Psoriasis

Gastroenterologists in 2023 will have more tools in their arsenal to treat patients with Crohn’s disease or ulcerative colitis. As many as 8-10 adalimumab biosimilars are anticipated to come on the market this year, giving mainstay drug Humira some vigorous competition.

Three scenarios will drive adalimumab biosimilar initiation: Insurance preference for the initial treatment of a newly diagnosed condition, a change in a patient’s insurance plan, or an insurance-mandated switch, said Edward C. Oldfield IV, MD, assistant professor at Eastern Virginia Medical School’s division of gastroenterology in Norfolk.

Even with more drugs to choose from, some gastroenterologists may be hesitant to make a switch. “Outside of these scenarios, I would encourage patients to remain on their current biologic so long as cost and accessibility remain stable,” said Dr. Oldfield.

Many factors will contribute to the success of biosimilars. Will physicians be prescribing them? How are biosimilars placed on formularies and will they be given preferred status?  How will manufacturers price their biosimilars? “We have to wait and see to get the answers to these questions,” said Steven Newmark, JD, MPA, chief legal officer and director of policy, Global Healthy Living Foundation/CreakyJoints, a nonprofit advocacy organization based in New York.

Prescribing biosimilars is no different than prescribing originator biologics, so providers should know how to use them, said Mr. Newmark. “Most important will be the availability of patient-friendly resources that providers can share with their patients to provide education about and confidence in using biosimilars,” he added.

Overall, biosimilars are a good thing, said Dr. Oldfield. “In the long run they should bring down costs and increase access to medications for our patients.”

Others are skeptical that the adalimumab biosimilars will save patients much money.

Biosimilar laws were created to lower costs. However, if a patient with insurance pays only $5 a month out of pocket for Humira – a drug that normally costs $7,000 without coverage – it’s unlikely they would want to switch unless there’s comparable savings from the biosimilar, said Stephen B. Hanauer, MD, medical director of the Digestive Health Center and professor of medicine at Northwestern Medicine, Northwestern University, Evanston, Ill.

Like generics, Humira biosimilars may face some initial backlash, said Dr. Hanauer.
 

2023 broadens scope of adalimumab treatments

The American Gastroenterological Association describes a biosimilar as something that’s “highly similar to, but not an exact copy of, a biologic reference product already approved” by the Food and Drug Administration. Congress under the 2010 Affordable Care Act created a special, abbreviated pathway to approval for biosimilars.

AbbVie’s Humira, the global revenue for which exceeded $20 billion in 2021, has long dominated the U.S. market on injectable treatments for autoimmune diseases. The popular drug faces some competition in 2023, however, following a series of legal settlements that allowed AbbVie competitors to release their own adalimumab biosimilars.

“So far, we haven’t seen biosimilars live up to their potential in the U.S. in the inflammatory space,” said Mr. Newmark. This may change, however. Previously, biosimilars have required infusion, which demanded more time, commitment, and travel from patients. “The new set of forthcoming Humira biosimilars are injectables, an administration method preferred by patients,” he said.

The FDA will approve a biosimilar if it determines that the biological product is highly similar to the reference product, and that there are no clinically meaningful differences between the biological and reference product in terms of the safety, purity, and potency of the product. 

The agency to date has approved 8 adalimumab biosimilars. These include: Idacio (adalimumab-aacf, Fresenius Kabi); Amjevita (adalimumab-atto, Amgen); Hadlima (adalimumab-bwwd, Organon); Cyltezo (adalimumab-adbm, Boehringer Ingelheim); Yusimry (adalimumab-aqvh from Coherus BioSciences); Hulio (adalimumab-fkjp; Mylan/Fujifilm Kyowa Kirin Biologics); Hyrimoz (adalimumab-adaz, Sandoz), and Abrilada (adalimumab-afzb, Pfizer).

“While FDA doesn’t formally track when products come to market, we know based on published reports that application holders for many of the currently FDA-approved biosimilars plan to market this year, starting with Amjevita being the first adalimumab biosimilar launched” in January, said Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars at the agency.

At press time, two other companies (Celltrion and Alvotech/Teva) were awaiting FDA approval for their adalimumab biosimilar drugs.

Among the eight approved drugs, Cyltezo is the only one that has a designation for interchangeability with Humira.

An interchangeable biosimilar may be substituted at the pharmacy without the intervention of the prescriber – much like generics are substituted, depending on state laws, said Dr. Yim. “However, in terms of safety and effectiveness, FDA’s standards for approval mean that biosimilar or interchangeable biosimilar products can be used in place of the reference product they were compared to.”

FDA-approved biosimilars undergo a rigorous evaluation for safety, effectiveness, and quality for their approved conditions of use, she continued. “Therefore, patients and health care providers can rely on a biosimilar to be as safe and effective for its approved uses as the original biological product.”
 

Remicade as a yard stick

Gastroenterologists dealt with this situation once before, when Remicade (infliximab) biosimilars came on the market in 2016, noted Miguel Regueiro, MD, chair of the Digestive Disease and Surgery Institute at the Cleveland Clinic.

Remicade and Humira are both tumor necrosis factor inhibitors with the same mechanism of action and many of the same indications. “We already had that experience with Remicade and biosimilar switch 2 or 3 years ago. Now we’re talking about Humira,” said Dr. Regueiro.

Most GI doctors have prescribed one of the more common infliximab biosimilars (Inflectra or Renflexis), noted Dr. Oldfield.

Cardinal Health, which recently surveyed 300 gastroenterologists, rheumatologists, and dermatologists about adalimumab biosimilars, found that gastroenterologists had the highest comfort level in prescribing them. Their top concern, however, was changing a patient from adalimumab to an adalimumab biosimilar.

For most patients, Dr. Oldfield sees the Humira reference biologic and biosimilar as equivalent.

However, he said he would change a patient’s drug only if there were a good reason or if his hand was forced by insurance. He would not make the change for a patient who recently began induction with the reference biologic or a patient with highly active clinical disease.

“While there is limited data to support this, I would also have some qualms about changing a patient from reference biologic to a biosimilar if they previously had immune-mediated pharmacokinetic failure due to antibody development with a biologic and were currently doing well on their new biologic,” he said.

Those with a new ulcerative colitis or Crohn’s diagnosis who are initiating a biologic for the first time might consider a biosimilar. If a patient is transitioning from a reference biologic to a biosimilar, “I would want to make that change during a time of stable remission and with the recognition that the switch is not a temporary switch, but a long-term switch,” he continued.

A paper that reviewed 23 observational studies of adalimumab and other biosimilars found that switching biosimilars was safe and effective. But if possible, patients should minimize the number of switches until more robust long-term data are available, added Dr. Oldfield.

If a patient is apprehensive about switching to a new therapy, “one may need to be cognizant of the ‘nocebo’ effect in which there is an unexplained or unfavorable therapeutic effect after switching,” he said.

Other gastroenterologists voiced similar reservations about switching. “I won’t use an adalimumab biosimilar unless the patient requests it, the insurance requires it, or there is a cost advantage for the patient such that they prefer it,” said Doug Wolf, MD, an Atlanta gastroenterologist.

“There is no medical treatment advantage to a biosimilar, especially if switching from Humira,” added Dr. Wolf.

Insurance will guide treatment

Once a drug is approved for use by the FDA, that drug will be available in all 50 states. “Different private insurance formularies, as well as state Medicaid formularies, might affect the actual ability of patients to receive such drugs,” said Mr. Newmark.

Patients should consult with their providers and insurance companies to see what therapies are available, he advised.

Dr. Hanauer anticipates some headaches arising for patients and doctors alike when negotiating for a specific drug.

Cyltezo may be the only biosimilar interchangeable with Humira, but the third-party pharmacy benefit manager (PBM) could negotiate for one of the noninterchangeable ones. “On a yearly basis they could switch their preference,” said Dr. Hanauer.

In the Cardinal Health survey, more than 60% of respondents said they would feel comfortable prescribing an adalimumab biosimilar only with an interchangeability designation.

A PBM may offer a patient Cyltezo if it’s cheaper than Humira. If the patient insists on staying on Humira, then they’ll have to pay more for that drug on their payer’s formulary, said Dr. Hanauer. In a worst-case scenario, a physician may have to appeal on a patient’s behalf to get Humira if the insurer offers only the biosimilar.

Taking that step to appeal is a major hassle for the physician, and leads to extra back door costs as well, said Dr. Hanauer.

Humira manufacturer AbbVie, in turn, may offer discounts and rebates to the PBMs to put Humira on their formulary. “That’s the AbbVie negotiating power. It’s not that the cost is going to be that much different. It’s going to be that there are rebates and discounts that are going to make the cost different,” he added.

As a community physician, Dr. Oldfield has specific concerns about accessibility.

The ever-increasing burden of insurance documentation and prior authorization means it can take weeks or months to get these medications approved. “The addition of new biosimilars is a welcome entrance if it can get patients the medications they need when they need it,” he said.

When it comes to prescribing biologics, many physicians rely on ancillary staff for assistance. It’s a team effort to sift through all the paperwork, observed Dr. Oldfield.

“While many community GI practices have specialized staff to deal with prior authorizations, they are still a far cry from the IBD [inflammatory bowel disease] academic centers where there are often pharmacists, nursing specialists, and home-monitoring programs to check in on patients,” he explained.

Landscape on cost is uncertain

At present, little is known about the cost of the biosimilars and impact on future drug pricing, said Dr. Oldfield.

At least for Medicare, Humira biosimilars will be considered Medicare Part D drugs if used for a medically accepted indication, said a spokesperson for the Centers for Medicare and Medicaid Services.

Part D sponsors (pharmacy and therapeutic committees) “will make the determination as to whether Amjevita and other products will be added to their formularies,” said the spokesperson.

Patients never saw a significant cost savings with Remicade biosimilars. “I imagine the same would be true with biosimilars for Humira,” said Dr. Regueiro. Patients may see greater access to these drugs, however, because the insurance plan or the pharmacy plan will make them more readily available, he added.

The hope is that, as biosimilars are introduced, the price of the originator biologic will go down, said Mr. Newmark. “Therefore, we can expect Humira to be offered at a lower price as it faces competition. Where it will sit in comparison to the forthcoming biosimilars will depend on how much biosimilar companies drop their price and how much pressure will be on PBMs and insurers to cover the lowest list price drug,” he said.

AbbVie did not respond to several requests for comment.

Charitable patient assistance programs for biosimilars or biologics can help offset the price of copayments, Mr. Newmark offered.

Ideally, insurers will offer designated biosimilars at a reduced or even no out-of-pocket expense on their formularies. This should lead to a decreased administrative burden for approval with streamlined (or even removal) of prior authorizations for certain medications, said Dr. Oldfield.

Without insurance or medication assistance programs, the cost of biosimilars is prohibitively expensive, he added.

“Biosimilars have higher research, development, and manufacturing costs than what people conventionally think of [for] a generic medication.”

Educating, advising patients

Dr. Oldfield advised that gastroenterologists refer to biologics by the generic name rather than branded name when initiating therapy unless there is a very specific reason not to. “This approach should make the process more streamlined and less subjected to quick denials for brand-only requests as biosimilars start to assume a larger market share,” he said.

Uptake of the Humira biosimilars also will depend on proper education of physicians and patients and their comfort level with the biosimilars, said Dr. Regueiro. Cleveland Clinic uses a team approach to educate on this topic, relying on pharmacists, clinicians, and nurses to explain that there’s no real difference between the reference drug and its biosimilars, based on efficacy and safety data.

Physicians can also direct patients to patient-friendly resources, said Mr. Newmark. “By starting the conversation early, it ensures that when/if the time comes that your patient is switched to or chooses a biosimilar they will feel more confident because they have the knowledge to make decisions about their care.”

The Global Healthy Living Foundation’s podcast, Breaking Down Biosimilars , is a free resource for patients, he added.

It’s important that doctors also understand these products so they can explain to their patients what to expect, said the FDA’s Dr. Yim. The FDA provides educational materials on its website, including a comprehensive curriculum toolkit.

Dr. Hanauer has served as a consultant for AbbVie, Amgen, American College of Gastroenterology, GlaxoSmithKline, American Gastroenterological Association, Pfizer, and a host of other companies . Dr. Regueiro has served on advisory boards and as a consultant for Abbvie, Janssen, UCB, Takeda, Pfizer, BMS, Organon, Amgen, Genentech, Gilead, Salix, Prometheus, Lilly, Celgene, TARGET Pharma Solutions,Trellis, and Boehringer Ingelheim Pharmaceuticals. Dr. Wolf, Dr. Yim, Dr. Oldfield, and Mr. Newmark have no financial conflicts of interest.

Gastroenterologists in 2023 will have more tools in their arsenal to treat patients with Crohn’s disease or ulcerative colitis. As many as 8-10 adalimumab biosimilars are anticipated to come on the market this year, giving mainstay drug Humira some vigorous competition.

Three scenarios will drive adalimumab biosimilar initiation: Insurance preference for the initial treatment of a newly diagnosed condition, a change in a patient’s insurance plan, or an insurance-mandated switch, said Edward C. Oldfield IV, MD, assistant professor at Eastern Virginia Medical School’s division of gastroenterology in Norfolk.

Even with more drugs to choose from, some gastroenterologists may be hesitant to make a switch. “Outside of these scenarios, I would encourage patients to remain on their current biologic so long as cost and accessibility remain stable,” said Dr. Oldfield.

Many factors will contribute to the success of biosimilars. Will physicians be prescribing them? How are biosimilars placed on formularies and will they be given preferred status?  How will manufacturers price their biosimilars? “We have to wait and see to get the answers to these questions,” said Steven Newmark, JD, MPA, chief legal officer and director of policy, Global Healthy Living Foundation/CreakyJoints, a nonprofit advocacy organization based in New York.

Prescribing biosimilars is no different than prescribing originator biologics, so providers should know how to use them, said Mr. Newmark. “Most important will be the availability of patient-friendly resources that providers can share with their patients to provide education about and confidence in using biosimilars,” he added.

Overall, biosimilars are a good thing, said Dr. Oldfield. “In the long run they should bring down costs and increase access to medications for our patients.”

Others are skeptical that the adalimumab biosimilars will save patients much money.

Biosimilar laws were created to lower costs. However, if a patient with insurance pays only $5 a month out of pocket for Humira – a drug that normally costs $7,000 without coverage – it’s unlikely they would want to switch unless there’s comparable savings from the biosimilar, said Stephen B. Hanauer, MD, medical director of the Digestive Health Center and professor of medicine at Northwestern Medicine, Northwestern University, Evanston, Ill.

Like generics, Humira biosimilars may face some initial backlash, said Dr. Hanauer.
 

2023 broadens scope of adalimumab treatments

The American Gastroenterological Association describes a biosimilar as something that’s “highly similar to, but not an exact copy of, a biologic reference product already approved” by the Food and Drug Administration. Congress under the 2010 Affordable Care Act created a special, abbreviated pathway to approval for biosimilars.

AbbVie’s Humira, the global revenue for which exceeded $20 billion in 2021, has long dominated the U.S. market on injectable treatments for autoimmune diseases. The popular drug faces some competition in 2023, however, following a series of legal settlements that allowed AbbVie competitors to release their own adalimumab biosimilars.

“So far, we haven’t seen biosimilars live up to their potential in the U.S. in the inflammatory space,” said Mr. Newmark. This may change, however. Previously, biosimilars have required infusion, which demanded more time, commitment, and travel from patients. “The new set of forthcoming Humira biosimilars are injectables, an administration method preferred by patients,” he said.

The FDA will approve a biosimilar if it determines that the biological product is highly similar to the reference product, and that there are no clinically meaningful differences between the biological and reference product in terms of the safety, purity, and potency of the product. 

The agency to date has approved 8 adalimumab biosimilars. These include: Idacio (adalimumab-aacf, Fresenius Kabi); Amjevita (adalimumab-atto, Amgen); Hadlima (adalimumab-bwwd, Organon); Cyltezo (adalimumab-adbm, Boehringer Ingelheim); Yusimry (adalimumab-aqvh from Coherus BioSciences); Hulio (adalimumab-fkjp; Mylan/Fujifilm Kyowa Kirin Biologics); Hyrimoz (adalimumab-adaz, Sandoz), and Abrilada (adalimumab-afzb, Pfizer).

“While FDA doesn’t formally track when products come to market, we know based on published reports that application holders for many of the currently FDA-approved biosimilars plan to market this year, starting with Amjevita being the first adalimumab biosimilar launched” in January, said Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars at the agency.

At press time, two other companies (Celltrion and Alvotech/Teva) were awaiting FDA approval for their adalimumab biosimilar drugs.

Among the eight approved drugs, Cyltezo is the only one that has a designation for interchangeability with Humira.

An interchangeable biosimilar may be substituted at the pharmacy without the intervention of the prescriber – much like generics are substituted, depending on state laws, said Dr. Yim. “However, in terms of safety and effectiveness, FDA’s standards for approval mean that biosimilar or interchangeable biosimilar products can be used in place of the reference product they were compared to.”

FDA-approved biosimilars undergo a rigorous evaluation for safety, effectiveness, and quality for their approved conditions of use, she continued. “Therefore, patients and health care providers can rely on a biosimilar to be as safe and effective for its approved uses as the original biological product.”
 

Remicade as a yard stick

Gastroenterologists dealt with this situation once before, when Remicade (infliximab) biosimilars came on the market in 2016, noted Miguel Regueiro, MD, chair of the Digestive Disease and Surgery Institute at the Cleveland Clinic.

Remicade and Humira are both tumor necrosis factor inhibitors with the same mechanism of action and many of the same indications. “We already had that experience with Remicade and biosimilar switch 2 or 3 years ago. Now we’re talking about Humira,” said Dr. Regueiro.

Most GI doctors have prescribed one of the more common infliximab biosimilars (Inflectra or Renflexis), noted Dr. Oldfield.

Cardinal Health, which recently surveyed 300 gastroenterologists, rheumatologists, and dermatologists about adalimumab biosimilars, found that gastroenterologists had the highest comfort level in prescribing them. Their top concern, however, was changing a patient from adalimumab to an adalimumab biosimilar.

For most patients, Dr. Oldfield sees the Humira reference biologic and biosimilar as equivalent.

However, he said he would change a patient’s drug only if there were a good reason or if his hand was forced by insurance. He would not make the change for a patient who recently began induction with the reference biologic or a patient with highly active clinical disease.

“While there is limited data to support this, I would also have some qualms about changing a patient from reference biologic to a biosimilar if they previously had immune-mediated pharmacokinetic failure due to antibody development with a biologic and were currently doing well on their new biologic,” he said.

Those with a new ulcerative colitis or Crohn’s diagnosis who are initiating a biologic for the first time might consider a biosimilar. If a patient is transitioning from a reference biologic to a biosimilar, “I would want to make that change during a time of stable remission and with the recognition that the switch is not a temporary switch, but a long-term switch,” he continued.

A paper that reviewed 23 observational studies of adalimumab and other biosimilars found that switching biosimilars was safe and effective. But if possible, patients should minimize the number of switches until more robust long-term data are available, added Dr. Oldfield.

If a patient is apprehensive about switching to a new therapy, “one may need to be cognizant of the ‘nocebo’ effect in which there is an unexplained or unfavorable therapeutic effect after switching,” he said.

Other gastroenterologists voiced similar reservations about switching. “I won’t use an adalimumab biosimilar unless the patient requests it, the insurance requires it, or there is a cost advantage for the patient such that they prefer it,” said Doug Wolf, MD, an Atlanta gastroenterologist.

“There is no medical treatment advantage to a biosimilar, especially if switching from Humira,” added Dr. Wolf.

Insurance will guide treatment

Once a drug is approved for use by the FDA, that drug will be available in all 50 states. “Different private insurance formularies, as well as state Medicaid formularies, might affect the actual ability of patients to receive such drugs,” said Mr. Newmark.

Patients should consult with their providers and insurance companies to see what therapies are available, he advised.

Dr. Hanauer anticipates some headaches arising for patients and doctors alike when negotiating for a specific drug.

Cyltezo may be the only biosimilar interchangeable with Humira, but the third-party pharmacy benefit manager (PBM) could negotiate for one of the noninterchangeable ones. “On a yearly basis they could switch their preference,” said Dr. Hanauer.

In the Cardinal Health survey, more than 60% of respondents said they would feel comfortable prescribing an adalimumab biosimilar only with an interchangeability designation.

A PBM may offer a patient Cyltezo if it’s cheaper than Humira. If the patient insists on staying on Humira, then they’ll have to pay more for that drug on their payer’s formulary, said Dr. Hanauer. In a worst-case scenario, a physician may have to appeal on a patient’s behalf to get Humira if the insurer offers only the biosimilar.

Taking that step to appeal is a major hassle for the physician, and leads to extra back door costs as well, said Dr. Hanauer.

