underdiagnosis and undertreatment of disease, and reduction of disease stigma.²² However, in our analyses, we found disease-specific factual content among all DTC advertisements to be sparse and obvious depictions of skin disease and symptoms to be uncommon, especially for psoriasis. As such, it seems unlikely that existing DTC advertisements for psoriasis and eczema can be expected to contribute to meaningful disease education, reduce underdiagnosis, and reduce the stigmatizing attitudes that have been documented for both skin diseases.^23-25

Furthermore, it is important to consider our findings in light of the role that social identity theory plays in marketing. Social identity theory supports the idea that a person’s social identity (eg, age, gender, race/ethnicity) influences his/her behavior, perceptions, and performance.²⁶ The principle of homophily—the tendency for individuals to have positive ties to those who are similar to themselves—is a critical concept in social identity theory and suggests that consumers are more likely to pay attention to and be influenced by sources perceived as similar to themselves.²⁰ Thus, even if the potential benefits of DTC advertisements were to be realized for psoriasis and eczema, the lack of adequate minority and older adult representation raises concerns about whether these benefits would reach a diverse population and if the advertisements might further potentiate existing knowledge and treatment disparities.

Limitations
Our study is not without limitations. The sampling period was short and might not reflect advertisement content over a longer time course. We did not evaluate other potential sources of information, such as the Internet and social media. Nevertheless, televised DTC advertisements remain a major source of medical and drug information for the general public. We did not directly evaluate viewers’ reactions to the DTC advertisements of interest; however, other literature lends support to the significance of social identity theory and its impact on consumer behavior.²⁶

Conclusion

Our study highlights a lost opportunity among psoriasis and eczema DTC advertisements for patient reach and disease education that may encourage existing and emerging knowledge and treatment disparities for both conditions. Our findings should serve as a call to action to pharmaceutical companies and other organizations involved in creating and supporting DTC advertisements for psoriasis and eczema to increase the educational content, diversify the depicted characters, and optimize advertisement placement.

With an average age of diagnosis of 28 years, and one of two incidence peaks occurring at 15-30 years, psoriasis affects many women in the midst of their reproductive years. The prospect of pregnancy – or the reality of a surprise pregnancy – drives questions about heritability of the disease in offspring, the impact of the disease on pregnancy outcomes and breastfeeding, and how to best balance risks of treatments with risks of uncontrolled psoriasis and/or psoriatic arthritis (PsA).

shironosov/Getty Images

While answers to these questions are not always clear, discussions about pregnancy and psoriasis management “shouldn’t be scary,” said Jenny E. Murase, MD, a dermatologist who speaks and writes widely about her research and experience with psoriasis and pregnancy. “We have access to information and data and educational resources to [work with] and reassure our patients – we just need to use it. Right now, there’s unnecessary suffering [with some patients unnecessarily stopping all treatment].”

Much has been learned in the past 2 decades about the course of psoriasis in pregnancy, and pregnancy outcomes data on the safety of biologics during pregnancy are increasingly emerging – particularly for tumor necrosis factor (TNF)–alpha inhibitors.

Ideally, since half of all pregnancies are unplanned, the implications of therapeutic options should be discussed with all women with psoriasis who are of reproductive age, whether they are sexually active or not. “The onus is on us to make sure that we’re considering the possibility [that our patient] could become pregnant without consulting us first,” said Dr. Murase, associate professor of dermatology at the University of California, San Francisco, and director of medical consultative dermatology for the Palo Alto Foundation Medical Group in Mountain View, Calif.

Lisa R. Sammaritano, MD, associate professor of clinical medicine at Weill Cornell Medicine and a rheumatologist at the Hospital for Special Surgery, both in New York, urges similar attention for PsA. “Pregnancy is best planned while patients have quiescent disease on pregnancy-compatible medications,” she said. “We encourage [more] rheumatologists to be actively involved in pregnancy planning [in order] to guide therapy.”

The impact of estrogen

Dr. Murase was inspired to study psoriasis and pregnancy in part by a patient she met as a medical student. “She had severe psoriasis covering her body, and she said that the only times her psoriasis cleared was during her three pregnancies,” Dr. Murase recalled. “I wondered: What about the pregnancies resulted in such a substantial reduction of her psoriasis?”

She subsequently led a study, published in 2005, of 47 pregnant and 27 nonpregnant patients with psoriasis. More than half of the patients – 55% – reported improvements in their psoriasis during pregnancy, 21% reported no change, and 23% reported worsening. Among the 16 patients who had 10% or greater psoriatic body surface area (BSA) involvement and reported improvements, lesions decreased by 84%.

In the postpartum period, only 9% reported improvement, 26% reported no change, and 65% reported worsening. The increased BSA values observed 6 weeks postpartum did not exceed those of the first trimester, suggesting a return to the patients’ baseline status.

Earlier and smaller retrospective studies had also shown that approximately half of patients improve during pregnancy, and it was believed that progesterone was most likely responsible for this improvement. Dr. Murase’s study moved the needle in that it examined BSA in pregnancy and the postpartum period. It also turned the spotlight on estrogen: Patients who had higher levels of improvement also had higher levels of estradiol, estrone, and the ratio of estrogen to progesterone. However, there was no correlation between psoriatic change and levels of progesterone.

To promote fetal survival, pregnancy triggers a shift from Th1 cell–mediated immunity – and Th17 immunity – to Th2 immunity. While there’s no proof of a causative effect, increased estrogen appears to play a role in this shift and in the reduced production of Th1 and Th17 cytokines. Psoriasis is believed to be primarily a Th17-mediated disease, with some Th1 involvement, so this down-regulation can result in improved disease status, Dr. Murase said. (A host of other autoimmune diseases categorized as Th1 mediated similarly tend to improve during pregnancy, she added.)

Information on the effect of pregnancy on PsA is “conflicting,” Dr. Sammaritano said. “Some [of a limited number of studies] suggest a beneficial effect as is generally seen for rheumatoid arthritis. Others, however, have found an increased risk of disease activity during pregnancy ... It may be that psoriatic arthritis can be quite variable from patient to patient in its clinical presentation.”

At least one study, Dr. Sammaritano added, “has shown that the arthritis in pregnancy patients with PsA did not improve, compared to control nonpregnant patients, while the psoriasis rash did improve.”

The mixed findings don’t surprise Dr. Murase. “It harder to quantify joint disease in general,” she said. “And during pregnancy, physiologic changes relating to the pregnancy itself can cause discomfort – your joints ache. The numbers [of improved] cases aren’t as high with PsA, but it’s a more complex question.”

In the postpartum period, however, research findings “all suggest an increased risk of flare” of PsA, Dr. Sammaritano said, just as with psoriasis.
 

Assessing risk of treatment

Understanding the immunologic effects of pregnancy on psoriasis and PsA – and appreciating the concept of a hormonal component – is an important part of treatment decision making. So is understanding pregnancy outcomes data.

Researchers have looked at a host of pregnancy outcomes – including congenital malformations, preterm birth, spontaneous abortion, low birth weight, macrosomia, and gestational diabetes and hypertension – in women with psoriasis or psoriasis/PsA, compared with control groups. Some studies have suggested a link between disease activity and pregnancy complications or adverse pregnancy outcomes, “just as a result of having moderate to severe disease,” while others have found no evidence of increased risk, Dr. Murase said.

“It’s a bit unclear and a difficult question to answer; it depends on what study you look at and what data you believe. It would be nice to have some clarity, but basically the jury is still out,” said Dr. Murase, who, with coauthors Alice B. Gottlieb, MD, PhD, of the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, and Caitriona Ryan, MD, of the Blackrock Clinic and Charles Institute of Dermatology, University College Dublin, discussed the pregnancy outcomes data in a recently published review of psoriasis in women.

“In my opinion, because we have therapies that are so low risk and well tolerated, it’s better to make sure that the inflammatory cascade and inflammation created by psoriasis is under control,” she said. “So whether or not the pregnancy itself causes the patient to go into remission, or whether you have to use therapy to help the patient stay in remission, it’s important to control the inflammation.”

Contraindicated in pregnancy are oral psoralen, methotrexate, and acitretin, the latter of which should be avoided for several years before pregnancy and “therefore shouldn’t be used in a woman of childbearing age,” said Dr. Murase. Methotrexate, said Dr. Sammaritano, should generally be stopped 1-3 months prior to conception.

