TBD Meeting (5458-23)

WASHINGTON – The approval last year of the interleukin (IL)-36 receptor antagonist spesolimab for treating generalized pustular psoriasis flares brightened the treatment landscape for this rare condition, and a recently published phase 2 study suggests a potential role of spesolimab for flare prevention. But when it comes to pustular disease localized to the hands and feet – palmoplantar pustulosis – treatment options have only modest efficacy, and spesolimab appears not to work, according to speakers at the annual research symposium of the National Psoriasis Foundation.

“The IL-36 receptor antagonists don’t seem to be quite the answer for [palmoplantar pustulosis] that they are for generalized pustular psoriasis [GPP],” Megan H. Noe, MD, MPH, assistant professor of dermatology at Harvard Medical School and a dermatologist at Brigham and Women’s Hospital, Boston, said at the meeting.

Psoriasis affecting the hands and feet – both pustular and nonpustular – has a higher impact on quality of life and higher functional disability than does non-acral psoriasis, is less responsive to treatment, and has a “very confusing nomenclature” that complicates research and thus management, said Jason Ezra Hawkes, MD, a dermatologist in Rocklin, Calif., and former faculty member of several departments of dermatology. Both he and Dr. Noe spoke during a tough-to-treat session at the NPF meeting.

IL-17 and IL-23 blockade, as well as tumor necrosis factor (TNF) inhibition, are effective overall for palmoplantar psoriasis (nonpustular), but in general, responses are lower than for plaque psoriasis. Apremilast (Otezla), a phosphodiesterase-4 inhibitor, has some efficacy for pustular variants, but for hyperkeratotic variants it “does not perform as well as more selective inhibition of IL-17 and IL-23 blockade,” he said.

Dr. Hawkes

Palmoplantar pustulosis, and a word on generalized disease

Dermatologists are using a variety of treatments for palmoplantar pustulosis, with no clear first-line choices, Dr. Noe said. In a case series of almost 200 patients with palmoplantar pustulosis across 20 dermatology practices, published in JAMA Dermatology, 35% of patients received a systemic therapy prescription at their initial encounter – most commonly acitretin, followed by methotrexate and phototherapy. “Biologics were used, but use was varied and not as often as with oral agents,” said Dr. Noe, a coauthor of the study.

TNF blockers led to improvements ranging from 57% to 84%, depending on the agent, in a 2020 retrospective study of patients with palmoplantar pustulosis or acrodermatitis continua of Hallopeau, Dr. Noe noted. However, rates of complete clearance were only 20%-29%.

Apremilast showed modest efficacy after 5 months of treatment, with 62% of patients achieving at least a 50% improvement in the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) in a 2021 open-label, phase 2 study involving 21 patients. “This may represent a potential treatment option,” Dr. Noe said. “It’s something, but not what we’re used to seeing in our plaque psoriasis patients.”

A 2021 phase 2a, double-blind, randomized, placebo-controlled study of spesolimab in patients with palmoplantar pustulosis, meanwhile, failed to meet its primary endpoint, with only 32% of patients achieving a 50% improvement at 16 weeks, compared with 24% of patients in the placebo arm. And a recently published network meta-analysis found that none of the five drugs studied in seven randomized controlled trials – biologic or oral – was more effective than placebo for clearance or improvement of palmoplantar pustulosis.

The spesolimab (Spevigo) results have been disappointing considering the biologic’s newfound efficacy and role as the first Food and Drug Administration–approved therapy for generalized pustular disease, according to Dr. Noe. The ability of a single 900-mg intravenous dose of the IL-36 receptor antagonist to completely clear pustules at 1 week in 54% of patients with generalized disease, compared with 6% of the placebo group, was “groundbreaking,” she said, referring to results of the pivotal trial published in the New England Journal of Medicine.

And given that “preventing GPP flares is ultimately what we want,” she said, more good news was reported this year in The Lancet: The finding from an international, randomized, placebo-controlled study that high-dose subcutaneous spesolimab significantly reduced the risk of a flare over 48 weeks. “There are lots of ongoing studies right now to understand the best way to dose spesolimab,” she said.

Moreover, another IL-36 receptor antagonist, imsidolimab, is being investigated in a phase 3 trial for generalized pustular disease, she noted. A phase 2, open-label study of patients with GPP found that “more than half of patients were very much improved at 4 weeks, and some patients started showing improvement at day 3,” Dr. Noe said.