Humira manufacturer AbbVie, in turn, may offer discounts and rebates to the PBMs to put Humira on their formulary. “That’s the AbbVie negotiating power. It’s not that the cost is going to be that much different. It’s going to be that there are rebates and discounts that are going to make the cost different,” he added.

As a community physician, Dr. Oldfield has specific concerns about accessibility.

The ever-increasing burden of insurance documentation and prior authorization means it can take weeks or months to get these medications approved. “The addition of new biosimilars is a welcome entrance if it can get patients the medications they need when they need it,” he said.

When it comes to prescribing biologics, many physicians rely on ancillary staff for assistance. It’s a team effort to sift through all the paperwork, observed Dr. Oldfield.

“While many community GI practices have specialized staff to deal with prior authorizations, they are still a far cry from the IBD [inflammatory bowel disease] academic centers where there are often pharmacists, nursing specialists, and home-monitoring programs to check in on patients,” he explained.

Landscape on cost is uncertain

At present, little is known about the cost of the biosimilars and impact on future drug pricing, said Dr. Oldfield.

At least for Medicare, Humira biosimilars will be considered Medicare Part D drugs if used for a medically accepted indication, said a spokesperson for the Centers for Medicare and Medicaid Services.

Part D sponsors (pharmacy and therapeutic committees) “will make the determination as to whether Amjevita and other products will be added to their formularies,” said the spokesperson.

Patients never saw a significant cost savings with Remicade biosimilars. “I imagine the same would be true with biosimilars for Humira,” said Dr. Regueiro. Patients may see greater access to these drugs, however, because the insurance plan or the pharmacy plan will make them more readily available, he added.

The hope is that, as biosimilars are introduced, the price of the originator biologic will go down, said Mr. Newmark. “Therefore, we can expect Humira to be offered at a lower price as it faces competition. Where it will sit in comparison to the forthcoming biosimilars will depend on how much biosimilar companies drop their price and how much pressure will be on PBMs and insurers to cover the lowest list price drug,” he said.

AbbVie did not respond to several requests for comment.

Charitable patient assistance programs for biosimilars or biologics can help offset the price of copayments, Mr. Newmark offered.

Ideally, insurers will offer designated biosimilars at a reduced or even no out-of-pocket expense on their formularies. This should lead to a decreased administrative burden for approval with streamlined (or even removal) of prior authorizations for certain medications, said Dr. Oldfield.

Without insurance or medication assistance programs, the cost of biosimilars is prohibitively expensive, he added.

“Biosimilars have higher research, development, and manufacturing costs than what people conventionally think of [for] a generic medication.”

Educating, advising patients

Dr. Oldfield advised that gastroenterologists refer to biologics by the generic name rather than branded name when initiating therapy unless there is a very specific reason not to. “This approach should make the process more streamlined and less subjected to quick denials for brand-only requests as biosimilars start to assume a larger market share,” he said.

Uptake of the Humira biosimilars also will depend on proper education of physicians and patients and their comfort level with the biosimilars, said Dr. Regueiro. Cleveland Clinic uses a team approach to educate on this topic, relying on pharmacists, clinicians, and nurses to explain that there’s no real difference between the reference drug and its biosimilars, based on efficacy and safety data.

Physicians can also direct patients to patient-friendly resources, said Mr. Newmark. “By starting the conversation early, it ensures that when/if the time comes that your patient is switched to or chooses a biosimilar they will feel more confident because they have the knowledge to make decisions about their care.”

The Global Healthy Living Foundation’s podcast, Breaking Down Biosimilars , is a free resource for patients, he added.

It’s important that doctors also understand these products so they can explain to their patients what to expect, said the FDA’s Dr. Yim. The FDA provides educational materials on its website, including a comprehensive curriculum toolkit.

Dr. Hanauer has served as a consultant for AbbVie, Amgen, American College of Gastroenterology, GlaxoSmithKline, American Gastroenterological Association, Pfizer, and a host of other companies . Dr. Regueiro has served on advisory boards and as a consultant for Abbvie, Janssen, UCB, Takeda, Pfizer, BMS, Organon, Amgen, Genentech, Gilead, Salix, Prometheus, Lilly, Celgene, TARGET Pharma Solutions,Trellis, and Boehringer Ingelheim Pharmaceuticals. Dr. Wolf, Dr. Yim, Dr. Oldfield, and Mr. Newmark have no financial conflicts of interest.

Gastroenterologists in 2023 will have more tools in their arsenal to treat patients with Crohn’s disease or ulcerative colitis. As many as 8-10 adalimumab biosimilars are anticipated to come on the market this year, giving mainstay drug Humira some vigorous competition.

Three scenarios will drive adalimumab biosimilar initiation: Insurance preference for the initial treatment of a newly diagnosed condition, a change in a patient’s insurance plan, or an insurance-mandated switch, said Edward C. Oldfield IV, MD, assistant professor at Eastern Virginia Medical School’s division of gastroenterology in Norfolk.

Even with more drugs to choose from, some gastroenterologists may be hesitant to make a switch. “Outside of these scenarios, I would encourage patients to remain on their current biologic so long as cost and accessibility remain stable,” said Dr. Oldfield.

Many factors will contribute to the success of biosimilars. Will physicians be prescribing them? How are biosimilars placed on formularies and will they be given preferred status?  How will manufacturers price their biosimilars? “We have to wait and see to get the answers to these questions,” said Steven Newmark, JD, MPA, chief legal officer and director of policy, Global Healthy Living Foundation/CreakyJoints, a nonprofit advocacy organization based in New York.

Prescribing biosimilars is no different than prescribing originator biologics, so providers should know how to use them, said Mr. Newmark. “Most important will be the availability of patient-friendly resources that providers can share with their patients to provide education about and confidence in using biosimilars,” he added.

Overall, biosimilars are a good thing, said Dr. Oldfield. “In the long run they should bring down costs and increase access to medications for our patients.”

Others are skeptical that the adalimumab biosimilars will save patients much money.

Biosimilar laws were created to lower costs. However, if a patient with insurance pays only $5 a month out of pocket for Humira – a drug that normally costs $7,000 without coverage – it’s unlikely they would want to switch unless there’s comparable savings from the biosimilar, said Stephen B. Hanauer, MD, medical director of the Digestive Health Center and professor of medicine at Northwestern Medicine, Northwestern University, Evanston, Ill.

Like generics, Humira biosimilars may face some initial backlash, said Dr. Hanauer.
 

2023 broadens scope of adalimumab treatments

The American Gastroenterological Association describes a biosimilar as something that’s “highly similar to, but not an exact copy of, a biologic reference product already approved” by the Food and Drug Administration. Congress under the 2010 Affordable Care Act created a special, abbreviated pathway to approval for biosimilars.

AbbVie’s Humira, the global revenue for which exceeded $20 billion in 2021, has long dominated the U.S. market on injectable treatments for autoimmune diseases. The popular drug faces some competition in 2023, however, following a series of legal settlements that allowed AbbVie competitors to release their own adalimumab biosimilars.

“So far, we haven’t seen biosimilars live up to their potential in the U.S. in the inflammatory space,” said Mr. Newmark. This may change, however. Previously, biosimilars have required infusion, which demanded more time, commitment, and travel from patients. “The new set of forthcoming Humira biosimilars are injectables, an administration method preferred by patients,” he said.

The FDA will approve a biosimilar if it determines that the biological product is highly similar to the reference product, and that there are no clinically meaningful differences between the biological and reference product in terms of the safety, purity, and potency of the product. 

The agency to date has approved 8 adalimumab biosimilars. These include: Idacio (adalimumab-aacf, Fresenius Kabi); Amjevita (adalimumab-atto, Amgen); Hadlima (adalimumab-bwwd, Organon); Cyltezo (adalimumab-adbm, Boehringer Ingelheim); Yusimry (adalimumab-aqvh from Coherus BioSciences); Hulio (adalimumab-fkjp; Mylan/Fujifilm Kyowa Kirin Biologics); Hyrimoz (adalimumab-adaz, Sandoz), and Abrilada (adalimumab-afzb, Pfizer).

“While FDA doesn’t formally track when products come to market, we know based on published reports that application holders for many of the currently FDA-approved biosimilars plan to market this year, starting with Amjevita being the first adalimumab biosimilar launched” in January, said Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars at the agency.

At press time, two other companies (Celltrion and Alvotech/Teva) were awaiting FDA approval for their adalimumab biosimilar drugs.

Among the eight approved drugs, Cyltezo is the only one that has a designation for interchangeability with Humira.

An interchangeable biosimilar may be substituted at the pharmacy without the intervention of the prescriber – much like generics are substituted, depending on state laws, said Dr. Yim. “However, in terms of safety and effectiveness, FDA’s standards for approval mean that biosimilar or interchangeable biosimilar products can be used in place of the reference product they were compared to.”

FDA-approved biosimilars undergo a rigorous evaluation for safety, effectiveness, and quality for their approved conditions of use, she continued. “Therefore, patients and health care providers can rely on a biosimilar to be as safe and effective for its approved uses as the original biological product.”
 

Remicade as a yard stick

Gastroenterologists dealt with this situation once before, when Remicade (infliximab) biosimilars came on the market in 2016, noted Miguel Regueiro, MD, chair of the Digestive Disease and Surgery Institute at the Cleveland Clinic.

Remicade and Humira are both tumor necrosis factor inhibitors with the same mechanism of action and many of the same indications. “We already had that experience with Remicade and biosimilar switch 2 or 3 years ago. Now we’re talking about Humira,” said Dr. Regueiro.

Most GI doctors have prescribed one of the more common infliximab biosimilars (Inflectra or Renflexis), noted Dr. Oldfield.

Cardinal Health, which recently surveyed 300 gastroenterologists, rheumatologists, and dermatologists about adalimumab biosimilars, found that gastroenterologists had the highest comfort level in prescribing them. Their top concern, however, was changing a patient from adalimumab to an adalimumab biosimilar.

For most patients, Dr. Oldfield sees the Humira reference biologic and biosimilar as equivalent.

However, he said he would change a patient’s drug only if there were a good reason or if his hand was forced by insurance. He would not make the change for a patient who recently began induction with the reference biologic or a patient with highly active clinical disease.

“While there is limited data to support this, I would also have some qualms about changing a patient from reference biologic to a biosimilar if they previously had immune-mediated pharmacokinetic failure due to antibody development with a biologic and were currently doing well on their new biologic,” he said.

Those with a new ulcerative colitis or Crohn’s diagnosis who are initiating a biologic for the first time might consider a biosimilar. If a patient is transitioning from a reference biologic to a biosimilar, “I would want to make that change during a time of stable remission and with the recognition that the switch is not a temporary switch, but a long-term switch,” he continued.

A paper that reviewed 23 observational studies of adalimumab and other biosimilars found that switching biosimilars was safe and effective. But if possible, patients should minimize the number of switches until more robust long-term data are available, added Dr. Oldfield.

If a patient is apprehensive about switching to a new therapy, “one may need to be cognizant of the ‘nocebo’ effect in which there is an unexplained or unfavorable therapeutic effect after switching,” he said.

Other gastroenterologists voiced similar reservations about switching. “I won’t use an adalimumab biosimilar unless the patient requests it, the insurance requires it, or there is a cost advantage for the patient such that they prefer it,” said Doug Wolf, MD, an Atlanta gastroenterologist.

“There is no medical treatment advantage to a biosimilar, especially if switching from Humira,” added Dr. Wolf.

Insurance will guide treatment

Once a drug is approved for use by the FDA, that drug will be available in all 50 states. “Different private insurance formularies, as well as state Medicaid formularies, might affect the actual ability of patients to receive such drugs,” said Mr. Newmark.

Patients should consult with their providers and insurance companies to see what therapies are available, he advised.

Dr. Hanauer anticipates some headaches arising for patients and doctors alike when negotiating for a specific drug.

Cyltezo may be the only biosimilar interchangeable with Humira, but the third-party pharmacy benefit manager (PBM) could negotiate for one of the noninterchangeable ones. “On a yearly basis they could switch their preference,” said Dr. Hanauer.

In the Cardinal Health survey, more than 60% of respondents said they would feel comfortable prescribing an adalimumab biosimilar only with an interchangeability designation.

A PBM may offer a patient Cyltezo if it’s cheaper than Humira. If the patient insists on staying on Humira, then they’ll have to pay more for that drug on their payer’s formulary, said Dr. Hanauer. In a worst-case scenario, a physician may have to appeal on a patient’s behalf to get Humira if the insurer offers only the biosimilar.

Taking that step to appeal is a major hassle for the physician, and leads to extra back door costs as well, said Dr. Hanauer.

Humira manufacturer AbbVie, in turn, may offer discounts and rebates to the PBMs to put Humira on their formulary. “That’s the AbbVie negotiating power. It’s not that the cost is going to be that much different. It’s going to be that there are rebates and discounts that are going to make the cost different,” he added.

As a community physician, Dr. Oldfield has specific concerns about accessibility.

The ever-increasing burden of insurance documentation and prior authorization means it can take weeks or months to get these medications approved. “The addition of new biosimilars is a welcome entrance if it can get patients the medications they need when they need it,” he said.

When it comes to prescribing biologics, many physicians rely on ancillary staff for assistance. It’s a team effort to sift through all the paperwork, observed Dr. Oldfield.

“While many community GI practices have specialized staff to deal with prior authorizations, they are still a far cry from the IBD [inflammatory bowel disease] academic centers where there are often pharmacists, nursing specialists, and home-monitoring programs to check in on patients,” he explained.

Landscape on cost is uncertain

At present, little is known about the cost of the biosimilars and impact on future drug pricing, said Dr. Oldfield.

At least for Medicare, Humira biosimilars will be considered Medicare Part D drugs if used for a medically accepted indication, said a spokesperson for the Centers for Medicare and Medicaid Services.

Part D sponsors (pharmacy and therapeutic committees) “will make the determination as to whether Amjevita and other products will be added to their formularies,” said the spokesperson.

Patients never saw a significant cost savings with Remicade biosimilars. “I imagine the same would be true with biosimilars for Humira,” said Dr. Regueiro. Patients may see greater access to these drugs, however, because the insurance plan or the pharmacy plan will make them more readily available, he added.

The hope is that, as biosimilars are introduced, the price of the originator biologic will go down, said Mr. Newmark. “Therefore, we can expect Humira to be offered at a lower price as it faces competition. Where it will sit in comparison to the forthcoming biosimilars will depend on how much biosimilar companies drop their price and how much pressure will be on PBMs and insurers to cover the lowest list price drug,” he said.

AbbVie did not respond to several requests for comment.

Charitable patient assistance programs for biosimilars or biologics can help offset the price of copayments, Mr. Newmark offered.

Ideally, insurers will offer designated biosimilars at a reduced or even no out-of-pocket expense on their formularies. This should lead to a decreased administrative burden for approval with streamlined (or even removal) of prior authorizations for certain medications, said Dr. Oldfield.

Without insurance or medication assistance programs, the cost of biosimilars is prohibitively expensive, he added.

“Biosimilars have higher research, development, and manufacturing costs than what people conventionally think of [for] a generic medication.”

Educating, advising patients

Dr. Oldfield advised that gastroenterologists refer to biologics by the generic name rather than branded name when initiating therapy unless there is a very specific reason not to. “This approach should make the process more streamlined and less subjected to quick denials for brand-only requests as biosimilars start to assume a larger market share,” he said.

Uptake of the Humira biosimilars also will depend on proper education of physicians and patients and their comfort level with the biosimilars, said Dr. Regueiro. Cleveland Clinic uses a team approach to educate on this topic, relying on pharmacists, clinicians, and nurses to explain that there’s no real difference between the reference drug and its biosimilars, based on efficacy and safety data.

Physicians can also direct patients to patient-friendly resources, said Mr. Newmark. “By starting the conversation early, it ensures that when/if the time comes that your patient is switched to or chooses a biosimilar they will feel more confident because they have the knowledge to make decisions about their care.”

The Global Healthy Living Foundation’s podcast, Breaking Down Biosimilars , is a free resource for patients, he added.

It’s important that doctors also understand these products so they can explain to their patients what to expect, said the FDA’s Dr. Yim. The FDA provides educational materials on its website, including a comprehensive curriculum toolkit.

Dr. Hanauer has served as a consultant for AbbVie, Amgen, American College of Gastroenterology, GlaxoSmithKline, American Gastroenterological Association, Pfizer, and a host of other companies . Dr. Regueiro has served on advisory boards and as a consultant for Abbvie, Janssen, UCB, Takeda, Pfizer, BMS, Organon, Amgen, Genentech, Gilead, Salix, Prometheus, Lilly, Celgene, TARGET Pharma Solutions,Trellis, and Boehringer Ingelheim Pharmaceuticals. Dr. Wolf, Dr. Yim, Dr. Oldfield, and Mr. Newmark have no financial conflicts of interest.

HONOLULU – During office visits with Andrew Blauvelt, MD, MBA, many patients well controlled on biologic therapy for their moderate to severe psoriasis often ask him when their scheduled injections can stop.

The most common question he hears is, “ ‘Why do I have to keep doing this? I’ve been clear for 2 or 3 years,’ ” Dr. Blauvelt, president of Oregon Medical Research Center, Portland, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “We have terrific drugs for psoriasis, but how can we do better?”

According to Dr. Blauvelt, there are at least six future strategies to treat psoriasis, induce remission, and/or cure the disease:

Development of oral biologics. At least two companies are developing a peptide-type small molecule that blocks interleukin (IL)-17 or IL-23 signaling, but would be given as a pill, he said. Another concept in the works is a robotic pill for drug delivery. The pill, which is being developed by Rani Therapeutics, protects the biotherapeutic drug payload from digestion in the GI tract and auto-injects it into the wall of the small intestine, according to a report of two studies that demonstrated the safety and tolerability of the robotic pill in healthy humans.

Doug Brunk/MDedge News

In an animal study, the same researchers showed that delivering monoclonal antibodies with the robotic pill achieved bioavailability on par with that obtained by standard subcutaneous injections.

Identifying “super responders” who require less frequent dosing of medication. “There’s data to suggest that we can kind of back off treatment in these patients,” Dr. Blauvelt said.

Hitting treatment hard and early. “There’s a concept in medicine of hitting disease hard and hitting it early, before the disease can establish itself and cause damage,” he said.

Targeting tissue resident memory T cells. In psoriasis, the idea is that if you treat earlier, when patients are just diagnosed, “perhaps you might be able to decrease resident memory T cells that set up shop in the skin and are responsible for disease recurrences,” Dr. Blauvelt said. “Research has shown that IL-23 blockers decrease tissue resident memory T cells, and IL-17 blockers don’t. This could explain why we see long remissions in this class of drug because we’re getting at these resident memory T cells and knocking them down,” he explained. “Our hypothesis is that hitting hard and early in the treatment course with high-dose IL-23 blockade may be an effective strategy to induce long-term remissions and possible cure, what we call ‘knock-out therapy.’ ”

In a pilot study of 20 patients, Dr. Blauvelt and colleagues are evaluating whether higher initial doses of the IL-23 antagonist risankizumab (300 mg and 600 mg, 2 times and 4 times the standard initial doses for plaque psoriasis) can more effectively target resident memory T cells. “This involves dosing at weeks 0, 4, and 16, then stopping and measuring resident T cells in the tissue to see how long we can induce psoriasis remissions,” Dr. Blauvelt said.

“I have no data to share, but I think we have the potential for unprecedented PASI-100 numbers with no added safety concerns, and the potential to break away from established regular dosing patterns,” such as the possibility of yearly dosing, the possibility of long-term remissions, and the possibility of cure in some patients, he noted.

Inducing tolerance. This refers to efforts aimed at increasing regulatory T cells, which are natural T cells that calm inflammation. He described it as “revving up our natural anti-inflammatory T cells to help balance the immune system.”

Gene editing. This involves using CRISPR gene editing technology to cut genes as a way to cure disease. “What if we cut the IL-23 receptor?” Dr. Blauvelt asked. “You would get rid of that whole signaling pathway. Would the patient be fine?”

In an interview a the meeting, Linda Stein Gold, MD, director of clinical research and division head of dermatology at the Henry Ford Health System, Detroit, said that Dr. Blauvelt “has a very exciting view” of the future of psoriasis treatments. “I think that some of it will come true; we’ll have to see which,” Dr. Stein Gold said. “The idea that we might be able to change the trajectory of disease by being aggressive upfront, and possibly modify the course, is exciting. That would be a wonderful new treatment approach.”