For psoriasis, the therapy that’s “classically considered the safest in pregnancy is UVB light therapy, specifically the 300-nm wavelength of light, which works really well as an anti-inflammatory,” Dr. Murase said. Because of the potential for maternal folate degradation with phototherapy and the long-known association of folate deficiency with neural tube defects, women of childbearing age who are receiving light therapy should take daily folic acid supplementation. (She prescribes a daily prenatal vitamin containing at least 1 mg of folic acid for women who are utilizing light therapy.)

Many topical agents can be used during pregnancy, Dr. Murase said. Topical corticosteroids, she noted, have the most safety-affirming data of any topical medication.

Regarding oral therapies, Dr. Murase recommends against the use of apremilast (Otezla) for her patients. “It’s not contraindicated, but the animal studies don’t look promising, so I don’t use that one in women of childbearing age just in case. There’s just very little data to support the safety of this medication [in pregnancy].”

There are no therapeutic guidelines in the United States for guiding the management of psoriasis in women who are considering pregnancy. In 2012, the medical board of the National Psoriasis Foundation published a review of treatment options for psoriasis in pregnant or lactating women, the “closest thing to guidelines that we’ve had,” said Dr. Murase. (Now almost a decade old, the review addresses TNF inhibitors but does not cover the anti-interleukin agents more recently approved for moderate to severe psoriasis and PsA.)

For treating PsA, rheumatologists now have the American College of Rheumatology’s first guideline for the management of reproductive health in rheumatic and musculoskeletal diseases to reference. The 2020 guideline does not address PsA specifically, but its section on pregnancy and lactation includes recommendations on biologic and other therapies used to treat the disease.

Guidelines aside, physician-patient discussions over drug safety have the potential to be much more meaningful now that drug labels offer clinical summaries, data, and risk summaries regarding potential use in pregnancy. The labels have “more of a narrative, which is a more useful way to counsel patients and make risk-benefit decisions” than the former system of five-letter categories, said Dr. Murase. (The changes were made per the Pregnancy and Lactation Labeling Rule of 2015.)

MothertoBaby, a service of the nonprofit Organization of Teratology Information Specialists, also provides good evidence-based information to physicians and mothers, Dr. Sammaritano noted.

The use of biologic therapies

In a 2017 review of biologic safety for patients with psoriasis during pregnancy, Alexa B. Kimball, MD, MPH, professor of dermatology at Harvard Medical School, Boston; Martina L. Porter, MD, currently with the department of dermatology at Beth Israel Deaconess Medical Center, Boston; and Stephen J. Lockwood, MD, MPH, of the department of dermatology at Harvard Medical School, concluded that an increasing body of literature suggests that biologic agents can be used during pregnancy and breastfeeding. Anti-TNF agents “should be considered over IL-12/23 and IL-17 inhibitors due to the increased availability of long-term data,” they wrote.

“In general,” said Dr. Murase, “there’s more and more data coming out from gastroenterology and rheumatology to reassure patients and prescribing physicians that the TNF-blocker class is likely safe to use in pregnancy,” particularly during the first trimester and early second trimester, when the transport of maternal antibodies across the placenta is “essentially nonexistent.” In the third trimester, the active transport of IgG antibodies increases rapidly.

If possible, said Dr. Sammaritano, who served as lead author of the ACR’s reproductive health guideline, TNF inhibitors “will be stopped prior to the third trimester to avoid [the possibility of] high drug levels in the infant at birth, which raises concern for immunosuppression in the newborn. If disease is very active, however, they can be continued throughout the pregnancy.”

The TNF inhibitor certolizumab pegol (Cimzia) has the advantage of being transported only minimally across the placenta, if at all, she and Dr. Murase both explained. “To be actively carried across, antibodies need what’s called an Fc region for the placenta to grab onto,” Dr. Murase said. Certolizumab – a pegylated anti–binding fragment antibody – lacks this Fc region.

Two recent studies – CRIB and a UCB Pharma safety database analysis – showed “essentially no medication crossing – there were barely detectable levels,” Dr. Murase said. Certolizumab’s label contains this information and other clinical trial data as well as findings from safety database analyses/surveillance registries.

“Before we had much data for the biologics, I’d advise transitioning patients to light therapy from their biologics and a lot of times their psoriasis would improve, but it was more of a dance,” she said. “Now we tend to look at [certolizumab] when they’re of childbearing age and keep them on the treatment. I know that the baby is not being immunosuppressed.”

Consideration of the use of certolizumab when treatment with biologic agents is required throughout the pregnancy is a recommendation included in Dr. Kimball’s 2017 review.

As newer anti-interleukin agents – the IL-12/23 and IL-17 inhibitors – play a growing role in the treatment of psoriasis and PsA, questions loom about their safety profile. Dr. Murase and Dr. Sammaritano are waiting for more data. “In general,” Dr. Sammaritano said, “we recommend stopping them at the time pregnancy is detected, based on a lack of data at this time.”

Small-molecule drugs are also less well studied, she noted. “Because of their low molecular weight, we anticipate they will easily cross the placenta, so we recommend avoiding use during pregnancy until more information is available.”

Postpartum care

The good news, both experts say, is that the vast majority of medications, including biologics, are safe to use during breastfeeding. Methotrexate should be avoided, Dr. Sammaritano pointed out, and the impact of novel small-molecule therapies on breast milk has not been studied.

In her 2019 review of psoriasis in women, Dr. Murase and coauthors wrote that too many dermatologists believe that breastfeeding women should either not be on biologics or are uncertain about biologic use during breastfeeding. However, “biologics are considered compatible for use while breastfeeding due to their large molecular size and the proteolytic environment in the neonatal gastrointestinal tract,” they added.

Counseling and support for breastfeeding is especially important for women with psoriasis, Dr. Murase emphasized. “Breastfeeding is very traumatizing to the skin, and psoriasis can form in skin that’s injured. I have my patients set up an office visit very soon after the pregnancy to make sure they’re doing alright with their breastfeeding and that they’re coating their nipple area with some type of moisturizer and keeping the health of their nipples in good shape.”

Timely reviews of therapy and adjustments are also a priority, she said. “We need to prepare for 6 weeks post partum” when psoriasis will often flare without treatment.

Dr. Murase disclosed that she is a consultant for Dermira, UCB Pharma, Sanofi, Ferndale, and Regeneron. She is also coeditor in chief of the International Journal of Women’s Dermatology. Dr. Sammaritano reported that she has no disclosures relating to the treatment of PsA.

With an average age of diagnosis of 28 years, and one of two incidence peaks occurring at 15-30 years, psoriasis affects many women in the midst of their reproductive years. The prospect of pregnancy – or the reality of a surprise pregnancy – drives questions about heritability of the disease in offspring, the impact of the disease on pregnancy outcomes and breastfeeding, and how to best balance risks of treatments with risks of uncontrolled psoriasis and/or psoriatic arthritis (PsA).

shironosov/Getty Images

While answers to these questions are not always clear, discussions about pregnancy and psoriasis management “shouldn’t be scary,” said Jenny E. Murase, MD, a dermatologist who speaks and writes widely about her research and experience with psoriasis and pregnancy. “We have access to information and data and educational resources to [work with] and reassure our patients – we just need to use it. Right now, there’s unnecessary suffering [with some patients unnecessarily stopping all treatment].”

Much has been learned in the past 2 decades about the course of psoriasis in pregnancy, and pregnancy outcomes data on the safety of biologics during pregnancy are increasingly emerging – particularly for tumor necrosis factor (TNF)–alpha inhibitors.

Ideally, since half of all pregnancies are unplanned, the implications of therapeutic options should be discussed with all women with psoriasis who are of reproductive age, whether they are sexually active or not. “The onus is on us to make sure that we’re considering the possibility [that our patient] could become pregnant without consulting us first,” said Dr. Murase, associate professor of dermatology at the University of California, San Francisco, and director of medical consultative dermatology for the Palo Alto Foundation Medical Group in Mountain View, Calif.

Lisa R. Sammaritano, MD, associate professor of clinical medicine at Weill Cornell Medicine and a rheumatologist at the Hospital for Special Surgery, both in New York, urges similar attention for PsA. “Pregnancy is best planned while patients have quiescent disease on pregnancy-compatible medications,” she said. “We encourage [more] rheumatologists to be actively involved in pregnancy planning [in order] to guide therapy.”