An area of research she is interested in is the potential for Janus kinase (JAK) inhibitors as a treatment for palmoplantar pustulosis. For pustulosis on the hands and feet, recent case reports describing the efficacy of JAK inhibitors have caught her eye. “Right now, all we have is this case report data, mostly with tofacitinib, but I think it’s exciting,” she said, noting a recently published report in the British Journal of Dermatology.

Palmoplantar psoriasis

Pustular psoriatic disease can be localized to the hand and/or feet only, or can co-occur with generalized pustular disease, just as palmoplantar psoriasis can be localized to the hands and/or feet or, more commonly, can co-occur with widespread plaque psoriasis. Research has shown, Dr. Hawkes said, that with both types of acral disease, many patients have or have had plaque psoriasis outside of acral sites.

The nomenclature and acronyms for palmoplantar psoriatic disease have complicated patient education, communication, and research, Dr. Hawkes said. Does PPP refer to palmoplantar psoriasis, or palmoplantar pustulosis, for instance? What is the difference between palmoplantar pustulosis (coined PPP) and palmoplantar pustular psoriasis (referred to as PPPP)?

What if disease is only on the hands, only on the feet, or only on the backs of the hands? And at what point is disease not classified as palmoplantar psoriasis, but plaque psoriasis with involvement of the hands and feet? Inconsistencies and lack of clarification lead to “confusing” literature, he said.

Heterogeneity in populations across trials resulting from “inconsistent categorization and phenotype inclusion” may partly account for the recalcitrance to treatment reported in the literature, he said. Misdiagnosis as psoriasis in cases of localized disease (confusion with eczema, for instance), and the fact that hands and feet are subject to increased trauma and injury, compared with non-acral sites, are also at play.

Trials may also allow insufficient time for improvement, compared with non-acral sites. “What we’ve learned about the hands and feet is that it takes a much longer time for disease to improve,” Dr. Hawkes said, so primary endpoints must take this into account.

There is unique immunologic signaling in palmoplantar disease that differs from the predominant signaling in traditional plaque psoriasis, he emphasized, and “mixed immunophenotypes” that need to be unraveled.

Dr. Hawkes disclosed ties with AbbVie, Arcutis, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, LEO, Lilly, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB. Dr. Noe disclosed ties to Bristol-Myers Squibb and Boehringer Ingelheim.

WASHINGTON – The approval last year of the interleukin (IL)-36 receptor antagonist spesolimab for treating generalized pustular psoriasis flares brightened the treatment landscape for this rare condition, and a recently published phase 2 study suggests a potential role of spesolimab for flare prevention. But when it comes to pustular disease localized to the hands and feet – palmoplantar pustulosis – treatment options have only modest efficacy, and spesolimab appears not to work, according to speakers at the annual research symposium of the National Psoriasis Foundation.

“The IL-36 receptor antagonists don’t seem to be quite the answer for [palmoplantar pustulosis] that they are for generalized pustular psoriasis [GPP],” Megan H. Noe, MD, MPH, assistant professor of dermatology at Harvard Medical School and a dermatologist at Brigham and Women’s Hospital, Boston, said at the meeting.

Psoriasis affecting the hands and feet – both pustular and nonpustular – has a higher impact on quality of life and higher functional disability than does non-acral psoriasis, is less responsive to treatment, and has a “very confusing nomenclature” that complicates research and thus management, said Jason Ezra Hawkes, MD, a dermatologist in Rocklin, Calif., and former faculty member of several departments of dermatology. Both he and Dr. Noe spoke during a tough-to-treat session at the NPF meeting.

IL-17 and IL-23 blockade, as well as tumor necrosis factor (TNF) inhibition, are effective overall for palmoplantar psoriasis (nonpustular), but in general, responses are lower than for plaque psoriasis. Apremilast (Otezla), a phosphodiesterase-4 inhibitor, has some efficacy for pustular variants, but for hyperkeratotic variants it “does not perform as well as more selective inhibition of IL-17 and IL-23 blockade,” he said.