Dr. Blauvelt disclosed ties with AbbVie, Abcentra, Affibody, Aligos, Almirall, Alumis, Amgen, AnaptysBio, Arcutis, Arena, ASLAN Pharma, Athenex, Bluefin, Boehringer Ingelheim, Bristol Myers Squibb, Cara, Dermavant, EcoR1, Escient, Evelo, Evommune, Forte, Galderma, Highlightll, Incyte, Innovent Bio, Janssen, Landos, Leo, Lilly, Merck, Novartis, Pfizer, Rapt, Regeneron, Sanofi-Genzyme, Spherix, Sun Pharmaceuticals Industries, TLL Pharmaceutical, TrialSpark, UCB Pharma, Vibliome, and Xencor.

Dr. Stein Gold disclosed ties with Almirall, Cutera, Dermata, Galderma, Novartis, Ortho Dermatologics, and Sun Pharmaceutical Industries, Ltd.

Medscape and this news organization are owned by the same parent company.

HONOLULU – During office visits with Andrew Blauvelt, MD, MBA, many patients well controlled on biologic therapy for their moderate to severe psoriasis often ask him when their scheduled injections can stop.

The most common question he hears is, “ ‘Why do I have to keep doing this? I’ve been clear for 2 or 3 years,’ ” Dr. Blauvelt, president of Oregon Medical Research Center, Portland, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “We have terrific drugs for psoriasis, but how can we do better?”

According to Dr. Blauvelt, there are at least six future strategies to treat psoriasis, induce remission, and/or cure the disease:

Development of oral biologics. At least two companies are developing a peptide-type small molecule that blocks interleukin (IL)-17 or IL-23 signaling, but would be given as a pill, he said. Another concept in the works is a robotic pill for drug delivery. The pill, which is being developed by Rani Therapeutics, protects the biotherapeutic drug payload from digestion in the GI tract and auto-injects it into the wall of the small intestine, according to a report of two studies that demonstrated the safety and tolerability of the robotic pill in healthy humans.

Doug Brunk/MDedge News

In an animal study, the same researchers showed that delivering monoclonal antibodies with the robotic pill achieved bioavailability on par with that obtained by standard subcutaneous injections.

Identifying “super responders” who require less frequent dosing of medication. “There’s data to suggest that we can kind of back off treatment in these patients,” Dr. Blauvelt said.

Hitting treatment hard and early. “There’s a concept in medicine of hitting disease hard and hitting it early, before the disease can establish itself and cause damage,” he said.

Targeting tissue resident memory T cells. In psoriasis, the idea is that if you treat earlier, when patients are just diagnosed, “perhaps you might be able to decrease resident memory T cells that set up shop in the skin and are responsible for disease recurrences,” Dr. Blauvelt said. “Research has shown that IL-23 blockers decrease tissue resident memory T cells, and IL-17 blockers don’t. This could explain why we see long remissions in this class of drug because we’re getting at these resident memory T cells and knocking them down,” he explained. “Our hypothesis is that hitting hard and early in the treatment course with high-dose IL-23 blockade may be an effective strategy to induce long-term remissions and possible cure, what we call ‘knock-out therapy.’ ”

In a pilot study of 20 patients, Dr. Blauvelt and colleagues are evaluating whether higher initial doses of the IL-23 antagonist risankizumab (300 mg and 600 mg, 2 times and 4 times the standard initial doses for plaque psoriasis) can more effectively target resident memory T cells. “This involves dosing at weeks 0, 4, and 16, then stopping and measuring resident T cells in the tissue to see how long we can induce psoriasis remissions,” Dr. Blauvelt said.

“I have no data to share, but I think we have the potential for unprecedented PASI-100 numbers with no added safety concerns, and the potential to break away from established regular dosing patterns,” such as the possibility of yearly dosing, the possibility of long-term remissions, and the possibility of cure in some patients, he noted.

Inducing tolerance. This refers to efforts aimed at increasing regulatory T cells, which are natural T cells that calm inflammation. He described it as “revving up our natural anti-inflammatory T cells to help balance the immune system.”

Gene editing. This involves using CRISPR gene editing technology to cut genes as a way to cure disease. “What if we cut the IL-23 receptor?” Dr. Blauvelt asked. “You would get rid of that whole signaling pathway. Would the patient be fine?”

In an interview a the meeting, Linda Stein Gold, MD, director of clinical research and division head of dermatology at the Henry Ford Health System, Detroit, said that Dr. Blauvelt “has a very exciting view” of the future of psoriasis treatments. “I think that some of it will come true; we’ll have to see which,” Dr. Stein Gold said. “The idea that we might be able to change the trajectory of disease by being aggressive upfront, and possibly modify the course, is exciting. That would be a wonderful new treatment approach.”

Dr. Blauvelt disclosed ties with AbbVie, Abcentra, Affibody, Aligos, Almirall, Alumis, Amgen, AnaptysBio, Arcutis, Arena, ASLAN Pharma, Athenex, Bluefin, Boehringer Ingelheim, Bristol Myers Squibb, Cara, Dermavant, EcoR1, Escient, Evelo, Evommune, Forte, Galderma, Highlightll, Incyte, Innovent Bio, Janssen, Landos, Leo, Lilly, Merck, Novartis, Pfizer, Rapt, Regeneron, Sanofi-Genzyme, Spherix, Sun Pharmaceuticals Industries, TLL Pharmaceutical, TrialSpark, UCB Pharma, Vibliome, and Xencor.

Dr. Stein Gold disclosed ties with Almirall, Cutera, Dermata, Galderma, Novartis, Ortho Dermatologics, and Sun Pharmaceutical Industries, Ltd.

Medscape and this news organization are owned by the same parent company.

HONOLULU – During office visits with Andrew Blauvelt, MD, MBA, many patients well controlled on biologic therapy for their moderate to severe psoriasis often ask him when their scheduled injections can stop.

The most common question he hears is, “ ‘Why do I have to keep doing this? I’ve been clear for 2 or 3 years,’ ” Dr. Blauvelt, president of Oregon Medical Research Center, Portland, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “We have terrific drugs for psoriasis, but how can we do better?”

According to Dr. Blauvelt, there are at least six future strategies to treat psoriasis, induce remission, and/or cure the disease:

Development of oral biologics. At least two companies are developing a peptide-type small molecule that blocks interleukin (IL)-17 or IL-23 signaling, but would be given as a pill, he said. Another concept in the works is a robotic pill for drug delivery. The pill, which is being developed by Rani Therapeutics, protects the biotherapeutic drug payload from digestion in the GI tract and auto-injects it into the wall of the small intestine, according to a report of two studies that demonstrated the safety and tolerability of the robotic pill in healthy humans.

Doug Brunk/MDedge News

In an animal study, the same researchers showed that delivering monoclonal antibodies with the robotic pill achieved bioavailability on par with that obtained by standard subcutaneous injections.

Identifying “super responders” who require less frequent dosing of medication. “There’s data to suggest that we can kind of back off treatment in these patients,” Dr. Blauvelt said.

Hitting treatment hard and early. “There’s a concept in medicine of hitting disease hard and hitting it early, before the disease can establish itself and cause damage,” he said.

Targeting tissue resident memory T cells. In psoriasis, the idea is that if you treat earlier, when patients are just diagnosed, “perhaps you might be able to decrease resident memory T cells that set up shop in the skin and are responsible for disease recurrences,” Dr. Blauvelt said. “Research has shown that IL-23 blockers decrease tissue resident memory T cells, and IL-17 blockers don’t. This could explain why we see long remissions in this class of drug because we’re getting at these resident memory T cells and knocking them down,” he explained. “Our hypothesis is that hitting hard and early in the treatment course with high-dose IL-23 blockade may be an effective strategy to induce long-term remissions and possible cure, what we call ‘knock-out therapy.’ ”

In a pilot study of 20 patients, Dr. Blauvelt and colleagues are evaluating whether higher initial doses of the IL-23 antagonist risankizumab (300 mg and 600 mg, 2 times and 4 times the standard initial doses for plaque psoriasis) can more effectively target resident memory T cells. “This involves dosing at weeks 0, 4, and 16, then stopping and measuring resident T cells in the tissue to see how long we can induce psoriasis remissions,” Dr. Blauvelt said.

“I have no data to share, but I think we have the potential for unprecedented PASI-100 numbers with no added safety concerns, and the potential to break away from established regular dosing patterns,” such as the possibility of yearly dosing, the possibility of long-term remissions, and the possibility of cure in some patients, he noted.

Inducing tolerance. This refers to efforts aimed at increasing regulatory T cells, which are natural T cells that calm inflammation. He described it as “revving up our natural anti-inflammatory T cells to help balance the immune system.”

Gene editing. This involves using CRISPR gene editing technology to cut genes as a way to cure disease. “What if we cut the IL-23 receptor?” Dr. Blauvelt asked. “You would get rid of that whole signaling pathway. Would the patient be fine?”

In an interview a the meeting, Linda Stein Gold, MD, director of clinical research and division head of dermatology at the Henry Ford Health System, Detroit, said that Dr. Blauvelt “has a very exciting view” of the future of psoriasis treatments. “I think that some of it will come true; we’ll have to see which,” Dr. Stein Gold said. “The idea that we might be able to change the trajectory of disease by being aggressive upfront, and possibly modify the course, is exciting. That would be a wonderful new treatment approach.”

Dr. Blauvelt disclosed ties with AbbVie, Abcentra, Affibody, Aligos, Almirall, Alumis, Amgen, AnaptysBio, Arcutis, Arena, ASLAN Pharma, Athenex, Bluefin, Boehringer Ingelheim, Bristol Myers Squibb, Cara, Dermavant, EcoR1, Escient, Evelo, Evommune, Forte, Galderma, Highlightll, Incyte, Innovent Bio, Janssen, Landos, Leo, Lilly, Merck, Novartis, Pfizer, Rapt, Regeneron, Sanofi-Genzyme, Spherix, Sun Pharmaceuticals Industries, TLL Pharmaceutical, TrialSpark, UCB Pharma, Vibliome, and Xencor.

Dr. Stein Gold disclosed ties with Almirall, Cutera, Dermata, Galderma, Novartis, Ortho Dermatologics, and Sun Pharmaceutical Industries, Ltd.

Medscape and this news organization are owned by the same parent company.

A new tool for predicting which patients with psoriasis will develop psoriatic arthritis (PsA) is showing promise for such clinical applications as early treatment in those at risk or trials to prevent PsA, according to a summary of progress at the annual meeting of the Canadian Rheumatology Association.

Based on current levels of sensitivity and specificity, psoriasis “can be predicted with reasonable accuracy,” reported Lihi Eder, MD, PhD, director of research in the rheumatology division at the University of Toronto.

The predictive method, called PRESTO (Prediction of Psoriatic Arthritis Tool), is based on variables readily available in clinical practice, according to Dr. Eder. Once values are assigned to the risk factors, the risk of PsA over a 1-year or 5-year time frame can be estimated with a calculator.

She called PRESTO the “first clinical tool for predicting PsA among psoriasis patients.”

The work on this tool began in 2006 when the International Psoriasis and Arthritis Research Team (IPART) initiated a prospectively collected cohort of psoriasis patients. To be enrolled, patients had to be free of signs and symptoms of arthritis upon examination by a rheumatologist. They were then invited to return annually for follow-up that again included screening for joint involvement by a rheumatologist.

At baseline and at follow-up evaluations, 13 predictors were evaluated. These involved psoriasis characteristics, such as nail pitting; symptoms, such as stiffness; comorbidities, such as additional inflammatory diseases; and laboratory values, such as upregulated markers of inflammation.

Symptoms and signs used to predict PsA

Dr. Eder and her colleagues applied regression models to select an optimal combination of variables weighted for predictive value. Variables offering predictive value included higher PASI (Psoriasis Area and Severity Index), greater fatigue score as measured by FACIT (Functional Assessment of Chronic Illness Therapy) score, greater morning stiffness, and greater pain.

When applied to 635 patients in the IPART cohort, in which there were 51 incident PsA cases over 1 year and 75 incident cases over 5 years, the area under the curve (AUC) for PRESTO at the cutoffs studied was 72% for the 1-year time window and 75% for the 5-year time window.

These levels are associated with adequate accuracy, according to Dr. Eder, who explained that “an AUC greater than 70% is considered reasonable” for clinical applicability.

Moreover, the cutoffs can be adjusted for the specific purpose of the predictive tool. For example, to screen patients for risk, lower cutoffs could be employed to increase sensitivity. In order to select patients for a clinical trial to prevent PsA, higher cutoffs could be employed to increase specificity.

But sensitivities and specificities move in opposite directions when cutoffs are adjusted. Showing data from the 5-year prediction model, Dr. Eder reported that specificities climbed from about 58% to 97% as cutoffs were increased. The sensitivities with these adjustments fell from 79% to 14%.

In general, Dr. Eder said there was “excellent calibration” for the cutoffs employed when they compared the predicted and observed rates of PsA according to quintile of predictive probability. The differences were particularly minor over a 1-year time period. Over the 5-year period, observed rates were somewhat higher than predicted in the fourth and fifth quintile, but, again, this discrepancy could be modified for specific applications with cutoff adjustments.

Validation studies are planned

Even though psoriasis patients in IPART represents one of the largest cohorts of prospectively collected psoriasis patients, Dr. Eder acknowledged that the sample size would be considered “moderate” for developing a predictive model. However, the fact that the data were collected prospectively using standardized methodology strengthens the findings and provides the basis for the next step.

“Validation studies are planned with external cohorts,” said Dr. Eder, who indicated that a viable tool for identifying psoriasis patients at risk for PsA is likely. Even if it is not employed routinely in its current form at the level of individual patient care, she predicted that it will have value at a research level for understanding the relationship of psoriasis to PsA.

Christopher T. Ritchlin, MD, a professor and researcher at the University of Rochester (N.Y.), agreed that PRESTO has important potential as a clinical tool. Dr. Ritchlin has been involved in the development of PRESTO but was not involved in the presentation made at the CRA annual meeting.

“The PRESTO tool has the ability to predict the 2- and 5-year risk of developing psoriatic arthritis, which is an important advance if confirmed,” he said in an interview. He pointed out that approximately 25%-30% who develop psoriasis will go on to develop PsA but until now there has been no way to identify them.

“This tool may provide a pathway to early intervention,” he said.

Dr. Eder has financial relationships with AbbVie, Eli Lilly, Fresenius Kabi, Janssen, Novartis, Pfizer, Sandoz, and UCB. Dr. Ritchlin has financial relationships with many of the same companies.

A new tool for predicting which patients with psoriasis will develop psoriatic arthritis (PsA) is showing promise for such clinical applications as early treatment in those at risk or trials to prevent PsA, according to a summary of progress at the annual meeting of the Canadian Rheumatology Association.

Based on current levels of sensitivity and specificity, psoriasis “can be predicted with reasonable accuracy,” reported Lihi Eder, MD, PhD, director of research in the rheumatology division at the University of Toronto.

The predictive method, called PRESTO (Prediction of Psoriatic Arthritis Tool), is based on variables readily available in clinical practice, according to Dr. Eder. Once values are assigned to the risk factors, the risk of PsA over a 1-year or 5-year time frame can be estimated with a calculator.

She called PRESTO the “first clinical tool for predicting PsA among psoriasis patients.”

The work on this tool began in 2006 when the International Psoriasis and Arthritis Research Team (IPART) initiated a prospectively collected cohort of psoriasis patients. To be enrolled, patients had to be free of signs and symptoms of arthritis upon examination by a rheumatologist. They were then invited to return annually for follow-up that again included screening for joint involvement by a rheumatologist.

At baseline and at follow-up evaluations, 13 predictors were evaluated. These involved psoriasis characteristics, such as nail pitting; symptoms, such as stiffness; comorbidities, such as additional inflammatory diseases; and laboratory values, such as upregulated markers of inflammation.

Symptoms and signs used to predict PsA

Dr. Eder and her colleagues applied regression models to select an optimal combination of variables weighted for predictive value. Variables offering predictive value included higher PASI (Psoriasis Area and Severity Index), greater fatigue score as measured by FACIT (Functional Assessment of Chronic Illness Therapy) score, greater morning stiffness, and greater pain.

When applied to 635 patients in the IPART cohort, in which there were 51 incident PsA cases over 1 year and 75 incident cases over 5 years, the area under the curve (AUC) for PRESTO at the cutoffs studied was 72% for the 1-year time window and 75% for the 5-year time window.

These levels are associated with adequate accuracy, according to Dr. Eder, who explained that “an AUC greater than 70% is considered reasonable” for clinical applicability.

Moreover, the cutoffs can be adjusted for the specific purpose of the predictive tool. For example, to screen patients for risk, lower cutoffs could be employed to increase sensitivity. In order to select patients for a clinical trial to prevent PsA, higher cutoffs could be employed to increase specificity.

But sensitivities and specificities move in opposite directions when cutoffs are adjusted. Showing data from the 5-year prediction model, Dr. Eder reported that specificities climbed from about 58% to 97% as cutoffs were increased. The sensitivities with these adjustments fell from 79% to 14%.

In general, Dr. Eder said there was “excellent calibration” for the cutoffs employed when they compared the predicted and observed rates of PsA according to quintile of predictive probability. The differences were particularly minor over a 1-year time period. Over the 5-year period, observed rates were somewhat higher than predicted in the fourth and fifth quintile, but, again, this discrepancy could be modified for specific applications with cutoff adjustments.

Validation studies are planned

Even though psoriasis patients in IPART represents one of the largest cohorts of prospectively collected psoriasis patients, Dr. Eder acknowledged that the sample size would be considered “moderate” for developing a predictive model. However, the fact that the data were collected prospectively using standardized methodology strengthens the findings and provides the basis for the next step.

“Validation studies are planned with external cohorts,” said Dr. Eder, who indicated that a viable tool for identifying psoriasis patients at risk for PsA is likely. Even if it is not employed routinely in its current form at the level of individual patient care, she predicted that it will have value at a research level for understanding the relationship of psoriasis to PsA.

Christopher T. Ritchlin, MD, a professor and researcher at the University of Rochester (N.Y.), agreed that PRESTO has important potential as a clinical tool. Dr. Ritchlin has been involved in the development of PRESTO but was not involved in the presentation made at the CRA annual meeting.

“The PRESTO tool has the ability to predict the 2- and 5-year risk of developing psoriatic arthritis, which is an important advance if confirmed,” he said in an interview. He pointed out that approximately 25%-30% who develop psoriasis will go on to develop PsA but until now there has been no way to identify them.

“This tool may provide a pathway to early intervention,” he said.

Dr. Eder has financial relationships with AbbVie, Eli Lilly, Fresenius Kabi, Janssen, Novartis, Pfizer, Sandoz, and UCB. Dr. Ritchlin has financial relationships with many of the same companies.

A new tool for predicting which patients with psoriasis will develop psoriatic arthritis (PsA) is showing promise for such clinical applications as early treatment in those at risk or trials to prevent PsA, according to a summary of progress at the annual meeting of the Canadian Rheumatology Association.

Based on current levels of sensitivity and specificity, psoriasis “can be predicted with reasonable accuracy,” reported Lihi Eder, MD, PhD, director of research in the rheumatology division at the University of Toronto.

The predictive method, called PRESTO (Prediction of Psoriatic Arthritis Tool), is based on variables readily available in clinical practice, according to Dr. Eder. Once values are assigned to the risk factors, the risk of PsA over a 1-year or 5-year time frame can be estimated with a calculator.

She called PRESTO the “first clinical tool for predicting PsA among psoriasis patients.”

The work on this tool began in 2006 when the International Psoriasis and Arthritis Research Team (IPART) initiated a prospectively collected cohort of psoriasis patients. To be enrolled, patients had to be free of signs and symptoms of arthritis upon examination by a rheumatologist. They were then invited to return annually for follow-up that again included screening for joint involvement by a rheumatologist.

At baseline and at follow-up evaluations, 13 predictors were evaluated. These involved psoriasis characteristics, such as nail pitting; symptoms, such as stiffness; comorbidities, such as additional inflammatory diseases; and laboratory values, such as upregulated markers of inflammation.

Symptoms and signs used to predict PsA

Dr. Eder and her colleagues applied regression models to select an optimal combination of variables weighted for predictive value. Variables offering predictive value included higher PASI (Psoriasis Area and Severity Index), greater fatigue score as measured by FACIT (Functional Assessment of Chronic Illness Therapy) score, greater morning stiffness, and greater pain.

When applied to 635 patients in the IPART cohort, in which there were 51 incident PsA cases over 1 year and 75 incident cases over 5 years, the area under the curve (AUC) for PRESTO at the cutoffs studied was 72% for the 1-year time window and 75% for the 5-year time window.

These levels are associated with adequate accuracy, according to Dr. Eder, who explained that “an AUC greater than 70% is considered reasonable” for clinical applicability.

Moreover, the cutoffs can be adjusted for the specific purpose of the predictive tool. For example, to screen patients for risk, lower cutoffs could be employed to increase sensitivity. In order to select patients for a clinical trial to prevent PsA, higher cutoffs could be employed to increase specificity.