The impact of estrogen

Dr. Murase was inspired to study psoriasis and pregnancy in part by a patient she met as a medical student. “She had severe psoriasis covering her body, and she said that the only times her psoriasis cleared was during her three pregnancies,” Dr. Murase recalled. “I wondered: What about the pregnancies resulted in such a substantial reduction of her psoriasis?”

She subsequently led a study, published in 2005, of 47 pregnant and 27 nonpregnant patients with psoriasis. More than half of the patients – 55% – reported improvements in their psoriasis during pregnancy, 21% reported no change, and 23% reported worsening. Among the 16 patients who had 10% or greater psoriatic body surface area (BSA) involvement and reported improvements, lesions decreased by 84%.

In the postpartum period, only 9% reported improvement, 26% reported no change, and 65% reported worsening. The increased BSA values observed 6 weeks postpartum did not exceed those of the first trimester, suggesting a return to the patients’ baseline status.

Earlier and smaller retrospective studies had also shown that approximately half of patients improve during pregnancy, and it was believed that progesterone was most likely responsible for this improvement. Dr. Murase’s study moved the needle in that it examined BSA in pregnancy and the postpartum period. It also turned the spotlight on estrogen: Patients who had higher levels of improvement also had higher levels of estradiol, estrone, and the ratio of estrogen to progesterone. However, there was no correlation between psoriatic change and levels of progesterone.

To promote fetal survival, pregnancy triggers a shift from Th1 cell–mediated immunity – and Th17 immunity – to Th2 immunity. While there’s no proof of a causative effect, increased estrogen appears to play a role in this shift and in the reduced production of Th1 and Th17 cytokines. Psoriasis is believed to be primarily a Th17-mediated disease, with some Th1 involvement, so this down-regulation can result in improved disease status, Dr. Murase said. (A host of other autoimmune diseases categorized as Th1 mediated similarly tend to improve during pregnancy, she added.)

Information on the effect of pregnancy on PsA is “conflicting,” Dr. Sammaritano said. “Some [of a limited number of studies] suggest a beneficial effect as is generally seen for rheumatoid arthritis. Others, however, have found an increased risk of disease activity during pregnancy ... It may be that psoriatic arthritis can be quite variable from patient to patient in its clinical presentation.”

At least one study, Dr. Sammaritano added, “has shown that the arthritis in pregnancy patients with PsA did not improve, compared to control nonpregnant patients, while the psoriasis rash did improve.”

The mixed findings don’t surprise Dr. Murase. “It harder to quantify joint disease in general,” she said. “And during pregnancy, physiologic changes relating to the pregnancy itself can cause discomfort – your joints ache. The numbers [of improved] cases aren’t as high with PsA, but it’s a more complex question.”

In the postpartum period, however, research findings “all suggest an increased risk of flare” of PsA, Dr. Sammaritano said, just as with psoriasis.
 

Assessing risk of treatment

Understanding the immunologic effects of pregnancy on psoriasis and PsA – and appreciating the concept of a hormonal component – is an important part of treatment decision making. So is understanding pregnancy outcomes data.

Researchers have looked at a host of pregnancy outcomes – including congenital malformations, preterm birth, spontaneous abortion, low birth weight, macrosomia, and gestational diabetes and hypertension – in women with psoriasis or psoriasis/PsA, compared with control groups. Some studies have suggested a link between disease activity and pregnancy complications or adverse pregnancy outcomes, “just as a result of having moderate to severe disease,” while others have found no evidence of increased risk, Dr. Murase said.

“It’s a bit unclear and a difficult question to answer; it depends on what study you look at and what data you believe. It would be nice to have some clarity, but basically the jury is still out,” said Dr. Murase, who, with coauthors Alice B. Gottlieb, MD, PhD, of the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, and Caitriona Ryan, MD, of the Blackrock Clinic and Charles Institute of Dermatology, University College Dublin, discussed the pregnancy outcomes data in a recently published review of psoriasis in women.

“In my opinion, because we have therapies that are so low risk and well tolerated, it’s better to make sure that the inflammatory cascade and inflammation created by psoriasis is under control,” she said. “So whether or not the pregnancy itself causes the patient to go into remission, or whether you have to use therapy to help the patient stay in remission, it’s important to control the inflammation.”

Contraindicated in pregnancy are oral psoralen, methotrexate, and acitretin, the latter of which should be avoided for several years before pregnancy and “therefore shouldn’t be used in a woman of childbearing age,” said Dr. Murase. Methotrexate, said Dr. Sammaritano, should generally be stopped 1-3 months prior to conception.

For psoriasis, the therapy that’s “classically considered the safest in pregnancy is UVB light therapy, specifically the 300-nm wavelength of light, which works really well as an anti-inflammatory,” Dr. Murase said. Because of the potential for maternal folate degradation with phototherapy and the long-known association of folate deficiency with neural tube defects, women of childbearing age who are receiving light therapy should take daily folic acid supplementation. (She prescribes a daily prenatal vitamin containing at least 1 mg of folic acid for women who are utilizing light therapy.)

Many topical agents can be used during pregnancy, Dr. Murase said. Topical corticosteroids, she noted, have the most safety-affirming data of any topical medication.

Regarding oral therapies, Dr. Murase recommends against the use of apremilast (Otezla) for her patients. “It’s not contraindicated, but the animal studies don’t look promising, so I don’t use that one in women of childbearing age just in case. There’s just very little data to support the safety of this medication [in pregnancy].”

There are no therapeutic guidelines in the United States for guiding the management of psoriasis in women who are considering pregnancy. In 2012, the medical board of the National Psoriasis Foundation published a review of treatment options for psoriasis in pregnant or lactating women, the “closest thing to guidelines that we’ve had,” said Dr. Murase. (Now almost a decade old, the review addresses TNF inhibitors but does not cover the anti-interleukin agents more recently approved for moderate to severe psoriasis and PsA.)

For treating PsA, rheumatologists now have the American College of Rheumatology’s first guideline for the management of reproductive health in rheumatic and musculoskeletal diseases to reference. The 2020 guideline does not address PsA specifically, but its section on pregnancy and lactation includes recommendations on biologic and other therapies used to treat the disease.

Guidelines aside, physician-patient discussions over drug safety have the potential to be much more meaningful now that drug labels offer clinical summaries, data, and risk summaries regarding potential use in pregnancy. The labels have “more of a narrative, which is a more useful way to counsel patients and make risk-benefit decisions” than the former system of five-letter categories, said Dr. Murase. (The changes were made per the Pregnancy and Lactation Labeling Rule of 2015.)

MothertoBaby, a service of the nonprofit Organization of Teratology Information Specialists, also provides good evidence-based information to physicians and mothers, Dr. Sammaritano noted.

The use of biologic therapies

In a 2017 review of biologic safety for patients with psoriasis during pregnancy, Alexa B. Kimball, MD, MPH, professor of dermatology at Harvard Medical School, Boston; Martina L. Porter, MD, currently with the department of dermatology at Beth Israel Deaconess Medical Center, Boston; and Stephen J. Lockwood, MD, MPH, of the department of dermatology at Harvard Medical School, concluded that an increasing body of literature suggests that biologic agents can be used during pregnancy and breastfeeding. Anti-TNF agents “should be considered over IL-12/23 and IL-17 inhibitors due to the increased availability of long-term data,” they wrote.

“In general,” said Dr. Murase, “there’s more and more data coming out from gastroenterology and rheumatology to reassure patients and prescribing physicians that the TNF-blocker class is likely safe to use in pregnancy,” particularly during the first trimester and early second trimester, when the transport of maternal antibodies across the placenta is “essentially nonexistent.” In the third trimester, the active transport of IgG antibodies increases rapidly.

If possible, said Dr. Sammaritano, who served as lead author of the ACR’s reproductive health guideline, TNF inhibitors “will be stopped prior to the third trimester to avoid [the possibility of] high drug levels in the infant at birth, which raises concern for immunosuppression in the newborn. If disease is very active, however, they can be continued throughout the pregnancy.”

The TNF inhibitor certolizumab pegol (Cimzia) has the advantage of being transported only minimally across the placenta, if at all, she and Dr. Murase both explained. “To be actively carried across, antibodies need what’s called an Fc region for the placenta to grab onto,” Dr. Murase said. Certolizumab – a pegylated anti–binding fragment antibody – lacks this Fc region.