Dr. Hawkes

Palmoplantar pustulosis, and a word on generalized disease

Dermatologists are using a variety of treatments for palmoplantar pustulosis, with no clear first-line choices, Dr. Noe said. In a case series of almost 200 patients with palmoplantar pustulosis across 20 dermatology practices, published in JAMA Dermatology, 35% of patients received a systemic therapy prescription at their initial encounter – most commonly acitretin, followed by methotrexate and phototherapy. “Biologics were used, but use was varied and not as often as with oral agents,” said Dr. Noe, a coauthor of the study.

TNF blockers led to improvements ranging from 57% to 84%, depending on the agent, in a 2020 retrospective study of patients with palmoplantar pustulosis or acrodermatitis continua of Hallopeau, Dr. Noe noted. However, rates of complete clearance were only 20%-29%.

Apremilast showed modest efficacy after 5 months of treatment, with 62% of patients achieving at least a 50% improvement in the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) in a 2021 open-label, phase 2 study involving 21 patients. “This may represent a potential treatment option,” Dr. Noe said. “It’s something, but not what we’re used to seeing in our plaque psoriasis patients.”

A 2021 phase 2a, double-blind, randomized, placebo-controlled study of spesolimab in patients with palmoplantar pustulosis, meanwhile, failed to meet its primary endpoint, with only 32% of patients achieving a 50% improvement at 16 weeks, compared with 24% of patients in the placebo arm. And a recently published network meta-analysis found that none of the five drugs studied in seven randomized controlled trials – biologic or oral – was more effective than placebo for clearance or improvement of palmoplantar pustulosis.

The spesolimab (Spevigo) results have been disappointing considering the biologic’s newfound efficacy and role as the first Food and Drug Administration–approved therapy for generalized pustular disease, according to Dr. Noe. The ability of a single 900-mg intravenous dose of the IL-36 receptor antagonist to completely clear pustules at 1 week in 54% of patients with generalized disease, compared with 6% of the placebo group, was “groundbreaking,” she said, referring to results of the pivotal trial published in the New England Journal of Medicine.

And given that “preventing GPP flares is ultimately what we want,” she said, more good news was reported this year in The Lancet: The finding from an international, randomized, placebo-controlled study that high-dose subcutaneous spesolimab significantly reduced the risk of a flare over 48 weeks. “There are lots of ongoing studies right now to understand the best way to dose spesolimab,” she said.

Moreover, another IL-36 receptor antagonist, imsidolimab, is being investigated in a phase 3 trial for generalized pustular disease, she noted. A phase 2, open-label study of patients with GPP found that “more than half of patients were very much improved at 4 weeks, and some patients started showing improvement at day 3,” Dr. Noe said.

An area of research she is interested in is the potential for Janus kinase (JAK) inhibitors as a treatment for palmoplantar pustulosis. For pustulosis on the hands and feet, recent case reports describing the efficacy of JAK inhibitors have caught her eye. “Right now, all we have is this case report data, mostly with tofacitinib, but I think it’s exciting,” she said, noting a recently published report in the British Journal of Dermatology.

Palmoplantar psoriasis

Pustular psoriatic disease can be localized to the hand and/or feet only, or can co-occur with generalized pustular disease, just as palmoplantar psoriasis can be localized to the hands and/or feet or, more commonly, can co-occur with widespread plaque psoriasis. Research has shown, Dr. Hawkes said, that with both types of acral disease, many patients have or have had plaque psoriasis outside of acral sites.

The nomenclature and acronyms for palmoplantar psoriatic disease have complicated patient education, communication, and research, Dr. Hawkes said. Does PPP refer to palmoplantar psoriasis, or palmoplantar pustulosis, for instance? What is the difference between palmoplantar pustulosis (coined PPP) and palmoplantar pustular psoriasis (referred to as PPPP)?

What if disease is only on the hands, only on the feet, or only on the backs of the hands? And at what point is disease not classified as palmoplantar psoriasis, but plaque psoriasis with involvement of the hands and feet? Inconsistencies and lack of clarification lead to “confusing” literature, he said.

Heterogeneity in populations across trials resulting from “inconsistent categorization and phenotype inclusion” may partly account for the recalcitrance to treatment reported in the literature, he said. Misdiagnosis as psoriasis in cases of localized disease (confusion with eczema, for instance), and the fact that hands and feet are subject to increased trauma and injury, compared with non-acral sites, are also at play.