But sensitivities and specificities move in opposite directions when cutoffs are adjusted. Showing data from the 5-year prediction model, Dr. Eder reported that specificities climbed from about 58% to 97% as cutoffs were increased. The sensitivities with these adjustments fell from 79% to 14%.

In general, Dr. Eder said there was “excellent calibration” for the cutoffs employed when they compared the predicted and observed rates of PsA according to quintile of predictive probability. The differences were particularly minor over a 1-year time period. Over the 5-year period, observed rates were somewhat higher than predicted in the fourth and fifth quintile, but, again, this discrepancy could be modified for specific applications with cutoff adjustments.

Validation studies are planned

Even though psoriasis patients in IPART represents one of the largest cohorts of prospectively collected psoriasis patients, Dr. Eder acknowledged that the sample size would be considered “moderate” for developing a predictive model. However, the fact that the data were collected prospectively using standardized methodology strengthens the findings and provides the basis for the next step.

“Validation studies are planned with external cohorts,” said Dr. Eder, who indicated that a viable tool for identifying psoriasis patients at risk for PsA is likely. Even if it is not employed routinely in its current form at the level of individual patient care, she predicted that it will have value at a research level for understanding the relationship of psoriasis to PsA.

Christopher T. Ritchlin, MD, a professor and researcher at the University of Rochester (N.Y.), agreed that PRESTO has important potential as a clinical tool. Dr. Ritchlin has been involved in the development of PRESTO but was not involved in the presentation made at the CRA annual meeting.

“The PRESTO tool has the ability to predict the 2- and 5-year risk of developing psoriatic arthritis, which is an important advance if confirmed,” he said in an interview. He pointed out that approximately 25%-30% who develop psoriasis will go on to develop PsA but until now there has been no way to identify them.

“This tool may provide a pathway to early intervention,” he said.

Dr. Eder has financial relationships with AbbVie, Eli Lilly, Fresenius Kabi, Janssen, Novartis, Pfizer, Sandoz, and UCB. Dr. Ritchlin has financial relationships with many of the same companies.

Friday, Feb. 10, 2023, marked the first time a patient told me they had used ChatGPT to answer a medical question. I’ve been reluctant to write about this super-buzzy new AI chatbot, but I am starting to think it is the real deal. Just how powerful is it? Well, ChatGPT might in fact be writing this column right now. It isn’t. No really, it’s me. But if not for the few cues (“super-buzzy”) that you’ll recognize as my writing voice, there might not be any way for you to know if I wrote this or not.

It’s perfectly OK if you’ve no clue what I’m talking about. ChatGPT is an AI chatbot that burst into public view just a couple months ago. Not your parent’s chatbot, this one is capable of answering questions in conversational language. It is jaw-droppingly good. Like Google, you can type in a question and it offers you answers. Rather than giving you a list of websites and a few Wikipedia blurbs, however, ChatGPT answers your question in human-like text. It can also create content on demand. For example, I asked it to write a Valentine poem to a dermatologist, and it gave me five stanzas starting with:

Oh gentle healer of skin so fair,
Your touch is soft and hands so rare,
With your skills and gentle care,
You make my heart skip with a flare.

Not good enough to send to my wife. But not bad.

If you ask it again, it will create a whole new one for you. Amusing, yes? What if you asked ChatGPT to explain psoriasis, or any medical condition for that matter, to a patient? The replies are quite good. Some even better than what I’m currently using for my patients. It can also offer treatment recommendations, vacation advice, and plan, with recipes, a dinner party for six with one vegan and one gluten-free couple. If you are a programmer, it can write code. Ask it for a Wordpress plugin to add to your website and your eyes will widen as you see it magically appear before you. What if you find that you just don’t like your daughter’s new boyfriend? Yep, it will write the text or email for you to help with this discussion. I’ve saved that one.

I tried “What are treatments for bullous pemphigoid that has been refractory to topical steroid, oral prednisone, and oral tetracyclines?” It replied with five ideas, including the standard methotrexate and azathioprine but also IVIG, Rituxan, even other biologics. Write an op note? Appeal a denied prior authorization to a payer? Write a clinic note for a complete skin exam? Check, check, check. Are you starting to think it might be the real deal, too?

Before we sell the farm though, there are significant limitations. Despite how swotty ChatGPT seems, it is not smart. That is, “it” has no idea what “it” is saying. ChatGPT is an incredibly sophisticated algorithm that has learned the probability of what word comes next in a conversation. To do so, it read the Internet. Billions (trillions?) of words make it possible to predict what is the best answer to any question. But – it’s only as good as the Internet, so there’s that. My patient who used ChatGPT has dissecting cellulitis and asked what to do for scarring alopecia. Some of the answers were reasonable, but some, such as transplanting hairs into the scarred areas, would not likely be helpful. That is unless ChatGPT knows something I don’t.

Having wasted hours of time playing with this thing rather than writing my column, I asked ChatGPT to write an article about itself in the style of Christopher Hitchens. It was nothing like his incisive and eloquent prose, but it wrote 500 words in a few seconds ending with:

“The reality is that there is no substitute for human interaction and empathy in the field of dermatology. Dermatologists must be cautious in their adoption of ChatGPT and ensure that they are not sacrificing the quality of patient care in the pursuit of efficiency and convenience.”

I’m not sure I could have said it better myself.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

Friday, Feb. 10, 2023, marked the first time a patient told me they had used ChatGPT to answer a medical question. I’ve been reluctant to write about this super-buzzy new AI chatbot, but I am starting to think it is the real deal. Just how powerful is it? Well, ChatGPT might in fact be writing this column right now. It isn’t. No really, it’s me. But if not for the few cues (“super-buzzy”) that you’ll recognize as my writing voice, there might not be any way for you to know if I wrote this or not.

It’s perfectly OK if you’ve no clue what I’m talking about. ChatGPT is an AI chatbot that burst into public view just a couple months ago. Not your parent’s chatbot, this one is capable of answering questions in conversational language. It is jaw-droppingly good. Like Google, you can type in a question and it offers you answers. Rather than giving you a list of websites and a few Wikipedia blurbs, however, ChatGPT answers your question in human-like text. It can also create content on demand. For example, I asked it to write a Valentine poem to a dermatologist, and it gave me five stanzas starting with:

Oh gentle healer of skin so fair,
Your touch is soft and hands so rare,
With your skills and gentle care,
You make my heart skip with a flare.

Not good enough to send to my wife. But not bad.

If you ask it again, it will create a whole new one for you. Amusing, yes? What if you asked ChatGPT to explain psoriasis, or any medical condition for that matter, to a patient? The replies are quite good. Some even better than what I’m currently using for my patients. It can also offer treatment recommendations, vacation advice, and plan, with recipes, a dinner party for six with one vegan and one gluten-free couple. If you are a programmer, it can write code. Ask it for a Wordpress plugin to add to your website and your eyes will widen as you see it magically appear before you. What if you find that you just don’t like your daughter’s new boyfriend? Yep, it will write the text or email for you to help with this discussion. I’ve saved that one.

I tried “What are treatments for bullous pemphigoid that has been refractory to topical steroid, oral prednisone, and oral tetracyclines?” It replied with five ideas, including the standard methotrexate and azathioprine but also IVIG, Rituxan, even other biologics. Write an op note? Appeal a denied prior authorization to a payer? Write a clinic note for a complete skin exam? Check, check, check. Are you starting to think it might be the real deal, too?

Before we sell the farm though, there are significant limitations. Despite how swotty ChatGPT seems, it is not smart. That is, “it” has no idea what “it” is saying. ChatGPT is an incredibly sophisticated algorithm that has learned the probability of what word comes next in a conversation. To do so, it read the Internet. Billions (trillions?) of words make it possible to predict what is the best answer to any question. But – it’s only as good as the Internet, so there’s that. My patient who used ChatGPT has dissecting cellulitis and asked what to do for scarring alopecia. Some of the answers were reasonable, but some, such as transplanting hairs into the scarred areas, would not likely be helpful. That is unless ChatGPT knows something I don’t.

Having wasted hours of time playing with this thing rather than writing my column, I asked ChatGPT to write an article about itself in the style of Christopher Hitchens. It was nothing like his incisive and eloquent prose, but it wrote 500 words in a few seconds ending with:

“The reality is that there is no substitute for human interaction and empathy in the field of dermatology. Dermatologists must be cautious in their adoption of ChatGPT and ensure that they are not sacrificing the quality of patient care in the pursuit of efficiency and convenience.”

I’m not sure I could have said it better myself.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

Friday, Feb. 10, 2023, marked the first time a patient told me they had used ChatGPT to answer a medical question. I’ve been reluctant to write about this super-buzzy new AI chatbot, but I am starting to think it is the real deal. Just how powerful is it? Well, ChatGPT might in fact be writing this column right now. It isn’t. No really, it’s me. But if not for the few cues (“super-buzzy”) that you’ll recognize as my writing voice, there might not be any way for you to know if I wrote this or not.

It’s perfectly OK if you’ve no clue what I’m talking about. ChatGPT is an AI chatbot that burst into public view just a couple months ago. Not your parent’s chatbot, this one is capable of answering questions in conversational language. It is jaw-droppingly good. Like Google, you can type in a question and it offers you answers. Rather than giving you a list of websites and a few Wikipedia blurbs, however, ChatGPT answers your question in human-like text. It can also create content on demand. For example, I asked it to write a Valentine poem to a dermatologist, and it gave me five stanzas starting with:

Oh gentle healer of skin so fair,
Your touch is soft and hands so rare,
With your skills and gentle care,
You make my heart skip with a flare.

Not good enough to send to my wife. But not bad.

If you ask it again, it will create a whole new one for you. Amusing, yes? What if you asked ChatGPT to explain psoriasis, or any medical condition for that matter, to a patient? The replies are quite good. Some even better than what I’m currently using for my patients. It can also offer treatment recommendations, vacation advice, and plan, with recipes, a dinner party for six with one vegan and one gluten-free couple. If you are a programmer, it can write code. Ask it for a Wordpress plugin to add to your website and your eyes will widen as you see it magically appear before you. What if you find that you just don’t like your daughter’s new boyfriend? Yep, it will write the text or email for you to help with this discussion. I’ve saved that one.

I tried “What are treatments for bullous pemphigoid that has been refractory to topical steroid, oral prednisone, and oral tetracyclines?” It replied with five ideas, including the standard methotrexate and azathioprine but also IVIG, Rituxan, even other biologics. Write an op note? Appeal a denied prior authorization to a payer? Write a clinic note for a complete skin exam? Check, check, check. Are you starting to think it might be the real deal, too?

Before we sell the farm though, there are significant limitations. Despite how swotty ChatGPT seems, it is not smart. That is, “it” has no idea what “it” is saying. ChatGPT is an incredibly sophisticated algorithm that has learned the probability of what word comes next in a conversation. To do so, it read the Internet. Billions (trillions?) of words make it possible to predict what is the best answer to any question. But – it’s only as good as the Internet, so there’s that. My patient who used ChatGPT has dissecting cellulitis and asked what to do for scarring alopecia. Some of the answers were reasonable, but some, such as transplanting hairs into the scarred areas, would not likely be helpful. That is unless ChatGPT knows something I don’t.

Having wasted hours of time playing with this thing rather than writing my column, I asked ChatGPT to write an article about itself in the style of Christopher Hitchens. It was nothing like his incisive and eloquent prose, but it wrote 500 words in a few seconds ending with:

“The reality is that there is no substitute for human interaction and empathy in the field of dermatology. Dermatologists must be cautious in their adoption of ChatGPT and ensure that they are not sacrificing the quality of patient care in the pursuit of efficiency and convenience.”

I’m not sure I could have said it better myself.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

Both public and private health plans score poorly when it comes to providing access to autoimmune medication, according to a report commissioned by the Autoimmune Association and Let My Doctors Decide, a national partnership of health care professionals. The analysis, published Jan. 26, found that 75% of insurers in the United States have policies that can limit coverage for Food and Drug Administration–approved medications for Crohn’s disease, lupus nephritis, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis.

“Choice among health plans is a hallmark of the American health insurance system, yet this analysis shows that people living with autoimmune conditions have few, if any, coverage choices that do not involve significant to severe access restrictions,” the authors wrote.

The study looked at three common utilization management policies by health plans that can limit coverage of certain medications: step therapy, formulary/tier placement, and prior authorization. To compare health plans, researchers weighted these policies using a point system. Each medication indicated for each condition was given a score of 0-4 based on access restrictions in a health plan. If a plan used step therapy, it received one point, and requiring prior authorization added an additional point. They also added points based on where a drug appeared on a plan’s formulary. A lower total score meant fewer access barriers. The numbers were then added, and each health plan received a grade of A, B, C, or F based on their average score. The datasets and analysis were provided and performed by the data analytics firm MMIT.

Nearly 9 in 10 Medicare plans received a C or worse for coverage of medication received via mail order or the pharmacy. In commercial plans, the majority of plans scored Cs or Fs for six of the seven conditions, excluding lupus nephritis, where 67% of all commercial health plans scored a B for access to these medications.

Physician-administered medications tended to receive poorer coverage than drugs received via pharmacy. Across all conditions, 65% of Medicare Advantage plans scored an F for physician-administered medication access. For both psoriasis and multiple sclerosis, at least 80% of Medicare plans earned failing scores because of these restrictions. Coverage was poorer on both commercial and health exchange plans, where across all conditions, 83% achieved failing scores. Two exceptions were the Southern and Northern California PPO plans by the Kaiser Foundation Health Plan. Out of the largest 25 health plans in the United States, these two plans earned As in coverage for physician-administered medications across all seven autoimmune conditions.

The report shows “a growing disconnect between science and health insurance benefit designs that were developed in the 1960s and 1970s,” Kenneth Thorpe, PhD, of Emory University, Atlanta, said in an interview. Insurers originally designed these benefits to prevent excessive utilization in a population of mostly acutely ill patients, he said, whereas now, 90% of healthcare spending is linked to chronic conditions. For these patients, research shows that incentivizing patients to adhere to medications results in fewer hospitalizations and, therefore, more cost savings, Thorpe noted. These plans also do not consider that there is no average patient, he said, and healthcare providers should be able to match each patient to the best treatment option for them rather than trying out other less expensive medications first. “To the extent that physicians can have the flexibility to provide medications and treatments to patients that are going to have the best clinical response, that’s better outcomes at lower cost,” Dr. Thorpe said. While research shows heterogeneity in patient outcomes with different medication, “benefit designs from the past just don’t recognize that.”

Neither America’s Health Insurance Plans nor Pharmaceutical Care Management Association responded to a request for comment.

Quardricos Driskell, executive director of Let My Doctors Decide and vice president of government relations and public policy at the Autoimmune Association, hopes the study will spur action by policy makers and health plans to improve access to medications for the people who need them. Another larger point of the report is to “uphold the sanctity of protecting the doctor and patient relationship,” he said in an interview, adding “that decisions fundamentally need to be made not by insurance plans or middleman pharmacy benefit managers, but by the provider and patient.”

Mr. Driskell and Dr. Thorpe reported no relevant financial relationships. 

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

Both public and private health plans score poorly when it comes to providing access to autoimmune medication, according to a report commissioned by the Autoimmune Association and Let My Doctors Decide, a national partnership of health care professionals. The analysis, published Jan. 26, found that 75% of insurers in the United States have policies that can limit coverage for Food and Drug Administration–approved medications for Crohn’s disease, lupus nephritis, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis.

“Choice among health plans is a hallmark of the American health insurance system, yet this analysis shows that people living with autoimmune conditions have few, if any, coverage choices that do not involve significant to severe access restrictions,” the authors wrote.

The study looked at three common utilization management policies by health plans that can limit coverage of certain medications: step therapy, formulary/tier placement, and prior authorization. To compare health plans, researchers weighted these policies using a point system. Each medication indicated for each condition was given a score of 0-4 based on access restrictions in a health plan. If a plan used step therapy, it received one point, and requiring prior authorization added an additional point. They also added points based on where a drug appeared on a plan’s formulary. A lower total score meant fewer access barriers. The numbers were then added, and each health plan received a grade of A, B, C, or F based on their average score. The datasets and analysis were provided and performed by the data analytics firm MMIT.

Nearly 9 in 10 Medicare plans received a C or worse for coverage of medication received via mail order or the pharmacy. In commercial plans, the majority of plans scored Cs or Fs for six of the seven conditions, excluding lupus nephritis, where 67% of all commercial health plans scored a B for access to these medications.

Physician-administered medications tended to receive poorer coverage than drugs received via pharmacy. Across all conditions, 65% of Medicare Advantage plans scored an F for physician-administered medication access. For both psoriasis and multiple sclerosis, at least 80% of Medicare plans earned failing scores because of these restrictions. Coverage was poorer on both commercial and health exchange plans, where across all conditions, 83% achieved failing scores. Two exceptions were the Southern and Northern California PPO plans by the Kaiser Foundation Health Plan. Out of the largest 25 health plans in the United States, these two plans earned As in coverage for physician-administered medications across all seven autoimmune conditions.

The report shows “a growing disconnect between science and health insurance benefit designs that were developed in the 1960s and 1970s,” Kenneth Thorpe, PhD, of Emory University, Atlanta, said in an interview. Insurers originally designed these benefits to prevent excessive utilization in a population of mostly acutely ill patients, he said, whereas now, 90% of healthcare spending is linked to chronic conditions. For these patients, research shows that incentivizing patients to adhere to medications results in fewer hospitalizations and, therefore, more cost savings, Thorpe noted. These plans also do not consider that there is no average patient, he said, and healthcare providers should be able to match each patient to the best treatment option for them rather than trying out other less expensive medications first. “To the extent that physicians can have the flexibility to provide medications and treatments to patients that are going to have the best clinical response, that’s better outcomes at lower cost,” Dr. Thorpe said. While research shows heterogeneity in patient outcomes with different medication, “benefit designs from the past just don’t recognize that.”

Neither America’s Health Insurance Plans nor Pharmaceutical Care Management Association responded to a request for comment.

Quardricos Driskell, executive director of Let My Doctors Decide and vice president of government relations and public policy at the Autoimmune Association, hopes the study will spur action by policy makers and health plans to improve access to medications for the people who need them. Another larger point of the report is to “uphold the sanctity of protecting the doctor and patient relationship,” he said in an interview, adding “that decisions fundamentally need to be made not by insurance plans or middleman pharmacy benefit managers, but by the provider and patient.”

Mr. Driskell and Dr. Thorpe reported no relevant financial relationships. 

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

Both public and private health plans score poorly when it comes to providing access to autoimmune medication, according to a report commissioned by the Autoimmune Association and Let My Doctors Decide, a national partnership of health care professionals. The analysis, published Jan. 26, found that 75% of insurers in the United States have policies that can limit coverage for Food and Drug Administration–approved medications for Crohn’s disease, lupus nephritis, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis.

“Choice among health plans is a hallmark of the American health insurance system, yet this analysis shows that people living with autoimmune conditions have few, if any, coverage choices that do not involve significant to severe access restrictions,” the authors wrote.

The study looked at three common utilization management policies by health plans that can limit coverage of certain medications: step therapy, formulary/tier placement, and prior authorization. To compare health plans, researchers weighted these policies using a point system. Each medication indicated for each condition was given a score of 0-4 based on access restrictions in a health plan. If a plan used step therapy, it received one point, and requiring prior authorization added an additional point. They also added points based on where a drug appeared on a plan’s formulary. A lower total score meant fewer access barriers. The numbers were then added, and each health plan received a grade of A, B, C, or F based on their average score. The datasets and analysis were provided and performed by the data analytics firm MMIT.

Nearly 9 in 10 Medicare plans received a C or worse for coverage of medication received via mail order or the pharmacy. In commercial plans, the majority of plans scored Cs or Fs for six of the seven conditions, excluding lupus nephritis, where 67% of all commercial health plans scored a B for access to these medications.

Physician-administered medications tended to receive poorer coverage than drugs received via pharmacy. Across all conditions, 65% of Medicare Advantage plans scored an F for physician-administered medication access. For both psoriasis and multiple sclerosis, at least 80% of Medicare plans earned failing scores because of these restrictions. Coverage was poorer on both commercial and health exchange plans, where across all conditions, 83% achieved failing scores. Two exceptions were the Southern and Northern California PPO plans by the Kaiser Foundation Health Plan. Out of the largest 25 health plans in the United States, these two plans earned As in coverage for physician-administered medications across all seven autoimmune conditions.