Two recent studies – CRIB and a UCB Pharma safety database analysis – showed “essentially no medication crossing – there were barely detectable levels,” Dr. Murase said. Certolizumab’s label contains this information and other clinical trial data as well as findings from safety database analyses/surveillance registries.

“Before we had much data for the biologics, I’d advise transitioning patients to light therapy from their biologics and a lot of times their psoriasis would improve, but it was more of a dance,” she said. “Now we tend to look at [certolizumab] when they’re of childbearing age and keep them on the treatment. I know that the baby is not being immunosuppressed.”

Consideration of the use of certolizumab when treatment with biologic agents is required throughout the pregnancy is a recommendation included in Dr. Kimball’s 2017 review.

As newer anti-interleukin agents – the IL-12/23 and IL-17 inhibitors – play a growing role in the treatment of psoriasis and PsA, questions loom about their safety profile. Dr. Murase and Dr. Sammaritano are waiting for more data. “In general,” Dr. Sammaritano said, “we recommend stopping them at the time pregnancy is detected, based on a lack of data at this time.”

Small-molecule drugs are also less well studied, she noted. “Because of their low molecular weight, we anticipate they will easily cross the placenta, so we recommend avoiding use during pregnancy until more information is available.”

Postpartum care

The good news, both experts say, is that the vast majority of medications, including biologics, are safe to use during breastfeeding. Methotrexate should be avoided, Dr. Sammaritano pointed out, and the impact of novel small-molecule therapies on breast milk has not been studied.

In her 2019 review of psoriasis in women, Dr. Murase and coauthors wrote that too many dermatologists believe that breastfeeding women should either not be on biologics or are uncertain about biologic use during breastfeeding. However, “biologics are considered compatible for use while breastfeeding due to their large molecular size and the proteolytic environment in the neonatal gastrointestinal tract,” they added.

Counseling and support for breastfeeding is especially important for women with psoriasis, Dr. Murase emphasized. “Breastfeeding is very traumatizing to the skin, and psoriasis can form in skin that’s injured. I have my patients set up an office visit very soon after the pregnancy to make sure they’re doing alright with their breastfeeding and that they’re coating their nipple area with some type of moisturizer and keeping the health of their nipples in good shape.”

Timely reviews of therapy and adjustments are also a priority, she said. “We need to prepare for 6 weeks post partum” when psoriasis will often flare without treatment.

Dr. Murase disclosed that she is a consultant for Dermira, UCB Pharma, Sanofi, Ferndale, and Regeneron. She is also coeditor in chief of the International Journal of Women’s Dermatology. Dr. Sammaritano reported that she has no disclosures relating to the treatment of PsA.

With an average age of diagnosis of 28 years, and one of two incidence peaks occurring at 15-30 years, psoriasis affects many women in the midst of their reproductive years. The prospect of pregnancy – or the reality of a surprise pregnancy – drives questions about heritability of the disease in offspring, the impact of the disease on pregnancy outcomes and breastfeeding, and how to best balance risks of treatments with risks of uncontrolled psoriasis and/or psoriatic arthritis (PsA).

shironosov/Getty Images

While answers to these questions are not always clear, discussions about pregnancy and psoriasis management “shouldn’t be scary,” said Jenny E. Murase, MD, a dermatologist who speaks and writes widely about her research and experience with psoriasis and pregnancy. “We have access to information and data and educational resources to [work with] and reassure our patients – we just need to use it. Right now, there’s unnecessary suffering [with some patients unnecessarily stopping all treatment].”

Much has been learned in the past 2 decades about the course of psoriasis in pregnancy, and pregnancy outcomes data on the safety of biologics during pregnancy are increasingly emerging – particularly for tumor necrosis factor (TNF)–alpha inhibitors.

Ideally, since half of all pregnancies are unplanned, the implications of therapeutic options should be discussed with all women with psoriasis who are of reproductive age, whether they are sexually active or not. “The onus is on us to make sure that we’re considering the possibility [that our patient] could become pregnant without consulting us first,” said Dr. Murase, associate professor of dermatology at the University of California, San Francisco, and director of medical consultative dermatology for the Palo Alto Foundation Medical Group in Mountain View, Calif.

Lisa R. Sammaritano, MD, associate professor of clinical medicine at Weill Cornell Medicine and a rheumatologist at the Hospital for Special Surgery, both in New York, urges similar attention for PsA. “Pregnancy is best planned while patients have quiescent disease on pregnancy-compatible medications,” she said. “We encourage [more] rheumatologists to be actively involved in pregnancy planning [in order] to guide therapy.”

The impact of estrogen

Dr. Murase was inspired to study psoriasis and pregnancy in part by a patient she met as a medical student. “She had severe psoriasis covering her body, and she said that the only times her psoriasis cleared was during her three pregnancies,” Dr. Murase recalled. “I wondered: What about the pregnancies resulted in such a substantial reduction of her psoriasis?”

She subsequently led a study, published in 2005, of 47 pregnant and 27 nonpregnant patients with psoriasis. More than half of the patients – 55% – reported improvements in their psoriasis during pregnancy, 21% reported no change, and 23% reported worsening. Among the 16 patients who had 10% or greater psoriatic body surface area (BSA) involvement and reported improvements, lesions decreased by 84%.

In the postpartum period, only 9% reported improvement, 26% reported no change, and 65% reported worsening. The increased BSA values observed 6 weeks postpartum did not exceed those of the first trimester, suggesting a return to the patients’ baseline status.

Earlier and smaller retrospective studies had also shown that approximately half of patients improve during pregnancy, and it was believed that progesterone was most likely responsible for this improvement. Dr. Murase’s study moved the needle in that it examined BSA in pregnancy and the postpartum period. It also turned the spotlight on estrogen: Patients who had higher levels of improvement also had higher levels of estradiol, estrone, and the ratio of estrogen to progesterone. However, there was no correlation between psoriatic change and levels of progesterone.

To promote fetal survival, pregnancy triggers a shift from Th1 cell–mediated immunity – and Th17 immunity – to Th2 immunity. While there’s no proof of a causative effect, increased estrogen appears to play a role in this shift and in the reduced production of Th1 and Th17 cytokines. Psoriasis is believed to be primarily a Th17-mediated disease, with some Th1 involvement, so this down-regulation can result in improved disease status, Dr. Murase said. (A host of other autoimmune diseases categorized as Th1 mediated similarly tend to improve during pregnancy, she added.)

Information on the effect of pregnancy on PsA is “conflicting,” Dr. Sammaritano said. “Some [of a limited number of studies] suggest a beneficial effect as is generally seen for rheumatoid arthritis. Others, however, have found an increased risk of disease activity during pregnancy ... It may be that psoriatic arthritis can be quite variable from patient to patient in its clinical presentation.”

At least one study, Dr. Sammaritano added, “has shown that the arthritis in pregnancy patients with PsA did not improve, compared to control nonpregnant patients, while the psoriasis rash did improve.”

The mixed findings don’t surprise Dr. Murase. “It harder to quantify joint disease in general,” she said. “And during pregnancy, physiologic changes relating to the pregnancy itself can cause discomfort – your joints ache. The numbers [of improved] cases aren’t as high with PsA, but it’s a more complex question.”

In the postpartum period, however, research findings “all suggest an increased risk of flare” of PsA, Dr. Sammaritano said, just as with psoriasis.
 

Assessing risk of treatment

Understanding the immunologic effects of pregnancy on psoriasis and PsA – and appreciating the concept of a hormonal component – is an important part of treatment decision making. So is understanding pregnancy outcomes data.

Researchers have looked at a host of pregnancy outcomes – including congenital malformations, preterm birth, spontaneous abortion, low birth weight, macrosomia, and gestational diabetes and hypertension – in women with psoriasis or psoriasis/PsA, compared with control groups. Some studies have suggested a link between disease activity and pregnancy complications or adverse pregnancy outcomes, “just as a result of having moderate to severe disease,” while others have found no evidence of increased risk, Dr. Murase said.

“It’s a bit unclear and a difficult question to answer; it depends on what study you look at and what data you believe. It would be nice to have some clarity, but basically the jury is still out,” said Dr. Murase, who, with coauthors Alice B. Gottlieb, MD, PhD, of the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, and Caitriona Ryan, MD, of the Blackrock Clinic and Charles Institute of Dermatology, University College Dublin, discussed the pregnancy outcomes data in a recently published review of psoriasis in women.