Trials may also allow insufficient time for improvement, compared with non-acral sites. “What we’ve learned about the hands and feet is that it takes a much longer time for disease to improve,” Dr. Hawkes said, so primary endpoints must take this into account.

There is unique immunologic signaling in palmoplantar disease that differs from the predominant signaling in traditional plaque psoriasis, he emphasized, and “mixed immunophenotypes” that need to be unraveled.

Dr. Hawkes disclosed ties with AbbVie, Arcutis, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, LEO, Lilly, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB. Dr. Noe disclosed ties to Bristol-Myers Squibb and Boehringer Ingelheim.

WASHINGTON – The approval last year of the interleukin (IL)-36 receptor antagonist spesolimab for treating generalized pustular psoriasis flares brightened the treatment landscape for this rare condition, and a recently published phase 2 study suggests a potential role of spesolimab for flare prevention. But when it comes to pustular disease localized to the hands and feet – palmoplantar pustulosis – treatment options have only modest efficacy, and spesolimab appears not to work, according to speakers at the annual research symposium of the National Psoriasis Foundation.

“The IL-36 receptor antagonists don’t seem to be quite the answer for [palmoplantar pustulosis] that they are for generalized pustular psoriasis [GPP],” Megan H. Noe, MD, MPH, assistant professor of dermatology at Harvard Medical School and a dermatologist at Brigham and Women’s Hospital, Boston, said at the meeting.

Psoriasis affecting the hands and feet – both pustular and nonpustular – has a higher impact on quality of life and higher functional disability than does non-acral psoriasis, is less responsive to treatment, and has a “very confusing nomenclature” that complicates research and thus management, said Jason Ezra Hawkes, MD, a dermatologist in Rocklin, Calif., and former faculty member of several departments of dermatology. Both he and Dr. Noe spoke during a tough-to-treat session at the NPF meeting.

IL-17 and IL-23 blockade, as well as tumor necrosis factor (TNF) inhibition, are effective overall for palmoplantar psoriasis (nonpustular), but in general, responses are lower than for plaque psoriasis. Apremilast (Otezla), a phosphodiesterase-4 inhibitor, has some efficacy for pustular variants, but for hyperkeratotic variants it “does not perform as well as more selective inhibition of IL-17 and IL-23 blockade,” he said.

Dr. Hawkes

Palmoplantar pustulosis, and a word on generalized disease

Dermatologists are using a variety of treatments for palmoplantar pustulosis, with no clear first-line choices, Dr. Noe said. In a case series of almost 200 patients with palmoplantar pustulosis across 20 dermatology practices, published in JAMA Dermatology, 35% of patients received a systemic therapy prescription at their initial encounter – most commonly acitretin, followed by methotrexate and phototherapy. “Biologics were used, but use was varied and not as often as with oral agents,” said Dr. Noe, a coauthor of the study.

TNF blockers led to improvements ranging from 57% to 84%, depending on the agent, in a 2020 retrospective study of patients with palmoplantar pustulosis or acrodermatitis continua of Hallopeau, Dr. Noe noted. However, rates of complete clearance were only 20%-29%.

Apremilast showed modest efficacy after 5 months of treatment, with 62% of patients achieving at least a 50% improvement in the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) in a 2021 open-label, phase 2 study involving 21 patients. “This may represent a potential treatment option,” Dr. Noe said. “It’s something, but not what we’re used to seeing in our plaque psoriasis patients.”

A 2021 phase 2a, double-blind, randomized, placebo-controlled study of spesolimab in patients with palmoplantar pustulosis, meanwhile, failed to meet its primary endpoint, with only 32% of patients achieving a 50% improvement at 16 weeks, compared with 24% of patients in the placebo arm. And a recently published network meta-analysis found that none of the five drugs studied in seven randomized controlled trials – biologic or oral – was more effective than placebo for clearance or improvement of palmoplantar pustulosis.

The spesolimab (Spevigo) results have been disappointing considering the biologic’s newfound efficacy and role as the first Food and Drug Administration–approved therapy for generalized pustular disease, according to Dr. Noe. The ability of a single 900-mg intravenous dose of the IL-36 receptor antagonist to completely clear pustules at 1 week in 54% of patients with generalized disease, compared with 6% of the placebo group, was “groundbreaking,” she said, referring to results of the pivotal trial published in the New England Journal of Medicine.