The report shows “a growing disconnect between science and health insurance benefit designs that were developed in the 1960s and 1970s,” Kenneth Thorpe, PhD, of Emory University, Atlanta, said in an interview. Insurers originally designed these benefits to prevent excessive utilization in a population of mostly acutely ill patients, he said, whereas now, 90% of healthcare spending is linked to chronic conditions. For these patients, research shows that incentivizing patients to adhere to medications results in fewer hospitalizations and, therefore, more cost savings, Thorpe noted. These plans also do not consider that there is no average patient, he said, and healthcare providers should be able to match each patient to the best treatment option for them rather than trying out other less expensive medications first. “To the extent that physicians can have the flexibility to provide medications and treatments to patients that are going to have the best clinical response, that’s better outcomes at lower cost,” Dr. Thorpe said. While research shows heterogeneity in patient outcomes with different medication, “benefit designs from the past just don’t recognize that.”

Neither America’s Health Insurance Plans nor Pharmaceutical Care Management Association responded to a request for comment.

Quardricos Driskell, executive director of Let My Doctors Decide and vice president of government relations and public policy at the Autoimmune Association, hopes the study will spur action by policy makers and health plans to improve access to medications for the people who need them. Another larger point of the report is to “uphold the sanctity of protecting the doctor and patient relationship,” he said in an interview, adding “that decisions fundamentally need to be made not by insurance plans or middleman pharmacy benefit managers, but by the provider and patient.”

Mr. Driskell and Dr. Thorpe reported no relevant financial relationships. 

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

The first biosimilar for Humira, adalimumab-atto (Amjevita), is now available in the United States, according to an announcement on Jan. 31 by the manufacturer, Amgen. At least seven other U.S. Food and Drug Administration–approved Humira biosimilars are expected to become available later in 2023.

Amjevita was approved by the FDA in September 2016 for multiple inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. The delayed launch was part of a global settlement with Humira’s manufacturer, AbbVie.

Humira (adalimumab) has been available since 2002 and is consistently one of the top-selling drugs in the United States. A single 40-mg Amjevita pen device will be available at two prices: a list price (wholesale acquisition cost) of $1,557.59, 55% below the current Humira list price, and a list price of $3,288.24, 5% below the current Humira list price, according to Amgen.

“Amgen’s goal is to provide broad access for patients by offering two options to health plans and pharmacy benefit managers,” the company said in the press release.

Patients are less likely to benefit from the more significant discount, said Marta Wosinska, PhD, a health care economist at the Brookings Institute in Washington, DC. It's expected that insurance companies will use the higher list price for Amjevita, she said, as this higher price will also likely have higher rebates. Rebates are payments to health insurance payers provided by drug manufacturers to promote use of an expensive drug. Some pharmacy benefit managers have already said that they plan to charge patients the same amount for Humira as its biosimilars, Dr. Wosinska said.

"For an existing patient, there's really no incentive for them to switch," she said in an interview.

So far only one insurance company, Kaiser Permanente, has plans to switch patients over to biosimilars, according to the health policy podcast Tradeoffs, and the insurer will stop covering Humira by the end of this year.

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

*This story was updated 2/1/2023.

The first biosimilar for Humira, adalimumab-atto (Amjevita), is now available in the United States, according to an announcement on Jan. 31 by the manufacturer, Amgen. At least seven other U.S. Food and Drug Administration–approved Humira biosimilars are expected to become available later in 2023.

Amjevita was approved by the FDA in September 2016 for multiple inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. The delayed launch was part of a global settlement with Humira’s manufacturer, AbbVie.

Humira (adalimumab) has been available since 2002 and is consistently one of the top-selling drugs in the United States. A single 40-mg Amjevita pen device will be available at two prices: a list price (wholesale acquisition cost) of $1,557.59, 55% below the current Humira list price, and a list price of $3,288.24, 5% below the current Humira list price, according to Amgen.

“Amgen’s goal is to provide broad access for patients by offering two options to health plans and pharmacy benefit managers,” the company said in the press release.

Patients are less likely to benefit from the more significant discount, said Marta Wosinska, PhD, a health care economist at the Brookings Institute in Washington, DC. It's expected that insurance companies will use the higher list price for Amjevita, she said, as this higher price will also likely have higher rebates. Rebates are payments to health insurance payers provided by drug manufacturers to promote use of an expensive drug. Some pharmacy benefit managers have already said that they plan to charge patients the same amount for Humira as its biosimilars, Dr. Wosinska said.

"For an existing patient, there's really no incentive for them to switch," she said in an interview.

So far only one insurance company, Kaiser Permanente, has plans to switch patients over to biosimilars, according to the health policy podcast Tradeoffs, and the insurer will stop covering Humira by the end of this year.

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

*This story was updated 2/1/2023.

The first biosimilar for Humira, adalimumab-atto (Amjevita), is now available in the United States, according to an announcement on Jan. 31 by the manufacturer, Amgen. At least seven other U.S. Food and Drug Administration–approved Humira biosimilars are expected to become available later in 2023.

Amjevita was approved by the FDA in September 2016 for multiple inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. The delayed launch was part of a global settlement with Humira’s manufacturer, AbbVie.

Humira (adalimumab) has been available since 2002 and is consistently one of the top-selling drugs in the United States. A single 40-mg Amjevita pen device will be available at two prices: a list price (wholesale acquisition cost) of $1,557.59, 55% below the current Humira list price, and a list price of $3,288.24, 5% below the current Humira list price, according to Amgen.

“Amgen’s goal is to provide broad access for patients by offering two options to health plans and pharmacy benefit managers,” the company said in the press release.

Patients are less likely to benefit from the more significant discount, said Marta Wosinska, PhD, a health care economist at the Brookings Institute in Washington, DC. It's expected that insurance companies will use the higher list price for Amjevita, she said, as this higher price will also likely have higher rebates. Rebates are payments to health insurance payers provided by drug manufacturers to promote use of an expensive drug. Some pharmacy benefit managers have already said that they plan to charge patients the same amount for Humira as its biosimilars, Dr. Wosinska said.

"For an existing patient, there's really no incentive for them to switch," she said in an interview.

So far only one insurance company, Kaiser Permanente, has plans to switch patients over to biosimilars, according to the health policy podcast Tradeoffs, and the insurer will stop covering Humira by the end of this year.

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

*This story was updated 2/1/2023.

To the Editor:

Generalized pustular psoriasis (GPP) is a rare but severe subtype of psoriasis that can present with systemic symptoms and organ failure, sometimes leading to hospitalization and even death.^1,2 Due to the rarity of this subtype and GPP being excluded from clinical trials for plaque psoriasis, there is limited information on the optimal treatment of this disease.

More than 20 systemic medications have been described in the literature for treating GPP, including systemic steroids, traditional immunosuppressants, retinoids, and biologics, which often are used in combination; none have been consistently effective.³ Among biologic therapies, the use of tumor necrosis factor α as well as IL-12/23 and IL-17 inhibitors has been reported, with the least amount of experience with IL-17 inhibitors.⁴

A 53-year-old Korean woman presented to the dermatology clinic for evaluation of a widespread painful rash involving the face, neck, torso, arms, and legs that had been treated intermittently with systemic steroids by her primary care physician for several months before presentation. She had no relevant medical or dermatologic history. She denied taking prescription or over-the-counter medications.

Physical examination revealed the patient was afebrile, but she reported general malaise and chills. She had widespread erythematous, annular, scaly plaques that coalesced into polycyclic plaques studded with nonfollicular-based pustules on the forehead, frontal hairline, neck, chest, abdomen, back, arms, and legs (Figure 1).

Two 4-mm punch biopsies were performed for hematoxylin and eosin staining and direct immunofluorescence. Histopathologic analysis showed prominent subcorneal neutrophilic pustules and spongiform collections of neutrophils in the spinous layer without notable eosinophils (Figure 2). Direct immunofluorescence was negative.

Based on the clinical history, physical examination, histopathology, and unremarkable drug history, a diagnosis of GPP was made. Initially, acitretin 25 mg/d was prescribed, but the patient was unable to start treatment because the cost of the drug was prohibitive. Her condition worsened, and she returned to the clinic 2 days later. Based on knowledge of an ongoing phase 3, open-label study for risankizumab in GPP, a sample of risankizumab 150 mg was administered subcutaneously in this patient. Three days later, most of the pustules on the upper half of the patient’s body had dried up and she began to desquamate from head to toe (Figure 3).The patient developed notable edema of the lower extremities, which required furosemide 20 mg/d andibuprofen 600 mg every 6 hours for symptom relief.

Ten days after the initial dose of risankizumab, the patient continued to steadily improve. All the pustules had dried up and she was already showing signs of re-epithelialization. Edema and pain also had notably improved. She received 2 additional samples of risankizumab 150 mg at weeks 4 and 16, at which point she was able to receive compassionate care through the drug manufacturer’s program. At follow-up 151 days after the initial dose of risankizumab, the patient’s skin was completely clear.

Generalized pustular psoriasis remains a difficult disease to study, given its rarity and unpredictable course. Spesolimab, a humanized anti–IL-36 receptor monoclonal antibody, was recently approved by the US Food and Drug Administration (FDA) for the treatment of GPP.⁵ In the pivotal trial (ClinicalTrials.gov Identifier NCT03782792),⁵ an astonishingly high 54% of patients (19/35) given a single dose of intravenous spesolimab reached the primary end point of no pustules at day 7. However, safety concerns, such as serious infections and severe cutaneous adverse reactions, as well as logistical challenges that come with intravenous administration for an acute disease, may prevent widespread adoption by community dermatologists.

Tumor necrosis factor α, IL-17, and IL-23 inhibitors currently are approved for the treatment of GPP in Japan, Thailand, and Taiwan based on small, nonrandomized, open-label studies.^6-10 More recently, results from a phase 3, randomized, open-label study to assess the efficacy and safety of 2 different dosing regimens of risankizumab with 8 Japanese patients with GPP were published.¹¹ However, there currently is only a single approved medication for GPP in Europe and the United States. Therefore, additional therapies, particularly those that have already been established in dermatology, would be welcome in treating this disease.

A number of questions still need to be answered regarding treating GPP with risankizumab:

• What is the optimal dose and schedule of this drug? Our patient received the standard 150-mg dose that is FDA approved for moderate to severe plaque psoriasis; would a higher dose, such as the FDA-approved 600-mg dosing used to treat Crohn disease, have led to a more rapid and durable response?¹²

• For how long should these patients be treated? Will their disease follow the same course as psoriasis vulgaris, requiring long-term, continuous treatment?

• An ongoing 5-year, open-label extension study of spesolimab might eventually answer that question and currently is recruiting participants (NCT03886246).

• Is there a way to predict a priori which patients will be responders? Biomarkers—especially through the use of tape stripping—are promising, but validation studies are still needed.¹³

• Because 69% (24/35) of enrolled patients in the treatment group of the spesolimab trial did not harbor a mutation of the IL36RN gene, how reliable is mutation status in predicting treatment response?⁵

Of note, some of these questions also apply to guttate psoriasis, a far more common subtype of psoriasis that also is worth exploring.

Nevertheless, these are exciting times for patients with GPP. What was once considered an obscure orphan disease is the focus of major recent publications³ and phase 3, randomized, placebo-controlled studies.⁵ We can be cautiously optimistic that in the next few years we will be in a better position to care for patients with GPP.

To the Editor:

Generalized pustular psoriasis (GPP) is a rare but severe subtype of psoriasis that can present with systemic symptoms and organ failure, sometimes leading to hospitalization and even death.^1,2 Due to the rarity of this subtype and GPP being excluded from clinical trials for plaque psoriasis, there is limited information on the optimal treatment of this disease.

More than 20 systemic medications have been described in the literature for treating GPP, including systemic steroids, traditional immunosuppressants, retinoids, and biologics, which often are used in combination; none have been consistently effective.³ Among biologic therapies, the use of tumor necrosis factor α as well as IL-12/23 and IL-17 inhibitors has been reported, with the least amount of experience with IL-17 inhibitors.⁴

A 53-year-old Korean woman presented to the dermatology clinic for evaluation of a widespread painful rash involving the face, neck, torso, arms, and legs that had been treated intermittently with systemic steroids by her primary care physician for several months before presentation. She had no relevant medical or dermatologic history. She denied taking prescription or over-the-counter medications.

Physical examination revealed the patient was afebrile, but she reported general malaise and chills. She had widespread erythematous, annular, scaly plaques that coalesced into polycyclic plaques studded with nonfollicular-based pustules on the forehead, frontal hairline, neck, chest, abdomen, back, arms, and legs (Figure 1).

Two 4-mm punch biopsies were performed for hematoxylin and eosin staining and direct immunofluorescence. Histopathologic analysis showed prominent subcorneal neutrophilic pustules and spongiform collections of neutrophils in the spinous layer without notable eosinophils (Figure 2). Direct immunofluorescence was negative.

Based on the clinical history, physical examination, histopathology, and unremarkable drug history, a diagnosis of GPP was made. Initially, acitretin 25 mg/d was prescribed, but the patient was unable to start treatment because the cost of the drug was prohibitive. Her condition worsened, and she returned to the clinic 2 days later. Based on knowledge of an ongoing phase 3, open-label study for risankizumab in GPP, a sample of risankizumab 150 mg was administered subcutaneously in this patient. Three days later, most of the pustules on the upper half of the patient’s body had dried up and she began to desquamate from head to toe (Figure 3).The patient developed notable edema of the lower extremities, which required furosemide 20 mg/d andibuprofen 600 mg every 6 hours for symptom relief.

Ten days after the initial dose of risankizumab, the patient continued to steadily improve. All the pustules had dried up and she was already showing signs of re-epithelialization. Edema and pain also had notably improved. She received 2 additional samples of risankizumab 150 mg at weeks 4 and 16, at which point she was able to receive compassionate care through the drug manufacturer’s program. At follow-up 151 days after the initial dose of risankizumab, the patient’s skin was completely clear.

Generalized pustular psoriasis remains a difficult disease to study, given its rarity and unpredictable course. Spesolimab, a humanized anti–IL-36 receptor monoclonal antibody, was recently approved by the US Food and Drug Administration (FDA) for the treatment of GPP.⁵ In the pivotal trial (ClinicalTrials.gov Identifier NCT03782792),⁵ an astonishingly high 54% of patients (19/35) given a single dose of intravenous spesolimab reached the primary end point of no pustules at day 7. However, safety concerns, such as serious infections and severe cutaneous adverse reactions, as well as logistical challenges that come with intravenous administration for an acute disease, may prevent widespread adoption by community dermatologists.

Tumor necrosis factor α, IL-17, and IL-23 inhibitors currently are approved for the treatment of GPP in Japan, Thailand, and Taiwan based on small, nonrandomized, open-label studies.^6-10 More recently, results from a phase 3, randomized, open-label study to assess the efficacy and safety of 2 different dosing regimens of risankizumab with 8 Japanese patients with GPP were published.¹¹ However, there currently is only a single approved medication for GPP in Europe and the United States. Therefore, additional therapies, particularly those that have already been established in dermatology, would be welcome in treating this disease.

A number of questions still need to be answered regarding treating GPP with risankizumab:

• What is the optimal dose and schedule of this drug? Our patient received the standard 150-mg dose that is FDA approved for moderate to severe plaque psoriasis; would a higher dose, such as the FDA-approved 600-mg dosing used to treat Crohn disease, have led to a more rapid and durable response?¹²

• For how long should these patients be treated? Will their disease follow the same course as psoriasis vulgaris, requiring long-term, continuous treatment?

• An ongoing 5-year, open-label extension study of spesolimab might eventually answer that question and currently is recruiting participants (NCT03886246).

• Is there a way to predict a priori which patients will be responders? Biomarkers—especially through the use of tape stripping—are promising, but validation studies are still needed.¹³

• Because 69% (24/35) of enrolled patients in the treatment group of the spesolimab trial did not harbor a mutation of the IL36RN gene, how reliable is mutation status in predicting treatment response?⁵

Of note, some of these questions also apply to guttate psoriasis, a far more common subtype of psoriasis that also is worth exploring.

Nevertheless, these are exciting times for patients with GPP. What was once considered an obscure orphan disease is the focus of major recent publications³ and phase 3, randomized, placebo-controlled studies.⁵ We can be cautiously optimistic that in the next few years we will be in a better position to care for patients with GPP.

To the Editor:

Generalized pustular psoriasis (GPP) is a rare but severe subtype of psoriasis that can present with systemic symptoms and organ failure, sometimes leading to hospitalization and even death.^1,2 Due to the rarity of this subtype and GPP being excluded from clinical trials for plaque psoriasis, there is limited information on the optimal treatment of this disease.

More than 20 systemic medications have been described in the literature for treating GPP, including systemic steroids, traditional immunosuppressants, retinoids, and biologics, which often are used in combination; none have been consistently effective.³ Among biologic therapies, the use of tumor necrosis factor α as well as IL-12/23 and IL-17 inhibitors has been reported, with the least amount of experience with IL-17 inhibitors.⁴

A 53-year-old Korean woman presented to the dermatology clinic for evaluation of a widespread painful rash involving the face, neck, torso, arms, and legs that had been treated intermittently with systemic steroids by her primary care physician for several months before presentation. She had no relevant medical or dermatologic history. She denied taking prescription or over-the-counter medications.

Physical examination revealed the patient was afebrile, but she reported general malaise and chills. She had widespread erythematous, annular, scaly plaques that coalesced into polycyclic plaques studded with nonfollicular-based pustules on the forehead, frontal hairline, neck, chest, abdomen, back, arms, and legs (Figure 1).

Two 4-mm punch biopsies were performed for hematoxylin and eosin staining and direct immunofluorescence. Histopathologic analysis showed prominent subcorneal neutrophilic pustules and spongiform collections of neutrophils in the spinous layer without notable eosinophils (Figure 2). Direct immunofluorescence was negative.

Based on the clinical history, physical examination, histopathology, and unremarkable drug history, a diagnosis of GPP was made. Initially, acitretin 25 mg/d was prescribed, but the patient was unable to start treatment because the cost of the drug was prohibitive. Her condition worsened, and she returned to the clinic 2 days later. Based on knowledge of an ongoing phase 3, open-label study for risankizumab in GPP, a sample of risankizumab 150 mg was administered subcutaneously in this patient. Three days later, most of the pustules on the upper half of the patient’s body had dried up and she began to desquamate from head to toe (Figure 3).The patient developed notable edema of the lower extremities, which required furosemide 20 mg/d andibuprofen 600 mg every 6 hours for symptom relief.

Ten days after the initial dose of risankizumab, the patient continued to steadily improve. All the pustules had dried up and she was already showing signs of re-epithelialization. Edema and pain also had notably improved. She received 2 additional samples of risankizumab 150 mg at weeks 4 and 16, at which point she was able to receive compassionate care through the drug manufacturer’s program. At follow-up 151 days after the initial dose of risankizumab, the patient’s skin was completely clear.

Generalized pustular psoriasis remains a difficult disease to study, given its rarity and unpredictable course. Spesolimab, a humanized anti–IL-36 receptor monoclonal antibody, was recently approved by the US Food and Drug Administration (FDA) for the treatment of GPP.⁵ In the pivotal trial (ClinicalTrials.gov Identifier NCT03782792),⁵ an astonishingly high 54% of patients (19/35) given a single dose of intravenous spesolimab reached the primary end point of no pustules at day 7. However, safety concerns, such as serious infections and severe cutaneous adverse reactions, as well as logistical challenges that come with intravenous administration for an acute disease, may prevent widespread adoption by community dermatologists.

Tumor necrosis factor α, IL-17, and IL-23 inhibitors currently are approved for the treatment of GPP in Japan, Thailand, and Taiwan based on small, nonrandomized, open-label studies.^6-10 More recently, results from a phase 3, randomized, open-label study to assess the efficacy and safety of 2 different dosing regimens of risankizumab with 8 Japanese patients with GPP were published.¹¹ However, there currently is only a single approved medication for GPP in Europe and the United States. Therefore, additional therapies, particularly those that have already been established in dermatology, would be welcome in treating this disease.

A number of questions still need to be answered regarding treating GPP with risankizumab:

• What is the optimal dose and schedule of this drug? Our patient received the standard 150-mg dose that is FDA approved for moderate to severe plaque psoriasis; would a higher dose, such as the FDA-approved 600-mg dosing used to treat Crohn disease, have led to a more rapid and durable response?¹²

• For how long should these patients be treated? Will their disease follow the same course as psoriasis vulgaris, requiring long-term, continuous treatment?

• An ongoing 5-year, open-label extension study of spesolimab might eventually answer that question and currently is recruiting participants (NCT03886246).

• Is there a way to predict a priori which patients will be responders? Biomarkers—especially through the use of tape stripping—are promising, but validation studies are still needed.¹³

• Because 69% (24/35) of enrolled patients in the treatment group of the spesolimab trial did not harbor a mutation of the IL36RN gene, how reliable is mutation status in predicting treatment response?⁵

Of note, some of these questions also apply to guttate psoriasis, a far more common subtype of psoriasis that also is worth exploring.