“In my opinion, because we have therapies that are so low risk and well tolerated, it’s better to make sure that the inflammatory cascade and inflammation created by psoriasis is under control,” she said. “So whether or not the pregnancy itself causes the patient to go into remission, or whether you have to use therapy to help the patient stay in remission, it’s important to control the inflammation.”

Contraindicated in pregnancy are oral psoralen, methotrexate, and acitretin, the latter of which should be avoided for several years before pregnancy and “therefore shouldn’t be used in a woman of childbearing age,” said Dr. Murase. Methotrexate, said Dr. Sammaritano, should generally be stopped 1-3 months prior to conception.

For psoriasis, the therapy that’s “classically considered the safest in pregnancy is UVB light therapy, specifically the 300-nm wavelength of light, which works really well as an anti-inflammatory,” Dr. Murase said. Because of the potential for maternal folate degradation with phototherapy and the long-known association of folate deficiency with neural tube defects, women of childbearing age who are receiving light therapy should take daily folic acid supplementation. (She prescribes a daily prenatal vitamin containing at least 1 mg of folic acid for women who are utilizing light therapy.)

Many topical agents can be used during pregnancy, Dr. Murase said. Topical corticosteroids, she noted, have the most safety-affirming data of any topical medication.

Regarding oral therapies, Dr. Murase recommends against the use of apremilast (Otezla) for her patients. “It’s not contraindicated, but the animal studies don’t look promising, so I don’t use that one in women of childbearing age just in case. There’s just very little data to support the safety of this medication [in pregnancy].”

There are no therapeutic guidelines in the United States for guiding the management of psoriasis in women who are considering pregnancy. In 2012, the medical board of the National Psoriasis Foundation published a review of treatment options for psoriasis in pregnant or lactating women, the “closest thing to guidelines that we’ve had,” said Dr. Murase. (Now almost a decade old, the review addresses TNF inhibitors but does not cover the anti-interleukin agents more recently approved for moderate to severe psoriasis and PsA.)

For treating PsA, rheumatologists now have the American College of Rheumatology’s first guideline for the management of reproductive health in rheumatic and musculoskeletal diseases to reference. The 2020 guideline does not address PsA specifically, but its section on pregnancy and lactation includes recommendations on biologic and other therapies used to treat the disease.

Guidelines aside, physician-patient discussions over drug safety have the potential to be much more meaningful now that drug labels offer clinical summaries, data, and risk summaries regarding potential use in pregnancy. The labels have “more of a narrative, which is a more useful way to counsel patients and make risk-benefit decisions” than the former system of five-letter categories, said Dr. Murase. (The changes were made per the Pregnancy and Lactation Labeling Rule of 2015.)

MothertoBaby, a service of the nonprofit Organization of Teratology Information Specialists, also provides good evidence-based information to physicians and mothers, Dr. Sammaritano noted.

The use of biologic therapies

In a 2017 review of biologic safety for patients with psoriasis during pregnancy, Alexa B. Kimball, MD, MPH, professor of dermatology at Harvard Medical School, Boston; Martina L. Porter, MD, currently with the department of dermatology at Beth Israel Deaconess Medical Center, Boston; and Stephen J. Lockwood, MD, MPH, of the department of dermatology at Harvard Medical School, concluded that an increasing body of literature suggests that biologic agents can be used during pregnancy and breastfeeding. Anti-TNF agents “should be considered over IL-12/23 and IL-17 inhibitors due to the increased availability of long-term data,” they wrote.

“In general,” said Dr. Murase, “there’s more and more data coming out from gastroenterology and rheumatology to reassure patients and prescribing physicians that the TNF-blocker class is likely safe to use in pregnancy,” particularly during the first trimester and early second trimester, when the transport of maternal antibodies across the placenta is “essentially nonexistent.” In the third trimester, the active transport of IgG antibodies increases rapidly.

If possible, said Dr. Sammaritano, who served as lead author of the ACR’s reproductive health guideline, TNF inhibitors “will be stopped prior to the third trimester to avoid [the possibility of] high drug levels in the infant at birth, which raises concern for immunosuppression in the newborn. If disease is very active, however, they can be continued throughout the pregnancy.”

The TNF inhibitor certolizumab pegol (Cimzia) has the advantage of being transported only minimally across the placenta, if at all, she and Dr. Murase both explained. “To be actively carried across, antibodies need what’s called an Fc region for the placenta to grab onto,” Dr. Murase said. Certolizumab – a pegylated anti–binding fragment antibody – lacks this Fc region.

Two recent studies – CRIB and a UCB Pharma safety database analysis – showed “essentially no medication crossing – there were barely detectable levels,” Dr. Murase said. Certolizumab’s label contains this information and other clinical trial data as well as findings from safety database analyses/surveillance registries.

“Before we had much data for the biologics, I’d advise transitioning patients to light therapy from their biologics and a lot of times their psoriasis would improve, but it was more of a dance,” she said. “Now we tend to look at [certolizumab] when they’re of childbearing age and keep them on the treatment. I know that the baby is not being immunosuppressed.”

Consideration of the use of certolizumab when treatment with biologic agents is required throughout the pregnancy is a recommendation included in Dr. Kimball’s 2017 review.

As newer anti-interleukin agents – the IL-12/23 and IL-17 inhibitors – play a growing role in the treatment of psoriasis and PsA, questions loom about their safety profile. Dr. Murase and Dr. Sammaritano are waiting for more data. “In general,” Dr. Sammaritano said, “we recommend stopping them at the time pregnancy is detected, based on a lack of data at this time.”

Small-molecule drugs are also less well studied, she noted. “Because of their low molecular weight, we anticipate they will easily cross the placenta, so we recommend avoiding use during pregnancy until more information is available.”

Postpartum care

The good news, both experts say, is that the vast majority of medications, including biologics, are safe to use during breastfeeding. Methotrexate should be avoided, Dr. Sammaritano pointed out, and the impact of novel small-molecule therapies on breast milk has not been studied.

In her 2019 review of psoriasis in women, Dr. Murase and coauthors wrote that too many dermatologists believe that breastfeeding women should either not be on biologics or are uncertain about biologic use during breastfeeding. However, “biologics are considered compatible for use while breastfeeding due to their large molecular size and the proteolytic environment in the neonatal gastrointestinal tract,” they added.

Counseling and support for breastfeeding is especially important for women with psoriasis, Dr. Murase emphasized. “Breastfeeding is very traumatizing to the skin, and psoriasis can form in skin that’s injured. I have my patients set up an office visit very soon after the pregnancy to make sure they’re doing alright with their breastfeeding and that they’re coating their nipple area with some type of moisturizer and keeping the health of their nipples in good shape.”

Timely reviews of therapy and adjustments are also a priority, she said. “We need to prepare for 6 weeks post partum” when psoriasis will often flare without treatment.

Dr. Murase disclosed that she is a consultant for Dermira, UCB Pharma, Sanofi, Ferndale, and Regeneron. She is also coeditor in chief of the International Journal of Women’s Dermatology. Dr. Sammaritano reported that she has no disclosures relating to the treatment of PsA.

About one-third of all patients with psoriasis will develop psoriatic arthritis (PsA), a condition that comes with a host of vague symptoms and no definitive blood test for diagnosis. Prevention trials could help to identify higher-risk groups for PsA, with a goal to catch disease early and improve outcomes. The challenge is finding enough participants in a disease that lacks a clear clinical profile, then tracking them for long periods of time to generate any significant data.

Researchers have been taking several approaches to improve outcomes in PsA, Christopher Ritchlin, MD, MPH, chief of the allergy/immunology and rheumatology division at the University of Rochester (N.Y.), said in an interview. “We are in the process of identifying biomarkers and imaging findings that characterize psoriasis patients at high risk to develop PsA.”

The next step would be to design an interventional trial to treat high-risk patients before they develop musculoskeletal inflammation, with a goal to delay onset, attenuate severity, or completely prevent arthritis. The issue now is “we don’t know which agents would be most effective in this prevention effort,” Dr. Ritchlin said. Biologics that target specific pathways significant in PsA pathogenesis are an appealing prospect. However, “it may be that alternative therapies such as methotrexate or ultraviolet A radiation therapy, for example, may help arrest the development of joint inflammation.”