And given that “preventing GPP flares is ultimately what we want,” she said, more good news was reported this year in The Lancet: The finding from an international, randomized, placebo-controlled study that high-dose subcutaneous spesolimab significantly reduced the risk of a flare over 48 weeks. “There are lots of ongoing studies right now to understand the best way to dose spesolimab,” she said.

Moreover, another IL-36 receptor antagonist, imsidolimab, is being investigated in a phase 3 trial for generalized pustular disease, she noted. A phase 2, open-label study of patients with GPP found that “more than half of patients were very much improved at 4 weeks, and some patients started showing improvement at day 3,” Dr. Noe said.

An area of research she is interested in is the potential for Janus kinase (JAK) inhibitors as a treatment for palmoplantar pustulosis. For pustulosis on the hands and feet, recent case reports describing the efficacy of JAK inhibitors have caught her eye. “Right now, all we have is this case report data, mostly with tofacitinib, but I think it’s exciting,” she said, noting a recently published report in the British Journal of Dermatology.

Palmoplantar psoriasis

Pustular psoriatic disease can be localized to the hand and/or feet only, or can co-occur with generalized pustular disease, just as palmoplantar psoriasis can be localized to the hands and/or feet or, more commonly, can co-occur with widespread plaque psoriasis. Research has shown, Dr. Hawkes said, that with both types of acral disease, many patients have or have had plaque psoriasis outside of acral sites.

The nomenclature and acronyms for palmoplantar psoriatic disease have complicated patient education, communication, and research, Dr. Hawkes said. Does PPP refer to palmoplantar psoriasis, or palmoplantar pustulosis, for instance? What is the difference between palmoplantar pustulosis (coined PPP) and palmoplantar pustular psoriasis (referred to as PPPP)?

What if disease is only on the hands, only on the feet, or only on the backs of the hands? And at what point is disease not classified as palmoplantar psoriasis, but plaque psoriasis with involvement of the hands and feet? Inconsistencies and lack of clarification lead to “confusing” literature, he said.

Heterogeneity in populations across trials resulting from “inconsistent categorization and phenotype inclusion” may partly account for the recalcitrance to treatment reported in the literature, he said. Misdiagnosis as psoriasis in cases of localized disease (confusion with eczema, for instance), and the fact that hands and feet are subject to increased trauma and injury, compared with non-acral sites, are also at play.

Trials may also allow insufficient time for improvement, compared with non-acral sites. “What we’ve learned about the hands and feet is that it takes a much longer time for disease to improve,” Dr. Hawkes said, so primary endpoints must take this into account.

There is unique immunologic signaling in palmoplantar disease that differs from the predominant signaling in traditional plaque psoriasis, he emphasized, and “mixed immunophenotypes” that need to be unraveled.

Dr. Hawkes disclosed ties with AbbVie, Arcutis, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, LEO, Lilly, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB. Dr. Noe disclosed ties to Bristol-Myers Squibb and Boehringer Ingelheim.

WASHINGTON – Multiple biologic failure in a minority of patients with psoriasis may have several causes, from genetic endotypes and immunologic factors to lower serum drug levels, the presence of anti-drug antibody levels, female sex, and certain comorbidities, Wilson Liao, MD, said at the annual research symposium of the National Psoriasis Foundation.

“Tough-to-treat psoriasis remains a challenge despite newer therapies ... Why do we still have this sub-population of patients who seem to be refractory?” said Dr. Liao, professor and associate vice chair of research in the department of dermatology at the University of California, San Francisco, who coauthored a 2015-2022 prospective cohort analysis that documented about 6% of patients failing two or more biologic agents of different mechanistic classes.

“These patients are really suffering,” he said. “We need to have better guidelines and treatment algorithms for these patients.”

A significant number of patients with psoriatic arthritis (PsA), meanwhile, are inadequate responders to tumor necrosis factor (TNF) inhibition, Christopher T. Ritchlin, MD, PhD, professor of medicine in the division of allergy/immunology and rheumatology and the Center of Musculoskeletal Research at the University of Rochester (N.Y.), said during another session at the meeting.