Nevertheless, these are exciting times for patients with GPP. What was once considered an obscure orphan disease is the focus of major recent publications³ and phase 3, randomized, placebo-controlled studies.⁵ We can be cautiously optimistic that in the next few years we will be in a better position to care for patients with GPP.

To the Editor:

Because the SARS-CoV-2 virus is constantly changing, routine vaccination to prevent COVID-19 infection is recommended. The messenger RNA (mRNA) vaccines from Pfizer-BioNTech and Moderna as well as the Ad26.COV2.S (Johnson & Johnson) and NVX-CoV2373 (Novavax) vaccines are the most commonly used COVID-19 vaccines in the United States. Adverse effects following vaccination against SARS-CoV-2 are well documented; recent studies report a small incidence of adverse effects in the general population, with most being minor (eg, headache, fever, muscle pain).^1,2 Interestingly, reports of exacerbation of psoriasis and new-onset psoriasis following COVID-19 vaccination suggest a potential association.^3,4 However, the literature investigating the vaccine adverse effect profile in this demographic is scarce. We examined the incidence of adverse effects from SARS-CoV-2 vaccines in patients with psoriasis.

This retrospective cohort study used the COVID-19 Research Database (https://covid19researchdatabase.org/) to examine the adverse effects following the first and second doses of the mRNA vaccines in patients with and without psoriasis. The sample size for the Ad26.COV2.S vaccine was too small to analyze.

Claims were evaluated from August to October 2021 for 2 diagnoses of psoriasis prior to January 1, 2020, using the International Classification of Diseases, Tenth Revision (ICD-10) code L40.9 to increase the positive predictive value and ensure that the diagnosis preceded the COVID-19 pandemic. Patients younger than 18 years and those who did not receive 2 doses of a SARS-CoV-2 vaccine were excluded. Controls who did not have a diagnosis of psoriasis were matched for age, sex, and hypertension at a 4:1 ratio. Hypertension represented the most common comorbidity that could feasibly be controlled for in this study population. Other comorbidities recorded included obesity, type 2 diabetes mellitus, congestive heart failure, asthma, chronic obstructive pulmonary disease, chronic ischemic heart disease, rhinitis, and chronic kidney disease.

Common adverse effects as long as 30 days after vaccination were identified using ICD-10 codes. Adverse effects of interest were anaphylactic reaction, initial encounter of adverse effect of viral vaccines, fever, allergic urticaria, weakness, altered mental status, malaise, allergic reaction, chest pain, symptoms involving circulatory or respiratory systems, localized rash, axillary lymphadenopathy, infection, and myocarditis.⁵ Poisson regression was performed using Stata 17 analytical software.

We identified 4273 patients with psoriasis and 17,092 controls who received mRNA COVID-19 vaccines (Table). Adjusted odds ratios (aORs) for doses 1 and 2 were calculated for each vaccine (eTable). Adverse effects with sufficient data to generate an aOR included weakness, altered mental status, malaise, chest pain, and symptoms involving the circulatory or respiratory system. The aORs for allergic urticaria and initial encounter of adverse effect of viral vaccines were only calculated for the Moderna mRNA vaccine due to low sample size.

This study demonstrated that patients with psoriasis do not appear to have a significantly increased risk of adverse effects from mRNA SARS-CoV-2 vaccines. Although the ORs in this study were not significant, most recorded adverse effects demonstrated an aOR less than 1, suggesting that there might be a lower risk of certain adverse effects in psoriasis patients. This could be explained by the immunomodulatory effects of certain systemic psoriasis treatments that might influence the adverse effect presentation.

The study is limited by the lack of treatment data, small sample size, and the fact that it did not assess flares or worsening of psoriasis with the vaccines. Underreporting of adverse effects by patients and underdiagnosis of adverse effects secondary to SARS-CoV-2 vaccines due to its novel nature, incompletely understood consequences, and limited ICD-10 codes associated with adverse effects all contributed to the small sample size.

Our findings suggest that the risk for immediate adverse effects from the mRNA SARS-CoV-2 vaccines is not increased among psoriasis patients. However, the impact of immunomodulatory agents on vaccine efficacy and expected adverse effects should be investigated. As more individuals receive the COVID-19 vaccine, the adverse effect profile in patients with psoriasis is an important area of investigation.

To the Editor:

Because the SARS-CoV-2 virus is constantly changing, routine vaccination to prevent COVID-19 infection is recommended. The messenger RNA (mRNA) vaccines from Pfizer-BioNTech and Moderna as well as the Ad26.COV2.S (Johnson & Johnson) and NVX-CoV2373 (Novavax) vaccines are the most commonly used COVID-19 vaccines in the United States. Adverse effects following vaccination against SARS-CoV-2 are well documented; recent studies report a small incidence of adverse effects in the general population, with most being minor (eg, headache, fever, muscle pain).^1,2 Interestingly, reports of exacerbation of psoriasis and new-onset psoriasis following COVID-19 vaccination suggest a potential association.^3,4 However, the literature investigating the vaccine adverse effect profile in this demographic is scarce. We examined the incidence of adverse effects from SARS-CoV-2 vaccines in patients with psoriasis.

This retrospective cohort study used the COVID-19 Research Database (https://covid19researchdatabase.org/) to examine the adverse effects following the first and second doses of the mRNA vaccines in patients with and without psoriasis. The sample size for the Ad26.COV2.S vaccine was too small to analyze.

Claims were evaluated from August to October 2021 for 2 diagnoses of psoriasis prior to January 1, 2020, using the International Classification of Diseases, Tenth Revision (ICD-10) code L40.9 to increase the positive predictive value and ensure that the diagnosis preceded the COVID-19 pandemic. Patients younger than 18 years and those who did not receive 2 doses of a SARS-CoV-2 vaccine were excluded. Controls who did not have a diagnosis of psoriasis were matched for age, sex, and hypertension at a 4:1 ratio. Hypertension represented the most common comorbidity that could feasibly be controlled for in this study population. Other comorbidities recorded included obesity, type 2 diabetes mellitus, congestive heart failure, asthma, chronic obstructive pulmonary disease, chronic ischemic heart disease, rhinitis, and chronic kidney disease.

Common adverse effects as long as 30 days after vaccination were identified using ICD-10 codes. Adverse effects of interest were anaphylactic reaction, initial encounter of adverse effect of viral vaccines, fever, allergic urticaria, weakness, altered mental status, malaise, allergic reaction, chest pain, symptoms involving circulatory or respiratory systems, localized rash, axillary lymphadenopathy, infection, and myocarditis.⁵ Poisson regression was performed using Stata 17 analytical software.

We identified 4273 patients with psoriasis and 17,092 controls who received mRNA COVID-19 vaccines (Table). Adjusted odds ratios (aORs) for doses 1 and 2 were calculated for each vaccine (eTable). Adverse effects with sufficient data to generate an aOR included weakness, altered mental status, malaise, chest pain, and symptoms involving the circulatory or respiratory system. The aORs for allergic urticaria and initial encounter of adverse effect of viral vaccines were only calculated for the Moderna mRNA vaccine due to low sample size.

This study demonstrated that patients with psoriasis do not appear to have a significantly increased risk of adverse effects from mRNA SARS-CoV-2 vaccines. Although the ORs in this study were not significant, most recorded adverse effects demonstrated an aOR less than 1, suggesting that there might be a lower risk of certain adverse effects in psoriasis patients. This could be explained by the immunomodulatory effects of certain systemic psoriasis treatments that might influence the adverse effect presentation.

The study is limited by the lack of treatment data, small sample size, and the fact that it did not assess flares or worsening of psoriasis with the vaccines. Underreporting of adverse effects by patients and underdiagnosis of adverse effects secondary to SARS-CoV-2 vaccines due to its novel nature, incompletely understood consequences, and limited ICD-10 codes associated with adverse effects all contributed to the small sample size.

Our findings suggest that the risk for immediate adverse effects from the mRNA SARS-CoV-2 vaccines is not increased among psoriasis patients. However, the impact of immunomodulatory agents on vaccine efficacy and expected adverse effects should be investigated. As more individuals receive the COVID-19 vaccine, the adverse effect profile in patients with psoriasis is an important area of investigation.

To the Editor:

Because the SARS-CoV-2 virus is constantly changing, routine vaccination to prevent COVID-19 infection is recommended. The messenger RNA (mRNA) vaccines from Pfizer-BioNTech and Moderna as well as the Ad26.COV2.S (Johnson & Johnson) and NVX-CoV2373 (Novavax) vaccines are the most commonly used COVID-19 vaccines in the United States. Adverse effects following vaccination against SARS-CoV-2 are well documented; recent studies report a small incidence of adverse effects in the general population, with most being minor (eg, headache, fever, muscle pain).^1,2 Interestingly, reports of exacerbation of psoriasis and new-onset psoriasis following COVID-19 vaccination suggest a potential association.^3,4 However, the literature investigating the vaccine adverse effect profile in this demographic is scarce. We examined the incidence of adverse effects from SARS-CoV-2 vaccines in patients with psoriasis.

This retrospective cohort study used the COVID-19 Research Database (https://covid19researchdatabase.org/) to examine the adverse effects following the first and second doses of the mRNA vaccines in patients with and without psoriasis. The sample size for the Ad26.COV2.S vaccine was too small to analyze.

Claims were evaluated from August to October 2021 for 2 diagnoses of psoriasis prior to January 1, 2020, using the International Classification of Diseases, Tenth Revision (ICD-10) code L40.9 to increase the positive predictive value and ensure that the diagnosis preceded the COVID-19 pandemic. Patients younger than 18 years and those who did not receive 2 doses of a SARS-CoV-2 vaccine were excluded. Controls who did not have a diagnosis of psoriasis were matched for age, sex, and hypertension at a 4:1 ratio. Hypertension represented the most common comorbidity that could feasibly be controlled for in this study population. Other comorbidities recorded included obesity, type 2 diabetes mellitus, congestive heart failure, asthma, chronic obstructive pulmonary disease, chronic ischemic heart disease, rhinitis, and chronic kidney disease.

Common adverse effects as long as 30 days after vaccination were identified using ICD-10 codes. Adverse effects of interest were anaphylactic reaction, initial encounter of adverse effect of viral vaccines, fever, allergic urticaria, weakness, altered mental status, malaise, allergic reaction, chest pain, symptoms involving circulatory or respiratory systems, localized rash, axillary lymphadenopathy, infection, and myocarditis.⁵ Poisson regression was performed using Stata 17 analytical software.

We identified 4273 patients with psoriasis and 17,092 controls who received mRNA COVID-19 vaccines (Table). Adjusted odds ratios (aORs) for doses 1 and 2 were calculated for each vaccine (eTable). Adverse effects with sufficient data to generate an aOR included weakness, altered mental status, malaise, chest pain, and symptoms involving the circulatory or respiratory system. The aORs for allergic urticaria and initial encounter of adverse effect of viral vaccines were only calculated for the Moderna mRNA vaccine due to low sample size.

This study demonstrated that patients with psoriasis do not appear to have a significantly increased risk of adverse effects from mRNA SARS-CoV-2 vaccines. Although the ORs in this study were not significant, most recorded adverse effects demonstrated an aOR less than 1, suggesting that there might be a lower risk of certain adverse effects in psoriasis patients. This could be explained by the immunomodulatory effects of certain systemic psoriasis treatments that might influence the adverse effect presentation.

The study is limited by the lack of treatment data, small sample size, and the fact that it did not assess flares or worsening of psoriasis with the vaccines. Underreporting of adverse effects by patients and underdiagnosis of adverse effects secondary to SARS-CoV-2 vaccines due to its novel nature, incompletely understood consequences, and limited ICD-10 codes associated with adverse effects all contributed to the small sample size.

Our findings suggest that the risk for immediate adverse effects from the mRNA SARS-CoV-2 vaccines is not increased among psoriasis patients. However, the impact of immunomodulatory agents on vaccine efficacy and expected adverse effects should be investigated. As more individuals receive the COVID-19 vaccine, the adverse effect profile in patients with psoriasis is an important area of investigation.

New treatments for psoriasis constitute an embarrassment of riches compared to any other area of dermatology. Despite the many advances over the last 25 years, additional topical and systemic treatments have recently become available. Gosh, it’s great!

In May 2022, once-daily tapinarof cream 1% was approved for the topical treatment of plaque psoriasis in adults.¹ Tapinarof was identified as a metabolite made by bacteria symbiotic to a nematode, allowing the nematode to infect insects.² Tapinarof’s anti-inflammatory effect extends to mammals. The drug works by activating the aryl hydrocarbon receptor, downregulating proinflammatory cytokines such as IL-17, and normalizing the expression of skin barrier proteins such as filaggrin.² In two 12-week, phase 3, randomized trials with 510 and 515 patients, respectively, 35% to 40% of tapinarof-treated psoriasis patients were clear or almost clear compared with only 6% of patients in the placebo group. The drug appears safe; common adverse events (AEs) included folliculitis, nasopharyngitis, contact dermatitis, headache, upper respiratory tract infection, and pruritus.³

A second new topical treatment for plaque psoriasis was approved in July 2022—once-daily roflumilast 0.3% cream—for patients 12 years and older.⁴ Similar to apremilast, roflumilast is a phosphodiesterase 4 inhibitor that blocks the degradation of cAMP and reduces the downstream production of inflammatory molecules implicated in psoriasis.⁵ In two 8-week, phase 3 clinical trials (ClinicalTrials.gov Identifiers NCT04211363 and NCT04211389)(N=881), approximately 40% of roflumilast-treated patients were clear or almost clear vs approximately 6% in the placebo group. Topical roflumilast was well-tolerated; the most common AEs included diarrhea, headache, insomnia, nausea, application-site pain, upper respiratory tract infection, and urinary tract infection.⁶

We have so many patients—and many more people with psoriasis who are not yet patients—with limited psoriasis who would be amenable to topical treatment but who are not responding to current treatments. There is considerable enthusiasm for the new topicals, but it is still questionable how much they will help our patients. The main reason the current topicals fail is poor adherence to the treatment. If we give these new treatments to patients who used existing topicals and failed, thereby inadvertently selecting patients with poor adherence to topicals, it will be surprising if the new treatments live up to expectations. Perhaps tapinarof and roflumilast will revolutionize the management of localized psoriasis; perhaps their impact will be similar to topical crisaborole— exciting in trials and less practical in real life. It may be that apremilast, which is now approved for psoriasis of any severity, will make a bigger difference for patients who can access it for limited psoriasis.

Deucravacitinib is a once-daily oral selective tyrosine kinase 2 inhibitor that blocks IL-23 and type I interferon signaling. It was approved for adults with moderate to severe plaque psoriasis in September 2021.⁷ We know patients want oral treatment; they ask for apremilast even though injections may be much more potent. In a 16-week, phase 3 clinical trial comparing daily deucravacitinib (n=332), apremilast (n=168), and placebo (n=166), rates of clear or almost clear were approximately 55% in the deucravacitinib group, 32% in the apremilast group, and 7% with placebo. The most common AEs included nasopharyngitis, upper respiratory tract infection, headache, diarrhea, and nausea.⁸ Although deucravacitinib is much more effective than apremilast, deucravacitinib will require monitoring and may have some risk for viral reactivation of herpes simplex and zoster (and hopefully not much else). Whether physicians view it as a replacement for apremilast, which requires no laboratory monitoring, remains to be seen.

Bimekizumab, a humanized monoclonal IgG1 antibody expected to receive US Food and Drug Administration approval in the coming months, inhibits both IL-17A and IL-17F and may become our most effective treatment of psoriasis. Although we are probably not hungering for a more effective psoriasis treatment (given our current embarrassment of riches), bimekizumab’s remarkably high efficacy for psoriatic arthritis may be a quantum leap forward, especially if no new safety signals are identified; bimekizumab treatment is associated with a higher risk of oral candidiasis than other currently available IL-17 antagonists.⁹ Biosimilars may reduce the cost of psoriasis management to the health system, but it seems unlikely that biosimilars will allow us to help patients who we cannot already help with the existing extensive psoriasis treatment armamentarium.

New treatments for psoriasis constitute an embarrassment of riches compared to any other area of dermatology. Despite the many advances over the last 25 years, additional topical and systemic treatments have recently become available. Gosh, it’s great!

In May 2022, once-daily tapinarof cream 1% was approved for the topical treatment of plaque psoriasis in adults.¹ Tapinarof was identified as a metabolite made by bacteria symbiotic to a nematode, allowing the nematode to infect insects.² Tapinarof’s anti-inflammatory effect extends to mammals. The drug works by activating the aryl hydrocarbon receptor, downregulating proinflammatory cytokines such as IL-17, and normalizing the expression of skin barrier proteins such as filaggrin.² In two 12-week, phase 3, randomized trials with 510 and 515 patients, respectively, 35% to 40% of tapinarof-treated psoriasis patients were clear or almost clear compared with only 6% of patients in the placebo group. The drug appears safe; common adverse events (AEs) included folliculitis, nasopharyngitis, contact dermatitis, headache, upper respiratory tract infection, and pruritus.³

A second new topical treatment for plaque psoriasis was approved in July 2022—once-daily roflumilast 0.3% cream—for patients 12 years and older.⁴ Similar to apremilast, roflumilast is a phosphodiesterase 4 inhibitor that blocks the degradation of cAMP and reduces the downstream production of inflammatory molecules implicated in psoriasis.⁵ In two 8-week, phase 3 clinical trials (ClinicalTrials.gov Identifiers NCT04211363 and NCT04211389)(N=881), approximately 40% of roflumilast-treated patients were clear or almost clear vs approximately 6% in the placebo group. Topical roflumilast was well-tolerated; the most common AEs included diarrhea, headache, insomnia, nausea, application-site pain, upper respiratory tract infection, and urinary tract infection.⁶

We have so many patients—and many more people with psoriasis who are not yet patients—with limited psoriasis who would be amenable to topical treatment but who are not responding to current treatments. There is considerable enthusiasm for the new topicals, but it is still questionable how much they will help our patients. The main reason the current topicals fail is poor adherence to the treatment. If we give these new treatments to patients who used existing topicals and failed, thereby inadvertently selecting patients with poor adherence to topicals, it will be surprising if the new treatments live up to expectations. Perhaps tapinarof and roflumilast will revolutionize the management of localized psoriasis; perhaps their impact will be similar to topical crisaborole— exciting in trials and less practical in real life. It may be that apremilast, which is now approved for psoriasis of any severity, will make a bigger difference for patients who can access it for limited psoriasis.

Deucravacitinib is a once-daily oral selective tyrosine kinase 2 inhibitor that blocks IL-23 and type I interferon signaling. It was approved for adults with moderate to severe plaque psoriasis in September 2021.⁷ We know patients want oral treatment; they ask for apremilast even though injections may be much more potent. In a 16-week, phase 3 clinical trial comparing daily deucravacitinib (n=332), apremilast (n=168), and placebo (n=166), rates of clear or almost clear were approximately 55% in the deucravacitinib group, 32% in the apremilast group, and 7% with placebo. The most common AEs included nasopharyngitis, upper respiratory tract infection, headache, diarrhea, and nausea.⁸ Although deucravacitinib is much more effective than apremilast, deucravacitinib will require monitoring and may have some risk for viral reactivation of herpes simplex and zoster (and hopefully not much else). Whether physicians view it as a replacement for apremilast, which requires no laboratory monitoring, remains to be seen.

Bimekizumab, a humanized monoclonal IgG1 antibody expected to receive US Food and Drug Administration approval in the coming months, inhibits both IL-17A and IL-17F and may become our most effective treatment of psoriasis. Although we are probably not hungering for a more effective psoriasis treatment (given our current embarrassment of riches), bimekizumab’s remarkably high efficacy for psoriatic arthritis may be a quantum leap forward, especially if no new safety signals are identified; bimekizumab treatment is associated with a higher risk of oral candidiasis than other currently available IL-17 antagonists.⁹ Biosimilars may reduce the cost of psoriasis management to the health system, but it seems unlikely that biosimilars will allow us to help patients who we cannot already help with the existing extensive psoriasis treatment armamentarium.

New treatments for psoriasis constitute an embarrassment of riches compared to any other area of dermatology. Despite the many advances over the last 25 years, additional topical and systemic treatments have recently become available. Gosh, it’s great!