Underdiagnosis impedes research

Several factors may undermine this important research.

For one, psoriasis patients are often unaware that they have PsA. “Many times they are diagnosed incorrectly by nonspecialists. As a consequence, they do not get access to appropriate medications,” said Lihi Eder, MD, PhD, staff rheumatologist and director of the psoriatic arthritis research program at the University of Toronto’s Women’s College Research Institute.

Courtesy Michael Wong/Women's College Hospital

The condition also lacks a good diagnostic tool, Dr. Eder said. There’s no blood test that identifies this condition in the same manner as RA and lupus, for example. For these conditions, a general practitioner such as a family physician may conduct a blood test, and if positive, refer them to a rheumatologist. Such a system doesn’t exist for PsA. “Instead, nonspecialists are ordering tests and when they’re negative, they assume wrongly that these patients don’t have a rheumatic condition,” she explained.

Many clinicians aren’t that well versed in PsA, although dermatology has taken steps to become better educated. As a result, more dermatologists are referring patients to rheumatologists for PsA. Despite this small step forward, the heterogeneous clinical presentation of this condition makes diagnosis especially difficult. Unlike RA, which presents with inflammation in the joints, PsA can present as back or joint pain, “which makes our life as rheumatologists much more complex,” Dr. Eder said.
 

Defining a risk group

Most experts agree that the presence of psoriasis isn’t sufficient to conduct a prevention trial. Ideally, the goal of a prevention study would be to identify a critical subgroup of psoriasis patients at high risk of developing PsA.

However, this presents a challenging task, Dr. Eder said. Psoriasis is a risk factor for PsA, but most patients with psoriasis won’t actually develop it. Given that there’s an incidence rate of 2.7% a year, “you would need to recruit many hundreds of psoriasis patients and follow them for a long period of time until you have enough events.”

Moving forward with prevention studies calls for a better definition of the PsA risk group, according to Georg Schett, MD, chair of internal medicine in the department of internal medicine, rheumatology, and immunology at Friedrich‐Alexander University, Erlangen, Germany. “That’s very important, because you need to define such a group to make a prevention trial feasible. The whole benefit of such an approach is to catch the disease early, to say that psoriasis is a biomarker that’s linked to psoriatic arthritis.”

Indicators of risk other than psoriasis, such as pain, inflammation seen in ultrasound or MRI, and other specificities of psoriasis, could be used to define a population where interception can take place, Dr. Schett added. Although it’s not always clinically recognized, the combination of pain and structural lesions can be an indicator for developing PsA.

One prospective study he and his colleagues conducted in 114 psoriasis patients cited structural entheseal lesions and low cortical volumetric bone mineral density as risk factors in developing PsA. Keeping these factors in mind, Dr. Schett expects to see more studies in biointervention in these populations, “with the idea to prevent the onset of PsA and also decrease pain and subcutaneous inflammation.”

Researchers are currently working to identify those high-risk patients to include in an interventional trial, Dr. Ritchlin said.

That said, there’s been a great deal of “clinical trial angst” among investigators, Dr. Ritchlin noted. Outcomes in clinical trials for a wide range of biologic agents have not demonstrated significant advances in outcomes, compared with initial studies with anti–tumor necrosis factor–alpha (TNF-alpha) agents 20 years ago.
 

Combination biologics

One approach that’s generated some interest is the use of combination biologics medications. Sequential inhibition of cytokines such as interleukin-17A and TNF-alpha is of interest given their central contribution in joint inflammation and damage. “The challenge here of course is toxicity,” Dr. Ritchlin said. Trials that combined blockade of IL-1 and TNF-alpha in a RA trial years ago resulted in significant adverse events without improving outcomes.

Comparatively, a recent study in The Lancet Rheumatology reported success in using the IL-17A inhibitor secukinumab (Cosentyx) to reduce PsA symptoms. Tested on patients in the FUTURE 2 trial, investigators demonstrated that secukinumab in 300- and 150-mg doses safely reduced PsA signs and symptoms over a period of 5 years. Secukinumab also outperformed the TNF-alpha inhibitor adalimumab in 853 PsA patients in the 52-week, randomized, head-to-head, phase 3b EXCEED study, which was recently reported in The Lancet. Articular outcomes were similar between the two therapies, yet the secukinumab group did markedly better in Psoriasis Area and Severity Index scores, compared with the adalimumab group.

Based on these findings, “I suspect that studies examining the efficacy of combination biologics for treatment of PsA will surface in the near future,” Dr. Ritchlin said.

Yet another approach encompasses the spirit of personalized medicine. Clinicians often treat PsA patients empirically because they lack biomarkers that indicate which drug may be most effective for an individual patient, Dr. Ritchlin said. However, the technologies for investigating specific cell subsets in both the blood and tissues have advanced greatly over the last decade. “I am confident that a more precision medicine–based approach to the diagnosis and treatment of PsA is on the near horizon.”
 

Diet as an intervention

Other research has looked at the strong link between metabolic abnormalities and psoriasis and PsA. Some diets, such as the Mediterranean diet, show promise in improving the metabolic profile of these patients, making it a candidate as a potential intervention to reduce PsA risk. Another strategy would be to focus on limiting calories and promoting weight reduction.

One study in the British Journal of Dermatology looked at the associations between PsA and smoking, alcohol, and body mass index, identifying obesity as an important risk factor. Analyzing more than 90,000 psoriasis cases from the U.K. Clinical Practice Research Datalink between 1998 and 2014, researchers identified 1,409 PsA diagnoses. Among this cohort, researchers found an association between PsA and increased body mass index and moderate drinking. This finding underscores the need to support weight-reduction programs to reduce risk, Dr. Eder and Alexis Ogdie, MD, of the University of Pennsylvania, Philadelphia, wrote in a related editorial.

While observational studies such as this one provide further guidance for interventional trials, confounders can affect results. “Patients who lost weight could have made a positive lifestyle change (e.g., a dietary change) that was associated with the decreased risk for PsA rather than weight loss specifically, or they could have lost weight for unhealthy reasons,” Dr. Eder and Dr. Ogdie explained. Future research could address whether weight loss or other interventional factors may reduce PsA progression.

To make this work, “we would need to select patients that would benefit from diet. Secondly, we’d need to identify what kind of diet would be good for preventing PsA. And we don’t know that yet,” Dr. Eder further elaborated.

As with any prevention trial, the challenge is to follow patients over a long period of time, making sure they comply with the restrictions of the prescribed diet, Dr. Eder noted. “I do think it’s a really exciting type of intervention because it’s something that people are very interested in. There’s little risk of side effects, and it’s not very expensive.”

In other research on weight-loss methods, an observational study from Denmark found that bariatric surgery, especially gastric bypass, reduced the risk of developing PsA. This suggests that weight reduction by itself is important, “although we don’t know that yet,” Dr. Eder said.

A risk model for PsA

Dr. Eder and colleagues have been working on an algorithm that will incorporate clinical information (for example, the presence of nail lesions and the severity of psoriasis) to provide an estimated risk of developing PsA over the next 5 years. Subsequently, this information could be used to identify high-risk psoriasis patients as candidates for a prevention trial.

Other groups are looking at laboratory or imaging biomarkers to help develop PsA prediction models, she said. “Once we have these tools, we can move to next steps of prevention trials. What kinds of interventions should we apply? Are we talking biologic medications or other lifestyle interventions like diet? We are still at the early stages. However, with an improved understanding of the underlying mechanisms and risk factors we are expected to see prevention trials for PsA in the future.”

About one-third of all patients with psoriasis will develop psoriatic arthritis (PsA), a condition that comes with a host of vague symptoms and no definitive blood test for diagnosis. Prevention trials could help to identify higher-risk groups for PsA, with a goal to catch disease early and improve outcomes. The challenge is finding enough participants in a disease that lacks a clear clinical profile, then tracking them for long periods of time to generate any significant data.

Researchers have been taking several approaches to improve outcomes in PsA, Christopher Ritchlin, MD, MPH, chief of the allergy/immunology and rheumatology division at the University of Rochester (N.Y.), said in an interview. “We are in the process of identifying biomarkers and imaging findings that characterize psoriasis patients at high risk to develop PsA.”