The long-term “persistence,” or usage, of first-line biologics in patients with PsA – and of second-line biologics in patients who failed one TNF-inhibitor – is low, but the literature offers little information on the reasons for TNF-inhibitor discontinuation, said Dr. Ritchlin, who coauthored a perspective piece in Arthritis & Rheumatology on managing the patient with PsA who fails one TNF inhibitor.

Dr. Ritchlin and his coauthors were asked to provide evidence-informed advice and algorithms, but the task was difficult. “It’s hard to know what to recommend for the next step if we don’t know why patients failed the first,” he said. “The point is, we need more data. [Clinical trials] are not recording the kind of information we need.”
 

Anti-drug antibodies, genetics, other factors in psoriasis

Research shows that in large cohorts, “all the biologics do seem to lose efficacy over time,” said Dr. Liao, who directs the UCSF Psoriasis and Skin Treatment Center. “Some are better than others, but we do see a loss of effectiveness over time.”

A cohort study published in 2022 in JAMA Dermatology, for instance, documented declining “drug survival” associated with ineffectiveness during 2 years of treatment for each of five biologics studied (adalimumab [Humira], ustekinumab [Stelara], secukinumab [Cosentyx], guselkumab [Tremfya], and ixekizumab [Taltz]).

“There have been a number of theories put forward” as to why that’s the case, including lower serum drug levels, “which of course can be related to anti-drug antibody production,” he said.

He pointed to two studies of ustekinumab: One prospective observational cohort study that reported an association of lower early drug levels of the IL-12/23 receptor antagonist with lower Psoriasis Area and Severity Index (PASI) scores, and another observational study that documented an association between anti-drug antibody positivity with lower ustekinumab levels and impaired clinical response.

“We also now know ... that there are genetic endotypes in psoriasis, and that patients who are [HLA-C*06:02]-positive tend to respond a little better to drugs like ustekinumab, and those who are [HLA-C*06:02]-negative tend to do a little better with the TNF inhibitors,” Dr. Liao said. The human leukocyte antigen (HLA) allele HLA-C*06:02 is associated with susceptibility to psoriasis.

In a study using a national psoriasis registry, HLA-C*06:02-negative patients were 3 times more likely to achieve PASI90 status in response to adalimumab, a TNF-alpha inhibitor, than with ustekinumab treatment. And in a meta-analysis covering eight studies with more than 1,000 patients with psoriasis, the median PASI75 response rate after 6 months of ustekinumab therapy was 92% in the HLA-C*06:02-positive group and 67% in HLA-C*06:02-negative patients.

The recently published cohort study showing a 6% rate of multiple biologic failure evaluated patients in the multicenter CorEvitas Psoriasis Registry who initiated their first biologic between 2015 and 2020 and were followed for 2 or more years. Investigators looked for sociodemographic and clinical differences between the patients who continued use of their first biologic for at least 2 years (“good response”), and those who discontinued two or more biologics of different classes, each used for at least 90 days, because of inadequate efficacy.

Of 1,039 evaluated patients, 490 (47.2%) had good clinical response to their first biologic and 65 (6.3%) had multiple biologic failure. All biologic classes were represented among those who failed multiple biologics. The first and second biologic classes used were attempted for a mean duration of 10 months – “an adequate trial” of each, Dr. Liao said.

In multivariable regression analysis, six variables were significantly associated with multiple biologic failure: female sex at birth, shorter disease duration, earlier year of biologic initiation, prior nonbiologic systemic therapy, having Medicaid insurance, and a history of hyperlipidemia. The latter is “interesting because other studies have shown that metabolic syndrome, of which hyperlipidemia is a component, can also relate to poor response to biologics,” Dr. Liao said.

The most common sequences of first-to-second biologics among those with multiple biologic failure were TNF inhibitor to IL-17 inhibitor (30.8%); IL-12/23 inhibitor to IL-17 inhibitor (21.5%); TNF inhibitor to IL-12/23 inhibitor (12.3%); and IL-17 inhibitor to IL-23 inhibitor (10.8%).

The vast majority of patients failed more than two biologics, however, and “more than 20% had five or more biologics tried over a relatively short period,” Dr. Liao said.
 

Comorbidities and biologic failure in psoriasis, PsA

In practice, it was said during a discussion period, biologic failures in psoriasis can be of two types: a primary inadequate response or initial failure, or a secondary failure with initial improvement followed by declining or no response. “I agree 100% that these probably represent two different endotypes,” Dr. Liao said. “There’s research emerging that psoriasis isn’t necessarily a clean phenotype.”