In May 2022, once-daily tapinarof cream 1% was approved for the topical treatment of plaque psoriasis in adults.¹ Tapinarof was identified as a metabolite made by bacteria symbiotic to a nematode, allowing the nematode to infect insects.² Tapinarof’s anti-inflammatory effect extends to mammals. The drug works by activating the aryl hydrocarbon receptor, downregulating proinflammatory cytokines such as IL-17, and normalizing the expression of skin barrier proteins such as filaggrin.² In two 12-week, phase 3, randomized trials with 510 and 515 patients, respectively, 35% to 40% of tapinarof-treated psoriasis patients were clear or almost clear compared with only 6% of patients in the placebo group. The drug appears safe; common adverse events (AEs) included folliculitis, nasopharyngitis, contact dermatitis, headache, upper respiratory tract infection, and pruritus.³

A second new topical treatment for plaque psoriasis was approved in July 2022—once-daily roflumilast 0.3% cream—for patients 12 years and older.⁴ Similar to apremilast, roflumilast is a phosphodiesterase 4 inhibitor that blocks the degradation of cAMP and reduces the downstream production of inflammatory molecules implicated in psoriasis.⁵ In two 8-week, phase 3 clinical trials (ClinicalTrials.gov Identifiers NCT04211363 and NCT04211389)(N=881), approximately 40% of roflumilast-treated patients were clear or almost clear vs approximately 6% in the placebo group. Topical roflumilast was well-tolerated; the most common AEs included diarrhea, headache, insomnia, nausea, application-site pain, upper respiratory tract infection, and urinary tract infection.⁶

We have so many patients—and many more people with psoriasis who are not yet patients—with limited psoriasis who would be amenable to topical treatment but who are not responding to current treatments. There is considerable enthusiasm for the new topicals, but it is still questionable how much they will help our patients. The main reason the current topicals fail is poor adherence to the treatment. If we give these new treatments to patients who used existing topicals and failed, thereby inadvertently selecting patients with poor adherence to topicals, it will be surprising if the new treatments live up to expectations. Perhaps tapinarof and roflumilast will revolutionize the management of localized psoriasis; perhaps their impact will be similar to topical crisaborole— exciting in trials and less practical in real life. It may be that apremilast, which is now approved for psoriasis of any severity, will make a bigger difference for patients who can access it for limited psoriasis.

Deucravacitinib is a once-daily oral selective tyrosine kinase 2 inhibitor that blocks IL-23 and type I interferon signaling. It was approved for adults with moderate to severe plaque psoriasis in September 2021.⁷ We know patients want oral treatment; they ask for apremilast even though injections may be much more potent. In a 16-week, phase 3 clinical trial comparing daily deucravacitinib (n=332), apremilast (n=168), and placebo (n=166), rates of clear or almost clear were approximately 55% in the deucravacitinib group, 32% in the apremilast group, and 7% with placebo. The most common AEs included nasopharyngitis, upper respiratory tract infection, headache, diarrhea, and nausea.⁸ Although deucravacitinib is much more effective than apremilast, deucravacitinib will require monitoring and may have some risk for viral reactivation of herpes simplex and zoster (and hopefully not much else). Whether physicians view it as a replacement for apremilast, which requires no laboratory monitoring, remains to be seen.

Bimekizumab, a humanized monoclonal IgG1 antibody expected to receive US Food and Drug Administration approval in the coming months, inhibits both IL-17A and IL-17F and may become our most effective treatment of psoriasis. Although we are probably not hungering for a more effective psoriasis treatment (given our current embarrassment of riches), bimekizumab’s remarkably high efficacy for psoriatic arthritis may be a quantum leap forward, especially if no new safety signals are identified; bimekizumab treatment is associated with a higher risk of oral candidiasis than other currently available IL-17 antagonists.⁹ Biosimilars may reduce the cost of psoriasis management to the health system, but it seems unlikely that biosimilars will allow us to help patients who we cannot already help with the existing extensive psoriasis treatment armamentarium.

The landscape of psoriasis treatments has undergone rapid change within the last decade, and the dizzying speed of drug development has not slowed, with 4 notable entries into the psoriasis treatment armamentarium within the last year: tapinarof, roflumilast, deucravacitinib, and spesolimab. Several others are in late-stage development, and these therapies represent new mechanisms, pathways, and delivery systems that will meaningfully broaden the spectrum of treatment choices for our patients. However, it can be quite difficult to keep track of all of the medication options. This review aims to present the mechanisms and data on both newly available therapeutics for psoriasis and products in the pipeline that may have a major impact on our treatment paradigm for psoriasis in the near future.

Topical Treatments

Tapinarof—Tapinarof is a topical aryl hydrocarbon receptor (AhR)–modulating agent derived from a secondary metabolite produced by a bacterial symbiont of entomopathogenic nematodes.¹ Tapinarof binds and activates AhR, inducing a signaling cascade that suppresses the expression of helper T cells T_H17 and T_H22, upregulates skin barrier protein expression, and reduces epidermal oxidative stress.² This is a familiar mechanism, as AhR agonism is one of the pathways modulated by coal tar. Tapinarof’s overall effects on immune function, skin barrier integrity, and antioxidant activity show great promise for the treatment of plaque psoriasis.

Two phase 3 trials (N=1025) evaluated the efficacy and safety of once-daily tapinarof cream 1% for plaque psoriasis.³ A physician global assessment (PGA) score of 0/1 occurred in 35.4% to 40.2% of patients in the tapinarof group and in 6.0% of patients in the vehicle group. At week 12, 36.1% to 47.6% of patients treated with daily applications of tapinarof cream achieved a 75% reduction in their baseline psoriasis area and severity index (PASI 75) score compared with 6.9% to 10.2% in the vehicle group.³ In a long-term extension study, a substantial remittive effect of at least 4 months off tapinarof therapy was observed in patients who achieved complete clearance (PGA=0).⁴ Use of tapinarof cream was associated with folliculitis in up to 23.5% of patients.^3,4

Roflumilast—Phosphodiesterase 4 (PDE-4) is an intracellular enzyme involved in the regulation of cell proliferation, differentiation, and immune responses.⁵ The inhibition of PDE-4 decreases the expression of proinflammatory cytokines implicated in the pathogenesis of plaque psoriasis, such as tumor necrosis factor α, IFN-γ, and IL-2, IL-12, and IL-23.⁶ Phosphodiesterase 4–targeted therapies have been thoroughly explored to treat various inflammatory conditions, including atopic dermatitis and plaque psoriasis. The oral PDE-4 inhibitor apremilast was shown to achieve PASI 75 in approximately 30% of 562 patients, accompanied by severe gastrointestinal adverse events (AEs) including diarrhea and nausea associated with treatment.⁷ Local irritation from the topical PDE-4 inhibitor crisaborole for atopic dermatitis and psoriasis (where it only completed phase 2 trials) limits its widespread use. The lack of tolerable and effective treatment alternatives for psoriasis prompted the investigation of new PDE-4–targeted therapies.

Topical roflumilast is a selective, highly potent PDE-4 inhibitor with greater affinity for PDE-4 compared to crisaborole and apremilast.⁸ Two phase 3 trials (N=881) evaluated the efficacy and safety profile of roflumilast cream for plaque psoriasis, with a particular interest in its use for intertriginous areas.⁹ At week 8, 37.5% to 42.4% of roflumilast-treated patients achieved investigator global assessment (IGA) success compared with 6.1% to 6.9% of vehicle-treated patients. Intertriginous IGA success was observed in 68.1% to 71.2% of patients treated with roflumilast cream compared with 13.8% to 18.5% of vehicle-treated patients. At 8-week follow-up, 39.0% to 41.6% of roflumilast-treated patients achieved PASI 75 vs 5.3% to 7.6% of patients in the vehicle group. Few stinging, burning, or application-site reactions were reported with roflumilast, along with rare instances of gastrointestinal AEs (<4%).⁹

Oral Therapy

Deucravacitinib—Tyrosine kinase 2 (TYK2) mediates the intracellular signaling of the T_H17 and T_H1 inflammatory cytokines IL-12/IL-23 and type I interferons, respectively, the former of which are critical in the development of psoriasis via the Janus kinase (JAK) signal transducer and activator of transcription pathway.¹⁰ Deucravacitinib is an oral selective TYK2 allosteric inhibitor that binds to the regulatory domain of the enzyme rather than the active catalytic domain, where other TYK2 and JAK1, JAK2, and JAK3 inhibitors bind.¹¹ This unique inhibitory mechanism accounts for the high functional selectivity of deucravacitinib for TYK2 vs the closely related JAK1, JAK2, and JAK3 kinases, thus avoiding the pitfall of prior JAK inhibitors that were associated with major AEs, including an increased risk for serious infections, malignancies, and thrombosis.¹² The selective suppression of the inflammatory TYK2 pathway has the potential to shift future therapeutic targets to a narrower range of receptors that may contribute to favorable benefit-risk profiles.

Two phase 3 trials (N=1686) compared the efficacy and safety of deucravacitinib vs placebo and apremilast in adults with moderate to severe plaque psoriasis.^13,14 At week 16, 53.0% to 58.4% of deucravacitinib-treated patients achieved PASI 75 compared with 35.1% to 39.8% of apremilast-treated patients. At 16-week follow-up, static PGA response was observed in 49.5% to 53.6% of patients in the deucravacitinib group and 32.1% to 33.9% of the apremilast group. The most frequent AEs associated with deucravacitinib therapy were nasopharyngitis and upper respiratory tract infection, whereas headache, diarrhea, and nausea were more common with apremilast. Treatment with deucravacitinib caused no meaningful changes in laboratory parameters, which are known to change with JAK1, JAK2, and JAK3 inhibitors.^13,14 A long-term extension study demonstrated that deucravacitinib had persistent efficacy and consistent safety for up to 2 years.¹⁵

Novel oral allosteric TYK2 inhibitors—VTX958 and NDI-034858—and the competitive TYK2 inhibitor PF-06826647 are being developed. Theoretically, these new allosteric inhibitors possess unique structural properties to provide greater TYK2 suppression while bypassing JAK1, JAK2, and JAK3 pathways that may contribute to improved efficacy and safety profiles compared with other TYK2 inhibitors such as deucravacitinib. The results of a phase 1b trial (ClinicalTrials.gov Identifier NCT04999839) showed a dose-dependent reduction of disease severity associated with NDI-034858 treatment for patients with moderate to severe plaque psoriasis, albeit in only 26 patients. At week 4, PASI 50 was achieved in 13%, 57%, and 40% of patients in the 5-, 10-, and 30-mg groups, respectively, compared with 0% in the placebo group.¹⁶ In a phase 2 trial of 179 patients, 46.5% and 33.0% of patients treated with 400 and 200 mg of PF-06826647, respectively, achieved PASI 90 at week 16. Conversely, dose-dependent laboratory abnormalities were observed with PF-06826647, including anemia, neutropenia, and increases in creatine phosphokinase.¹⁷ At high concentrations, PF-06826647 may disrupt JAK signaling pathways involved in hematopoiesis and renal functions owing to its mode of action as a competitive inhibitor. Overall, these agents are much farther from market, and long-term studies with larger diverse patient cohorts are required to adequately assess the efficacy and safety data of these novel oral TYK2 inhibitors for patients with psoriasis.

EDP1815—EDP1815 is an oral preparation of a single strain of Prevotella histicola being developed for the treatment of inflammatory diseases, including psoriasis. EDP1815 interacts with host intestinal immune cells through the small intestinal axis (SINTAX) to suppress systemic inflammation across the T_H1, T_H2, and T_H17 pathways. Therapy triggers broad immunomodulatory effects without causing systemic absorption, colonic colonization, or modification of the gut microbiome.¹⁸ In a phase 2 study (NCT04603027), the primary end point analysis, mean percentage change in PASI between treatment and placebo, demonstrated that at week 16, EDP1815 was superior to placebo with 80% to 90% probability across each cohort. At week 16, 25% to 32% of patients across the 3 cohorts treated with EDP1815 achieved PASI 50 compared with 12% of patients receiving placebo. Gastrointestinal AEs were comparable between treatment and placebo groups. These results suggest that SINTAX-targeted therapies may provide efficacious and safe immunomodulatory effects for patients with mild to moderate psoriasis, who often have limited treatment options. Although improvements may be mild, SINTAX-targeted therapies can be seen as a particularly attractive adjunctive treatment for patients with severe psoriasis taking other medications or as part of a treatment approach for a patient with milder psoriasis.

Biologics

Bimekizumab—Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits IL-17A and IL-17F. Although IL-17A is a more potent cytokine, IL-17F may be more highly expressed in psoriatic lesional skin and independently contribute to the activation of proinflammatory signaling pathways implicated in the pathophysiology of psoriasis.¹⁹ Evidence suggests that dual inhibition of IL-17A and IL-17F may provide more complete suppression of inflammation and improved clinical responses than IL-17A inhibition alone.²⁰

Prior bimekizumab phase 3 clinical studies have shown both rapid and durable clinical improvements in skin clearance compared with placebo.²¹ Three phase 3 trials—BE VIVID (N=567),²² BE SURE (N=478),²³ and BE RADIANT (N=743)²⁴—assessed the efficacy and safety of bimekizumab vs the IL-12/IL-23 inhibitor ustekinumab, the tumor necrosis factor inhibitor adalimumab, and the selective IL-17A inhibitor secukinumab, respectively. At week 4, significantly more patients treated with bimekizumab (71%–77%) achieved PASI 75 than patients treated with ustekinumab (15%; P<.0001), adalimumab (31.4%; P<.001), or secukinumab (47.3%; P<.001).^22-24 After 16 weeks of treatment, PASI 90 was achieved by 85% to 86.2%, 50%, and 47.2% of patients treated with bimekizumab, ustekinumab, and adalimumab, respectively.^22,23 At week 16, PASI 100 was observed in 59% to 61.7%, 21%, 23.9%, and 48.9% of patients treated with bimekizumab, ustekinumab, adalimumab, and secukinumab, respectively. An IGA response (score of 0/1) at week 16 was achieved by 84% to 85.5%, 53%, 57.2%, and 78.6% of patients receiving bimekizumab, ustekinumab, adalimumab, and secukinumab, respectively.^22-24

The most common AEs in bimekizumab-treated patients were nasopharyngitis, oral candidiasis, and upper respiratory tract infection.^22-24 The dual inhibition of IL-17A and IL-17F suppresses host defenses against Candida at the oral mucosa, increasing the incidence of bimekizumab-associated oral candidiasis.²⁵ Despite the increased risk of Candida infections, these data suggest that inhibition of both IL-17A and IL-17F with bimekizumab may provide faster and greater clinical benefit for patients with moderate to severe plaque psoriasis than inhibition of IL-17A alone and other biologic therapies, as the PASI 100 clearance rates across the multiple comparator trials and the placebo-controlled pivotal trial are consistently the highest among any biologic for the treatment of psoriasis.

Spesolimab—The IL-36 pathway and IL-36 receptor genes have been linked to the pathogenesis of generalized pustular psoriasis.²⁶ In a phase 2 trial, 19 of 35 patients (54%) receiving an intravenous dose of spesolimab, an IL-36 receptor inhibitor, had a generalized pustular psoriasis PGA pustulation subscore of 0 (no visible pustules) at the end of week 1 vs 6% of patients in the placebo group.²⁷ A generalized pustular psoriasis PGA total score of 0 or 1 was observed in 43% (15/35) of spesolimab-treated patients compared with 11% (2/18) of patients in the placebo group. The most common AEs in patients treated with spesolimab were minor infections.²⁷ Two open-label phase 3 trials—NCT05200247 and NCT05239039—are underway to determine the long-term efficacy and safety of spesolimab in patients with generalized pustular psoriasis.

Conclusion

Although we have seen a renaissance in psoriasis therapies with the advent of biologics in the last 20 years, recent evidence shows that more innovation is underway. Just in the last year, 2 new mechanisms for treating psoriasis topically without steroids have come to fruition, and there have not been truly novel mechanisms for treating psoriasis topically since approvals for tazarotene and calcipotriene in the 1990s. An entirely new class—TYK2 inhibitors—was developed and landed in psoriasis first, greatly improving the efficacy measures attained with oral medications in general. Finally, an orphan diagnosis got its due with an ambitiously designed study looking at a previously unheard-of 1-week end point, but it comes for one of the few true dermatologic emergencies we encounter, generalized pustular psoriasis. We are fortunate to have so many meaningful new treatments available to us, and it is invigorating to see that even more efficacious biologics and treatments are coming, along with novel concepts such as a treatment affecting the microbiome. Now, we just need to make sure that our patients have the access they deserve to the wide array of available treatments.

The landscape of psoriasis treatments has undergone rapid change within the last decade, and the dizzying speed of drug development has not slowed, with 4 notable entries into the psoriasis treatment armamentarium within the last year: tapinarof, roflumilast, deucravacitinib, and spesolimab. Several others are in late-stage development, and these therapies represent new mechanisms, pathways, and delivery systems that will meaningfully broaden the spectrum of treatment choices for our patients. However, it can be quite difficult to keep track of all of the medication options. This review aims to present the mechanisms and data on both newly available therapeutics for psoriasis and products in the pipeline that may have a major impact on our treatment paradigm for psoriasis in the near future.

Topical Treatments

Tapinarof—Tapinarof is a topical aryl hydrocarbon receptor (AhR)–modulating agent derived from a secondary metabolite produced by a bacterial symbiont of entomopathogenic nematodes.¹ Tapinarof binds and activates AhR, inducing a signaling cascade that suppresses the expression of helper T cells T_H17 and T_H22, upregulates skin barrier protein expression, and reduces epidermal oxidative stress.² This is a familiar mechanism, as AhR agonism is one of the pathways modulated by coal tar. Tapinarof’s overall effects on immune function, skin barrier integrity, and antioxidant activity show great promise for the treatment of plaque psoriasis.

Two phase 3 trials (N=1025) evaluated the efficacy and safety of once-daily tapinarof cream 1% for plaque psoriasis.³ A physician global assessment (PGA) score of 0/1 occurred in 35.4% to 40.2% of patients in the tapinarof group and in 6.0% of patients in the vehicle group. At week 12, 36.1% to 47.6% of patients treated with daily applications of tapinarof cream achieved a 75% reduction in their baseline psoriasis area and severity index (PASI 75) score compared with 6.9% to 10.2% in the vehicle group.³ In a long-term extension study, a substantial remittive effect of at least 4 months off tapinarof therapy was observed in patients who achieved complete clearance (PGA=0).⁴ Use of tapinarof cream was associated with folliculitis in up to 23.5% of patients.^3,4

Roflumilast—Phosphodiesterase 4 (PDE-4) is an intracellular enzyme involved in the regulation of cell proliferation, differentiation, and immune responses.⁵ The inhibition of PDE-4 decreases the expression of proinflammatory cytokines implicated in the pathogenesis of plaque psoriasis, such as tumor necrosis factor α, IFN-γ, and IL-2, IL-12, and IL-23.⁶ Phosphodiesterase 4–targeted therapies have been thoroughly explored to treat various inflammatory conditions, including atopic dermatitis and plaque psoriasis. The oral PDE-4 inhibitor apremilast was shown to achieve PASI 75 in approximately 30% of 562 patients, accompanied by severe gastrointestinal adverse events (AEs) including diarrhea and nausea associated with treatment.⁷ Local irritation from the topical PDE-4 inhibitor crisaborole for atopic dermatitis and psoriasis (where it only completed phase 2 trials) limits its widespread use. The lack of tolerable and effective treatment alternatives for psoriasis prompted the investigation of new PDE-4–targeted therapies.

Topical roflumilast is a selective, highly potent PDE-4 inhibitor with greater affinity for PDE-4 compared to crisaborole and apremilast.⁸ Two phase 3 trials (N=881) evaluated the efficacy and safety profile of roflumilast cream for plaque psoriasis, with a particular interest in its use for intertriginous areas.⁹ At week 8, 37.5% to 42.4% of roflumilast-treated patients achieved investigator global assessment (IGA) success compared with 6.1% to 6.9% of vehicle-treated patients. Intertriginous IGA success was observed in 68.1% to 71.2% of patients treated with roflumilast cream compared with 13.8% to 18.5% of vehicle-treated patients. At 8-week follow-up, 39.0% to 41.6% of roflumilast-treated patients achieved PASI 75 vs 5.3% to 7.6% of patients in the vehicle group. Few stinging, burning, or application-site reactions were reported with roflumilast, along with rare instances of gastrointestinal AEs (<4%).⁹

Oral Therapy

Deucravacitinib—Tyrosine kinase 2 (TYK2) mediates the intracellular signaling of the T_H17 and T_H1 inflammatory cytokines IL-12/IL-23 and type I interferons, respectively, the former of which are critical in the development of psoriasis via the Janus kinase (JAK) signal transducer and activator of transcription pathway.¹⁰ Deucravacitinib is an oral selective TYK2 allosteric inhibitor that binds to the regulatory domain of the enzyme rather than the active catalytic domain, where other TYK2 and JAK1, JAK2, and JAK3 inhibitors bind.¹¹ This unique inhibitory mechanism accounts for the high functional selectivity of deucravacitinib for TYK2 vs the closely related JAK1, JAK2, and JAK3 kinases, thus avoiding the pitfall of prior JAK inhibitors that were associated with major AEs, including an increased risk for serious infections, malignancies, and thrombosis.¹² The selective suppression of the inflammatory TYK2 pathway has the potential to shift future therapeutic targets to a narrower range of receptors that may contribute to favorable benefit-risk profiles.