The next step would be to design an interventional trial to treat high-risk patients before they develop musculoskeletal inflammation, with a goal to delay onset, attenuate severity, or completely prevent arthritis. The issue now is “we don’t know which agents would be most effective in this prevention effort,” Dr. Ritchlin said. Biologics that target specific pathways significant in PsA pathogenesis are an appealing prospect. However, “it may be that alternative therapies such as methotrexate or ultraviolet A radiation therapy, for example, may help arrest the development of joint inflammation.”

Underdiagnosis impedes research

Several factors may undermine this important research.

For one, psoriasis patients are often unaware that they have PsA. “Many times they are diagnosed incorrectly by nonspecialists. As a consequence, they do not get access to appropriate medications,” said Lihi Eder, MD, PhD, staff rheumatologist and director of the psoriatic arthritis research program at the University of Toronto’s Women’s College Research Institute.

Courtesy Michael Wong/Women's College Hospital

The condition also lacks a good diagnostic tool, Dr. Eder said. There’s no blood test that identifies this condition in the same manner as RA and lupus, for example. For these conditions, a general practitioner such as a family physician may conduct a blood test, and if positive, refer them to a rheumatologist. Such a system doesn’t exist for PsA. “Instead, nonspecialists are ordering tests and when they’re negative, they assume wrongly that these patients don’t have a rheumatic condition,” she explained.

Many clinicians aren’t that well versed in PsA, although dermatology has taken steps to become better educated. As a result, more dermatologists are referring patients to rheumatologists for PsA. Despite this small step forward, the heterogeneous clinical presentation of this condition makes diagnosis especially difficult. Unlike RA, which presents with inflammation in the joints, PsA can present as back or joint pain, “which makes our life as rheumatologists much more complex,” Dr. Eder said.
 

Defining a risk group

Most experts agree that the presence of psoriasis isn’t sufficient to conduct a prevention trial. Ideally, the goal of a prevention study would be to identify a critical subgroup of psoriasis patients at high risk of developing PsA.

However, this presents a challenging task, Dr. Eder said. Psoriasis is a risk factor for PsA, but most patients with psoriasis won’t actually develop it. Given that there’s an incidence rate of 2.7% a year, “you would need to recruit many hundreds of psoriasis patients and follow them for a long period of time until you have enough events.”

Moving forward with prevention studies calls for a better definition of the PsA risk group, according to Georg Schett, MD, chair of internal medicine in the department of internal medicine, rheumatology, and immunology at Friedrich‐Alexander University, Erlangen, Germany. “That’s very important, because you need to define such a group to make a prevention trial feasible. The whole benefit of such an approach is to catch the disease early, to say that psoriasis is a biomarker that’s linked to psoriatic arthritis.”

Indicators of risk other than psoriasis, such as pain, inflammation seen in ultrasound or MRI, and other specificities of psoriasis, could be used to define a population where interception can take place, Dr. Schett added. Although it’s not always clinically recognized, the combination of pain and structural lesions can be an indicator for developing PsA.

One prospective study he and his colleagues conducted in 114 psoriasis patients cited structural entheseal lesions and low cortical volumetric bone mineral density as risk factors in developing PsA. Keeping these factors in mind, Dr. Schett expects to see more studies in biointervention in these populations, “with the idea to prevent the onset of PsA and also decrease pain and subcutaneous inflammation.”

Researchers are currently working to identify those high-risk patients to include in an interventional trial, Dr. Ritchlin said.

That said, there’s been a great deal of “clinical trial angst” among investigators, Dr. Ritchlin noted. Outcomes in clinical trials for a wide range of biologic agents have not demonstrated significant advances in outcomes, compared with initial studies with anti–tumor necrosis factor–alpha (TNF-alpha) agents 20 years ago.
 

Combination biologics

One approach that’s generated some interest is the use of combination biologics medications. Sequential inhibition of cytokines such as interleukin-17A and TNF-alpha is of interest given their central contribution in joint inflammation and damage. “The challenge here of course is toxicity,” Dr. Ritchlin said. Trials that combined blockade of IL-1 and TNF-alpha in a RA trial years ago resulted in significant adverse events without improving outcomes.

Comparatively, a recent study in The Lancet Rheumatology reported success in using the IL-17A inhibitor secukinumab (Cosentyx) to reduce PsA symptoms. Tested on patients in the FUTURE 2 trial, investigators demonstrated that secukinumab in 300- and 150-mg doses safely reduced PsA signs and symptoms over a period of 5 years. Secukinumab also outperformed the TNF-alpha inhibitor adalimumab in 853 PsA patients in the 52-week, randomized, head-to-head, phase 3b EXCEED study, which was recently reported in The Lancet. Articular outcomes were similar between the two therapies, yet the secukinumab group did markedly better in Psoriasis Area and Severity Index scores, compared with the adalimumab group.

Based on these findings, “I suspect that studies examining the efficacy of combination biologics for treatment of PsA will surface in the near future,” Dr. Ritchlin said.

Yet another approach encompasses the spirit of personalized medicine. Clinicians often treat PsA patients empirically because they lack biomarkers that indicate which drug may be most effective for an individual patient, Dr. Ritchlin said. However, the technologies for investigating specific cell subsets in both the blood and tissues have advanced greatly over the last decade. “I am confident that a more precision medicine–based approach to the diagnosis and treatment of PsA is on the near horizon.”
 

Diet as an intervention

Other research has looked at the strong link between metabolic abnormalities and psoriasis and PsA. Some diets, such as the Mediterranean diet, show promise in improving the metabolic profile of these patients, making it a candidate as a potential intervention to reduce PsA risk. Another strategy would be to focus on limiting calories and promoting weight reduction.

One study in the British Journal of Dermatology looked at the associations between PsA and smoking, alcohol, and body mass index, identifying obesity as an important risk factor. Analyzing more than 90,000 psoriasis cases from the U.K. Clinical Practice Research Datalink between 1998 and 2014, researchers identified 1,409 PsA diagnoses. Among this cohort, researchers found an association between PsA and increased body mass index and moderate drinking. This finding underscores the need to support weight-reduction programs to reduce risk, Dr. Eder and Alexis Ogdie, MD, of the University of Pennsylvania, Philadelphia, wrote in a related editorial.

While observational studies such as this one provide further guidance for interventional trials, confounders can affect results. “Patients who lost weight could have made a positive lifestyle change (e.g., a dietary change) that was associated with the decreased risk for PsA rather than weight loss specifically, or they could have lost weight for unhealthy reasons,” Dr. Eder and Dr. Ogdie explained. Future research could address whether weight loss or other interventional factors may reduce PsA progression.

To make this work, “we would need to select patients that would benefit from diet. Secondly, we’d need to identify what kind of diet would be good for preventing PsA. And we don’t know that yet,” Dr. Eder further elaborated.

As with any prevention trial, the challenge is to follow patients over a long period of time, making sure they comply with the restrictions of the prescribed diet, Dr. Eder noted. “I do think it’s a really exciting type of intervention because it’s something that people are very interested in. There’s little risk of side effects, and it’s not very expensive.”

In other research on weight-loss methods, an observational study from Denmark found that bariatric surgery, especially gastric bypass, reduced the risk of developing PsA. This suggests that weight reduction by itself is important, “although we don’t know that yet,” Dr. Eder said.

A risk model for PsA

Dr. Eder and colleagues have been working on an algorithm that will incorporate clinical information (for example, the presence of nail lesions and the severity of psoriasis) to provide an estimated risk of developing PsA over the next 5 years. Subsequently, this information could be used to identify high-risk psoriasis patients as candidates for a prevention trial.

Other groups are looking at laboratory or imaging biomarkers to help develop PsA prediction models, she said. “Once we have these tools, we can move to next steps of prevention trials. What kinds of interventions should we apply? Are we talking biologic medications or other lifestyle interventions like diet? We are still at the early stages. However, with an improved understanding of the underlying mechanisms and risk factors we are expected to see prevention trials for PsA in the future.”

About one-third of all patients with psoriasis will develop psoriatic arthritis (PsA), a condition that comes with a host of vague symptoms and no definitive blood test for diagnosis. Prevention trials could help to identify higher-risk groups for PsA, with a goal to catch disease early and improve outcomes. The challenge is finding enough participants in a disease that lacks a clear clinical profile, then tracking them for long periods of time to generate any significant data.