The option of focusing on comorbidities in the face of biologic failure was another point of discussion. “Maybe the next biologic is not the answer,” a meeting participant said. “Maybe we should focus on metabolic syndrome.”

“I agree,” Dr. Liao said. “In clinic, there are people who may not respond to therapies but have other comorbidities and factors that make it difficult to manage [their psoriasis] ... that may be causative for psoriasis. Maybe if we treat the comorbidities, it will make it easier to treat the psoriasis.”

Addressing comorbidities and “extra-articular traits” such as poorly controlled diabetes, centralized pain, anxiety and depression, and obesity is something Dr. Ritchlin advocates for PsA. “Centralized pain, I believe, is a major driver of nonresponse,” he said at the meeting. “We have to be careful about blaming nonresponse and lack of efficacy of biologics when it could be a wholly different mechanism the biologic won’t treat ... for example, centralized pain.”

As with psoriasis, the emergence of antidrug antibodies may be one reason for the secondary failure of biologic agents for PsA, Dr. Ritchlin and his coauthors wrote in their paper on management of PsA after failure of one TNF inhibitor. Other areas to consider in evaluating failure, they wrote, are compliance and time of dosing, and financial barriers.

Low long-term persistence of second-line biologics for patients with PsA was demonstrated in a national cohort study utilizing the French health insurance database, Dr. Ritchlin noted at the research meeting. 

The French study covered almost 3,000 patients who started a second biologic after discontinuing a TNF inhibitor during 2015-2020. Overall, 1-year and 3-year persistence rates were 42% and 17%, respectively.

Dr. Liao disclosed research grant funding from AbbVie, Amgen, Janssen, Leo, Novartis, Pfizer, Regeneron, and Trex Bio. Dr. Ritchlin reported no disclosures.

WASHINGTON – Multiple biologic failure in a minority of patients with psoriasis may have several causes, from genetic endotypes and immunologic factors to lower serum drug levels, the presence of anti-drug antibody levels, female sex, and certain comorbidities, Wilson Liao, MD, said at the annual research symposium of the National Psoriasis Foundation.

“Tough-to-treat psoriasis remains a challenge despite newer therapies ... Why do we still have this sub-population of patients who seem to be refractory?” said Dr. Liao, professor and associate vice chair of research in the department of dermatology at the University of California, San Francisco, who coauthored a 2015-2022 prospective cohort analysis that documented about 6% of patients failing two or more biologic agents of different mechanistic classes.

“These patients are really suffering,” he said. “We need to have better guidelines and treatment algorithms for these patients.”

A significant number of patients with psoriatic arthritis (PsA), meanwhile, are inadequate responders to tumor necrosis factor (TNF) inhibition, Christopher T. Ritchlin, MD, PhD, professor of medicine in the division of allergy/immunology and rheumatology and the Center of Musculoskeletal Research at the University of Rochester (N.Y.), said during another session at the meeting.

The long-term “persistence,” or usage, of first-line biologics in patients with PsA – and of second-line biologics in patients who failed one TNF-inhibitor – is low, but the literature offers little information on the reasons for TNF-inhibitor discontinuation, said Dr. Ritchlin, who coauthored a perspective piece in Arthritis & Rheumatology on managing the patient with PsA who fails one TNF inhibitor.

Dr. Ritchlin and his coauthors were asked to provide evidence-informed advice and algorithms, but the task was difficult. “It’s hard to know what to recommend for the next step if we don’t know why patients failed the first,” he said. “The point is, we need more data. [Clinical trials] are not recording the kind of information we need.”
 

Anti-drug antibodies, genetics, other factors in psoriasis

Research shows that in large cohorts, “all the biologics do seem to lose efficacy over time,” said Dr. Liao, who directs the UCSF Psoriasis and Skin Treatment Center. “Some are better than others, but we do see a loss of effectiveness over time.”

A cohort study published in 2022 in JAMA Dermatology, for instance, documented declining “drug survival” associated with ineffectiveness during 2 years of treatment for each of five biologics studied (adalimumab [Humira], ustekinumab [Stelara], secukinumab [Cosentyx], guselkumab [Tremfya], and ixekizumab [Taltz]).