Two phase 3 trials (N=1686) compared the efficacy and safety of deucravacitinib vs placebo and apremilast in adults with moderate to severe plaque psoriasis.^13,14 At week 16, 53.0% to 58.4% of deucravacitinib-treated patients achieved PASI 75 compared with 35.1% to 39.8% of apremilast-treated patients. At 16-week follow-up, static PGA response was observed in 49.5% to 53.6% of patients in the deucravacitinib group and 32.1% to 33.9% of the apremilast group. The most frequent AEs associated with deucravacitinib therapy were nasopharyngitis and upper respiratory tract infection, whereas headache, diarrhea, and nausea were more common with apremilast. Treatment with deucravacitinib caused no meaningful changes in laboratory parameters, which are known to change with JAK1, JAK2, and JAK3 inhibitors.^13,14 A long-term extension study demonstrated that deucravacitinib had persistent efficacy and consistent safety for up to 2 years.¹⁵

Novel oral allosteric TYK2 inhibitors—VTX958 and NDI-034858—and the competitive TYK2 inhibitor PF-06826647 are being developed. Theoretically, these new allosteric inhibitors possess unique structural properties to provide greater TYK2 suppression while bypassing JAK1, JAK2, and JAK3 pathways that may contribute to improved efficacy and safety profiles compared with other TYK2 inhibitors such as deucravacitinib. The results of a phase 1b trial (ClinicalTrials.gov Identifier NCT04999839) showed a dose-dependent reduction of disease severity associated with NDI-034858 treatment for patients with moderate to severe plaque psoriasis, albeit in only 26 patients. At week 4, PASI 50 was achieved in 13%, 57%, and 40% of patients in the 5-, 10-, and 30-mg groups, respectively, compared with 0% in the placebo group.¹⁶ In a phase 2 trial of 179 patients, 46.5% and 33.0% of patients treated with 400 and 200 mg of PF-06826647, respectively, achieved PASI 90 at week 16. Conversely, dose-dependent laboratory abnormalities were observed with PF-06826647, including anemia, neutropenia, and increases in creatine phosphokinase.¹⁷ At high concentrations, PF-06826647 may disrupt JAK signaling pathways involved in hematopoiesis and renal functions owing to its mode of action as a competitive inhibitor. Overall, these agents are much farther from market, and long-term studies with larger diverse patient cohorts are required to adequately assess the efficacy and safety data of these novel oral TYK2 inhibitors for patients with psoriasis.

EDP1815—EDP1815 is an oral preparation of a single strain of Prevotella histicola being developed for the treatment of inflammatory diseases, including psoriasis. EDP1815 interacts with host intestinal immune cells through the small intestinal axis (SINTAX) to suppress systemic inflammation across the T_H1, T_H2, and T_H17 pathways. Therapy triggers broad immunomodulatory effects without causing systemic absorption, colonic colonization, or modification of the gut microbiome.¹⁸ In a phase 2 study (NCT04603027), the primary end point analysis, mean percentage change in PASI between treatment and placebo, demonstrated that at week 16, EDP1815 was superior to placebo with 80% to 90% probability across each cohort. At week 16, 25% to 32% of patients across the 3 cohorts treated with EDP1815 achieved PASI 50 compared with 12% of patients receiving placebo. Gastrointestinal AEs were comparable between treatment and placebo groups. These results suggest that SINTAX-targeted therapies may provide efficacious and safe immunomodulatory effects for patients with mild to moderate psoriasis, who often have limited treatment options. Although improvements may be mild, SINTAX-targeted therapies can be seen as a particularly attractive adjunctive treatment for patients with severe psoriasis taking other medications or as part of a treatment approach for a patient with milder psoriasis.

Biologics

Bimekizumab—Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits IL-17A and IL-17F. Although IL-17A is a more potent cytokine, IL-17F may be more highly expressed in psoriatic lesional skin and independently contribute to the activation of proinflammatory signaling pathways implicated in the pathophysiology of psoriasis.¹⁹ Evidence suggests that dual inhibition of IL-17A and IL-17F may provide more complete suppression of inflammation and improved clinical responses than IL-17A inhibition alone.²⁰

Prior bimekizumab phase 3 clinical studies have shown both rapid and durable clinical improvements in skin clearance compared with placebo.²¹ Three phase 3 trials—BE VIVID (N=567),²² BE SURE (N=478),²³ and BE RADIANT (N=743)²⁴—assessed the efficacy and safety of bimekizumab vs the IL-12/IL-23 inhibitor ustekinumab, the tumor necrosis factor inhibitor adalimumab, and the selective IL-17A inhibitor secukinumab, respectively. At week 4, significantly more patients treated with bimekizumab (71%–77%) achieved PASI 75 than patients treated with ustekinumab (15%; P<.0001), adalimumab (31.4%; P<.001), or secukinumab (47.3%; P<.001).^22-24 After 16 weeks of treatment, PASI 90 was achieved by 85% to 86.2%, 50%, and 47.2% of patients treated with bimekizumab, ustekinumab, and adalimumab, respectively.^22,23 At week 16, PASI 100 was observed in 59% to 61.7%, 21%, 23.9%, and 48.9% of patients treated with bimekizumab, ustekinumab, adalimumab, and secukinumab, respectively. An IGA response (score of 0/1) at week 16 was achieved by 84% to 85.5%, 53%, 57.2%, and 78.6% of patients receiving bimekizumab, ustekinumab, adalimumab, and secukinumab, respectively.^22-24

The most common AEs in bimekizumab-treated patients were nasopharyngitis, oral candidiasis, and upper respiratory tract infection.^22-24 The dual inhibition of IL-17A and IL-17F suppresses host defenses against Candida at the oral mucosa, increasing the incidence of bimekizumab-associated oral candidiasis.²⁵ Despite the increased risk of Candida infections, these data suggest that inhibition of both IL-17A and IL-17F with bimekizumab may provide faster and greater clinical benefit for patients with moderate to severe plaque psoriasis than inhibition of IL-17A alone and other biologic therapies, as the PASI 100 clearance rates across the multiple comparator trials and the placebo-controlled pivotal trial are consistently the highest among any biologic for the treatment of psoriasis.

Spesolimab—The IL-36 pathway and IL-36 receptor genes have been linked to the pathogenesis of generalized pustular psoriasis.²⁶ In a phase 2 trial, 19 of 35 patients (54%) receiving an intravenous dose of spesolimab, an IL-36 receptor inhibitor, had a generalized pustular psoriasis PGA pustulation subscore of 0 (no visible pustules) at the end of week 1 vs 6% of patients in the placebo group.²⁷ A generalized pustular psoriasis PGA total score of 0 or 1 was observed in 43% (15/35) of spesolimab-treated patients compared with 11% (2/18) of patients in the placebo group. The most common AEs in patients treated with spesolimab were minor infections.²⁷ Two open-label phase 3 trials—NCT05200247 and NCT05239039—are underway to determine the long-term efficacy and safety of spesolimab in patients with generalized pustular psoriasis.

Conclusion

Although we have seen a renaissance in psoriasis therapies with the advent of biologics in the last 20 years, recent evidence shows that more innovation is underway. Just in the last year, 2 new mechanisms for treating psoriasis topically without steroids have come to fruition, and there have not been truly novel mechanisms for treating psoriasis topically since approvals for tazarotene and calcipotriene in the 1990s. An entirely new class—TYK2 inhibitors—was developed and landed in psoriasis first, greatly improving the efficacy measures attained with oral medications in general. Finally, an orphan diagnosis got its due with an ambitiously designed study looking at a previously unheard-of 1-week end point, but it comes for one of the few true dermatologic emergencies we encounter, generalized pustular psoriasis. We are fortunate to have so many meaningful new treatments available to us, and it is invigorating to see that even more efficacious biologics and treatments are coming, along with novel concepts such as a treatment affecting the microbiome. Now, we just need to make sure that our patients have the access they deserve to the wide array of available treatments.

The landscape of psoriasis treatments has undergone rapid change within the last decade, and the dizzying speed of drug development has not slowed, with 4 notable entries into the psoriasis treatment armamentarium within the last year: tapinarof, roflumilast, deucravacitinib, and spesolimab. Several others are in late-stage development, and these therapies represent new mechanisms, pathways, and delivery systems that will meaningfully broaden the spectrum of treatment choices for our patients. However, it can be quite difficult to keep track of all of the medication options. This review aims to present the mechanisms and data on both newly available therapeutics for psoriasis and products in the pipeline that may have a major impact on our treatment paradigm for psoriasis in the near future.

Topical Treatments

Tapinarof—Tapinarof is a topical aryl hydrocarbon receptor (AhR)–modulating agent derived from a secondary metabolite produced by a bacterial symbiont of entomopathogenic nematodes.¹ Tapinarof binds and activates AhR, inducing a signaling cascade that suppresses the expression of helper T cells T_H17 and T_H22, upregulates skin barrier protein expression, and reduces epidermal oxidative stress.² This is a familiar mechanism, as AhR agonism is one of the pathways modulated by coal tar. Tapinarof’s overall effects on immune function, skin barrier integrity, and antioxidant activity show great promise for the treatment of plaque psoriasis.

Two phase 3 trials (N=1025) evaluated the efficacy and safety of once-daily tapinarof cream 1% for plaque psoriasis.³ A physician global assessment (PGA) score of 0/1 occurred in 35.4% to 40.2% of patients in the tapinarof group and in 6.0% of patients in the vehicle group. At week 12, 36.1% to 47.6% of patients treated with daily applications of tapinarof cream achieved a 75% reduction in their baseline psoriasis area and severity index (PASI 75) score compared with 6.9% to 10.2% in the vehicle group.³ In a long-term extension study, a substantial remittive effect of at least 4 months off tapinarof therapy was observed in patients who achieved complete clearance (PGA=0).⁴ Use of tapinarof cream was associated with folliculitis in up to 23.5% of patients.^3,4

Roflumilast—Phosphodiesterase 4 (PDE-4) is an intracellular enzyme involved in the regulation of cell proliferation, differentiation, and immune responses.⁵ The inhibition of PDE-4 decreases the expression of proinflammatory cytokines implicated in the pathogenesis of plaque psoriasis, such as tumor necrosis factor α, IFN-γ, and IL-2, IL-12, and IL-23.⁶ Phosphodiesterase 4–targeted therapies have been thoroughly explored to treat various inflammatory conditions, including atopic dermatitis and plaque psoriasis. The oral PDE-4 inhibitor apremilast was shown to achieve PASI 75 in approximately 30% of 562 patients, accompanied by severe gastrointestinal adverse events (AEs) including diarrhea and nausea associated with treatment.⁷ Local irritation from the topical PDE-4 inhibitor crisaborole for atopic dermatitis and psoriasis (where it only completed phase 2 trials) limits its widespread use. The lack of tolerable and effective treatment alternatives for psoriasis prompted the investigation of new PDE-4–targeted therapies.

Topical roflumilast is a selective, highly potent PDE-4 inhibitor with greater affinity for PDE-4 compared to crisaborole and apremilast.⁸ Two phase 3 trials (N=881) evaluated the efficacy and safety profile of roflumilast cream for plaque psoriasis, with a particular interest in its use for intertriginous areas.⁹ At week 8, 37.5% to 42.4% of roflumilast-treated patients achieved investigator global assessment (IGA) success compared with 6.1% to 6.9% of vehicle-treated patients. Intertriginous IGA success was observed in 68.1% to 71.2% of patients treated with roflumilast cream compared with 13.8% to 18.5% of vehicle-treated patients. At 8-week follow-up, 39.0% to 41.6% of roflumilast-treated patients achieved PASI 75 vs 5.3% to 7.6% of patients in the vehicle group. Few stinging, burning, or application-site reactions were reported with roflumilast, along with rare instances of gastrointestinal AEs (<4%).⁹

Oral Therapy

Deucravacitinib—Tyrosine kinase 2 (TYK2) mediates the intracellular signaling of the T_H17 and T_H1 inflammatory cytokines IL-12/IL-23 and type I interferons, respectively, the former of which are critical in the development of psoriasis via the Janus kinase (JAK) signal transducer and activator of transcription pathway.¹⁰ Deucravacitinib is an oral selective TYK2 allosteric inhibitor that binds to the regulatory domain of the enzyme rather than the active catalytic domain, where other TYK2 and JAK1, JAK2, and JAK3 inhibitors bind.¹¹ This unique inhibitory mechanism accounts for the high functional selectivity of deucravacitinib for TYK2 vs the closely related JAK1, JAK2, and JAK3 kinases, thus avoiding the pitfall of prior JAK inhibitors that were associated with major AEs, including an increased risk for serious infections, malignancies, and thrombosis.¹² The selective suppression of the inflammatory TYK2 pathway has the potential to shift future therapeutic targets to a narrower range of receptors that may contribute to favorable benefit-risk profiles.

Two phase 3 trials (N=1686) compared the efficacy and safety of deucravacitinib vs placebo and apremilast in adults with moderate to severe plaque psoriasis.^13,14 At week 16, 53.0% to 58.4% of deucravacitinib-treated patients achieved PASI 75 compared with 35.1% to 39.8% of apremilast-treated patients. At 16-week follow-up, static PGA response was observed in 49.5% to 53.6% of patients in the deucravacitinib group and 32.1% to 33.9% of the apremilast group. The most frequent AEs associated with deucravacitinib therapy were nasopharyngitis and upper respiratory tract infection, whereas headache, diarrhea, and nausea were more common with apremilast. Treatment with deucravacitinib caused no meaningful changes in laboratory parameters, which are known to change with JAK1, JAK2, and JAK3 inhibitors.^13,14 A long-term extension study demonstrated that deucravacitinib had persistent efficacy and consistent safety for up to 2 years.¹⁵

Novel oral allosteric TYK2 inhibitors—VTX958 and NDI-034858—and the competitive TYK2 inhibitor PF-06826647 are being developed. Theoretically, these new allosteric inhibitors possess unique structural properties to provide greater TYK2 suppression while bypassing JAK1, JAK2, and JAK3 pathways that may contribute to improved efficacy and safety profiles compared with other TYK2 inhibitors such as deucravacitinib. The results of a phase 1b trial (ClinicalTrials.gov Identifier NCT04999839) showed a dose-dependent reduction of disease severity associated with NDI-034858 treatment for patients with moderate to severe plaque psoriasis, albeit in only 26 patients. At week 4, PASI 50 was achieved in 13%, 57%, and 40% of patients in the 5-, 10-, and 30-mg groups, respectively, compared with 0% in the placebo group.¹⁶ In a phase 2 trial of 179 patients, 46.5% and 33.0% of patients treated with 400 and 200 mg of PF-06826647, respectively, achieved PASI 90 at week 16. Conversely, dose-dependent laboratory abnormalities were observed with PF-06826647, including anemia, neutropenia, and increases in creatine phosphokinase.¹⁷ At high concentrations, PF-06826647 may disrupt JAK signaling pathways involved in hematopoiesis and renal functions owing to its mode of action as a competitive inhibitor. Overall, these agents are much farther from market, and long-term studies with larger diverse patient cohorts are required to adequately assess the efficacy and safety data of these novel oral TYK2 inhibitors for patients with psoriasis.

EDP1815—EDP1815 is an oral preparation of a single strain of Prevotella histicola being developed for the treatment of inflammatory diseases, including psoriasis. EDP1815 interacts with host intestinal immune cells through the small intestinal axis (SINTAX) to suppress systemic inflammation across the T_H1, T_H2, and T_H17 pathways. Therapy triggers broad immunomodulatory effects without causing systemic absorption, colonic colonization, or modification of the gut microbiome.¹⁸ In a phase 2 study (NCT04603027), the primary end point analysis, mean percentage change in PASI between treatment and placebo, demonstrated that at week 16, EDP1815 was superior to placebo with 80% to 90% probability across each cohort. At week 16, 25% to 32% of patients across the 3 cohorts treated with EDP1815 achieved PASI 50 compared with 12% of patients receiving placebo. Gastrointestinal AEs were comparable between treatment and placebo groups. These results suggest that SINTAX-targeted therapies may provide efficacious and safe immunomodulatory effects for patients with mild to moderate psoriasis, who often have limited treatment options. Although improvements may be mild, SINTAX-targeted therapies can be seen as a particularly attractive adjunctive treatment for patients with severe psoriasis taking other medications or as part of a treatment approach for a patient with milder psoriasis.

Biologics

Bimekizumab—Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits IL-17A and IL-17F. Although IL-17A is a more potent cytokine, IL-17F may be more highly expressed in psoriatic lesional skin and independently contribute to the activation of proinflammatory signaling pathways implicated in the pathophysiology of psoriasis.¹⁹ Evidence suggests that dual inhibition of IL-17A and IL-17F may provide more complete suppression of inflammation and improved clinical responses than IL-17A inhibition alone.²⁰

Prior bimekizumab phase 3 clinical studies have shown both rapid and durable clinical improvements in skin clearance compared with placebo.²¹ Three phase 3 trials—BE VIVID (N=567),²² BE SURE (N=478),²³ and BE RADIANT (N=743)²⁴—assessed the efficacy and safety of bimekizumab vs the IL-12/IL-23 inhibitor ustekinumab, the tumor necrosis factor inhibitor adalimumab, and the selective IL-17A inhibitor secukinumab, respectively. At week 4, significantly more patients treated with bimekizumab (71%–77%) achieved PASI 75 than patients treated with ustekinumab (15%; P<.0001), adalimumab (31.4%; P<.001), or secukinumab (47.3%; P<.001).^22-24 After 16 weeks of treatment, PASI 90 was achieved by 85% to 86.2%, 50%, and 47.2% of patients treated with bimekizumab, ustekinumab, and adalimumab, respectively.^22,23 At week 16, PASI 100 was observed in 59% to 61.7%, 21%, 23.9%, and 48.9% of patients treated with bimekizumab, ustekinumab, adalimumab, and secukinumab, respectively. An IGA response (score of 0/1) at week 16 was achieved by 84% to 85.5%, 53%, 57.2%, and 78.6% of patients receiving bimekizumab, ustekinumab, adalimumab, and secukinumab, respectively.^22-24

The most common AEs in bimekizumab-treated patients were nasopharyngitis, oral candidiasis, and upper respiratory tract infection.^22-24 The dual inhibition of IL-17A and IL-17F suppresses host defenses against Candida at the oral mucosa, increasing the incidence of bimekizumab-associated oral candidiasis.²⁵ Despite the increased risk of Candida infections, these data suggest that inhibition of both IL-17A and IL-17F with bimekizumab may provide faster and greater clinical benefit for patients with moderate to severe plaque psoriasis than inhibition of IL-17A alone and other biologic therapies, as the PASI 100 clearance rates across the multiple comparator trials and the placebo-controlled pivotal trial are consistently the highest among any biologic for the treatment of psoriasis.

Spesolimab—The IL-36 pathway and IL-36 receptor genes have been linked to the pathogenesis of generalized pustular psoriasis.²⁶ In a phase 2 trial, 19 of 35 patients (54%) receiving an intravenous dose of spesolimab, an IL-36 receptor inhibitor, had a generalized pustular psoriasis PGA pustulation subscore of 0 (no visible pustules) at the end of week 1 vs 6% of patients in the placebo group.²⁷ A generalized pustular psoriasis PGA total score of 0 or 1 was observed in 43% (15/35) of spesolimab-treated patients compared with 11% (2/18) of patients in the placebo group. The most common AEs in patients treated with spesolimab were minor infections.²⁷ Two open-label phase 3 trials—NCT05200247 and NCT05239039—are underway to determine the long-term efficacy and safety of spesolimab in patients with generalized pustular psoriasis.

Conclusion

Although we have seen a renaissance in psoriasis therapies with the advent of biologics in the last 20 years, recent evidence shows that more innovation is underway. Just in the last year, 2 new mechanisms for treating psoriasis topically without steroids have come to fruition, and there have not been truly novel mechanisms for treating psoriasis topically since approvals for tazarotene and calcipotriene in the 1990s. An entirely new class—TYK2 inhibitors—was developed and landed in psoriasis first, greatly improving the efficacy measures attained with oral medications in general. Finally, an orphan diagnosis got its due with an ambitiously designed study looking at a previously unheard-of 1-week end point, but it comes for one of the few true dermatologic emergencies we encounter, generalized pustular psoriasis. We are fortunate to have so many meaningful new treatments available to us, and it is invigorating to see that even more efficacious biologics and treatments are coming, along with novel concepts such as a treatment affecting the microbiome. Now, we just need to make sure that our patients have the access they deserve to the wide array of available treatments.