Researchers have been taking several approaches to improve outcomes in PsA, Christopher Ritchlin, MD, MPH, chief of the allergy/immunology and rheumatology division at the University of Rochester (N.Y.), said in an interview. “We are in the process of identifying biomarkers and imaging findings that characterize psoriasis patients at high risk to develop PsA.”

The next step would be to design an interventional trial to treat high-risk patients before they develop musculoskeletal inflammation, with a goal to delay onset, attenuate severity, or completely prevent arthritis. The issue now is “we don’t know which agents would be most effective in this prevention effort,” Dr. Ritchlin said. Biologics that target specific pathways significant in PsA pathogenesis are an appealing prospect. However, “it may be that alternative therapies such as methotrexate or ultraviolet A radiation therapy, for example, may help arrest the development of joint inflammation.”

Underdiagnosis impedes research

Several factors may undermine this important research.

For one, psoriasis patients are often unaware that they have PsA. “Many times they are diagnosed incorrectly by nonspecialists. As a consequence, they do not get access to appropriate medications,” said Lihi Eder, MD, PhD, staff rheumatologist and director of the psoriatic arthritis research program at the University of Toronto’s Women’s College Research Institute.

Courtesy Michael Wong/Women's College Hospital

The condition also lacks a good diagnostic tool, Dr. Eder said. There’s no blood test that identifies this condition in the same manner as RA and lupus, for example. For these conditions, a general practitioner such as a family physician may conduct a blood test, and if positive, refer them to a rheumatologist. Such a system doesn’t exist for PsA. “Instead, nonspecialists are ordering tests and when they’re negative, they assume wrongly that these patients don’t have a rheumatic condition,” she explained.

Many clinicians aren’t that well versed in PsA, although dermatology has taken steps to become better educated. As a result, more dermatologists are referring patients to rheumatologists for PsA. Despite this small step forward, the heterogeneous clinical presentation of this condition makes diagnosis especially difficult. Unlike RA, which presents with inflammation in the joints, PsA can present as back or joint pain, “which makes our life as rheumatologists much more complex,” Dr. Eder said.
 

Defining a risk group

Most experts agree that the presence of psoriasis isn’t sufficient to conduct a prevention trial. Ideally, the goal of a prevention study would be to identify a critical subgroup of psoriasis patients at high risk of developing PsA.

However, this presents a challenging task, Dr. Eder said. Psoriasis is a risk factor for PsA, but most patients with psoriasis won’t actually develop it. Given that there’s an incidence rate of 2.7% a year, “you would need to recruit many hundreds of psoriasis patients and follow them for a long period of time until you have enough events.”

Moving forward with prevention studies calls for a better definition of the PsA risk group, according to Georg Schett, MD, chair of internal medicine in the department of internal medicine, rheumatology, and immunology at Friedrich‐Alexander University, Erlangen, Germany. “That’s very important, because you need to define such a group to make a prevention trial feasible. The whole benefit of such an approach is to catch the disease early, to say that psoriasis is a biomarker that’s linked to psoriatic arthritis.”

Indicators of risk other than psoriasis, such as pain, inflammation seen in ultrasound or MRI, and other specificities of psoriasis, could be used to define a population where interception can take place, Dr. Schett added. Although it’s not always clinically recognized, the combination of pain and structural lesions can be an indicator for developing PsA.

One prospective study he and his colleagues conducted in 114 psoriasis patients cited structural entheseal lesions and low cortical volumetric bone mineral density as risk factors in developing PsA. Keeping these factors in mind, Dr. Schett expects to see more studies in biointervention in these populations, “with the idea to prevent the onset of PsA and also decrease pain and subcutaneous inflammation.”

Researchers are currently working to identify those high-risk patients to include in an interventional trial, Dr. Ritchlin said.

That said, there’s been a great deal of “clinical trial angst” among investigators, Dr. Ritchlin noted. Outcomes in clinical trials for a wide range of biologic agents have not demonstrated significant advances in outcomes, compared with initial studies with anti–tumor necrosis factor–alpha (TNF-alpha) agents 20 years ago.
 

Combination biologics

One approach that’s generated some interest is the use of combination biologics medications. Sequential inhibition of cytokines such as interleukin-17A and TNF-alpha is of interest given their central contribution in joint inflammation and damage. “The challenge here of course is toxicity,” Dr. Ritchlin said. Trials that combined blockade of IL-1 and TNF-alpha in a RA trial years ago resulted in significant adverse events without improving outcomes.

Comparatively, a recent study in The Lancet Rheumatology reported success in using the IL-17A inhibitor secukinumab (Cosentyx) to reduce PsA symptoms. Tested on patients in the FUTURE 2 trial, investigators demonstrated that secukinumab in 300- and 150-mg doses safely reduced PsA signs and symptoms over a period of 5 years. Secukinumab also outperformed the TNF-alpha inhibitor adalimumab in 853 PsA patients in the 52-week, randomized, head-to-head, phase 3b EXCEED study, which was recently reported in The Lancet. Articular outcomes were similar between the two therapies, yet the secukinumab group did markedly better in Psoriasis Area and Severity Index scores, compared with the adalimumab group.

Based on these findings, “I suspect that studies examining the efficacy of combination biologics for treatment of PsA will surface in the near future,” Dr. Ritchlin said.

Yet another approach encompasses the spirit of personalized medicine. Clinicians often treat PsA patients empirically because they lack biomarkers that indicate which drug may be most effective for an individual patient, Dr. Ritchlin said. However, the technologies for investigating specific cell subsets in both the blood and tissues have advanced greatly over the last decade. “I am confident that a more precision medicine–based approach to the diagnosis and treatment of PsA is on the near horizon.”
 

Diet as an intervention

Other research has looked at the strong link between metabolic abnormalities and psoriasis and PsA. Some diets, such as the Mediterranean diet, show promise in improving the metabolic profile of these patients, making it a candidate as a potential intervention to reduce PsA risk. Another strategy would be to focus on limiting calories and promoting weight reduction.

One study in the British Journal of Dermatology looked at the associations between PsA and smoking, alcohol, and body mass index, identifying obesity as an important risk factor. Analyzing more than 90,000 psoriasis cases from the U.K. Clinical Practice Research Datalink between 1998 and 2014, researchers identified 1,409 PsA diagnoses. Among this cohort, researchers found an association between PsA and increased body mass index and moderate drinking. This finding underscores the need to support weight-reduction programs to reduce risk, Dr. Eder and Alexis Ogdie, MD, of the University of Pennsylvania, Philadelphia, wrote in a related editorial.

While observational studies such as this one provide further guidance for interventional trials, confounders can affect results. “Patients who lost weight could have made a positive lifestyle change (e.g., a dietary change) that was associated with the decreased risk for PsA rather than weight loss specifically, or they could have lost weight for unhealthy reasons,” Dr. Eder and Dr. Ogdie explained. Future research could address whether weight loss or other interventional factors may reduce PsA progression.

To make this work, “we would need to select patients that would benefit from diet. Secondly, we’d need to identify what kind of diet would be good for preventing PsA. And we don’t know that yet,” Dr. Eder further elaborated.

As with any prevention trial, the challenge is to follow patients over a long period of time, making sure they comply with the restrictions of the prescribed diet, Dr. Eder noted. “I do think it’s a really exciting type of intervention because it’s something that people are very interested in. There’s little risk of side effects, and it’s not very expensive.”

In other research on weight-loss methods, an observational study from Denmark found that bariatric surgery, especially gastric bypass, reduced the risk of developing PsA. This suggests that weight reduction by itself is important, “although we don’t know that yet,” Dr. Eder said.

A risk model for PsA

Dr. Eder and colleagues have been working on an algorithm that will incorporate clinical information (for example, the presence of nail lesions and the severity of psoriasis) to provide an estimated risk of developing PsA over the next 5 years. Subsequently, this information could be used to identify high-risk psoriasis patients as candidates for a prevention trial.

Other groups are looking at laboratory or imaging biomarkers to help develop PsA prediction models, she said. “Once we have these tools, we can move to next steps of prevention trials. What kinds of interventions should we apply? Are we talking biologic medications or other lifestyle interventions like diet? We are still at the early stages. However, with an improved understanding of the underlying mechanisms and risk factors we are expected to see prevention trials for PsA in the future.”