“There have been a number of theories put forward” as to why that’s the case, including lower serum drug levels, “which of course can be related to anti-drug antibody production,” he said.

He pointed to two studies of ustekinumab: One prospective observational cohort study that reported an association of lower early drug levels of the IL-12/23 receptor antagonist with lower Psoriasis Area and Severity Index (PASI) scores, and another observational study that documented an association between anti-drug antibody positivity with lower ustekinumab levels and impaired clinical response.

“We also now know ... that there are genetic endotypes in psoriasis, and that patients who are [HLA-C*06:02]-positive tend to respond a little better to drugs like ustekinumab, and those who are [HLA-C*06:02]-negative tend to do a little better with the TNF inhibitors,” Dr. Liao said. The human leukocyte antigen (HLA) allele HLA-C*06:02 is associated with susceptibility to psoriasis.

In a study using a national psoriasis registry, HLA-C*06:02-negative patients were 3 times more likely to achieve PASI90 status in response to adalimumab, a TNF-alpha inhibitor, than with ustekinumab treatment. And in a meta-analysis covering eight studies with more than 1,000 patients with psoriasis, the median PASI75 response rate after 6 months of ustekinumab therapy was 92% in the HLA-C*06:02-positive group and 67% in HLA-C*06:02-negative patients.

The recently published cohort study showing a 6% rate of multiple biologic failure evaluated patients in the multicenter CorEvitas Psoriasis Registry who initiated their first biologic between 2015 and 2020 and were followed for 2 or more years. Investigators looked for sociodemographic and clinical differences between the patients who continued use of their first biologic for at least 2 years (“good response”), and those who discontinued two or more biologics of different classes, each used for at least 90 days, because of inadequate efficacy.

Of 1,039 evaluated patients, 490 (47.2%) had good clinical response to their first biologic and 65 (6.3%) had multiple biologic failure. All biologic classes were represented among those who failed multiple biologics. The first and second biologic classes used were attempted for a mean duration of 10 months – “an adequate trial” of each, Dr. Liao said.

In multivariable regression analysis, six variables were significantly associated with multiple biologic failure: female sex at birth, shorter disease duration, earlier year of biologic initiation, prior nonbiologic systemic therapy, having Medicaid insurance, and a history of hyperlipidemia. The latter is “interesting because other studies have shown that metabolic syndrome, of which hyperlipidemia is a component, can also relate to poor response to biologics,” Dr. Liao said.

The most common sequences of first-to-second biologics among those with multiple biologic failure were TNF inhibitor to IL-17 inhibitor (30.8%); IL-12/23 inhibitor to IL-17 inhibitor (21.5%); TNF inhibitor to IL-12/23 inhibitor (12.3%); and IL-17 inhibitor to IL-23 inhibitor (10.8%).

The vast majority of patients failed more than two biologics, however, and “more than 20% had five or more biologics tried over a relatively short period,” Dr. Liao said.
 

Comorbidities and biologic failure in psoriasis, PsA

In practice, it was said during a discussion period, biologic failures in psoriasis can be of two types: a primary inadequate response or initial failure, or a secondary failure with initial improvement followed by declining or no response. “I agree 100% that these probably represent two different endotypes,” Dr. Liao said. “There’s research emerging that psoriasis isn’t necessarily a clean phenotype.”

The option of focusing on comorbidities in the face of biologic failure was another point of discussion. “Maybe the next biologic is not the answer,” a meeting participant said. “Maybe we should focus on metabolic syndrome.”

“I agree,” Dr. Liao said. “In clinic, there are people who may not respond to therapies but have other comorbidities and factors that make it difficult to manage [their psoriasis] ... that may be causative for psoriasis. Maybe if we treat the comorbidities, it will make it easier to treat the psoriasis.”

Addressing comorbidities and “extra-articular traits” such as poorly controlled diabetes, centralized pain, anxiety and depression, and obesity is something Dr. Ritchlin advocates for PsA. “Centralized pain, I believe, is a major driver of nonresponse,” he said at the meeting. “We have to be careful about blaming nonresponse and lack of efficacy of biologics when it could be a wholly different mechanism the biologic won’t treat ... for example, centralized pain.”

As with psoriasis, the emergence of antidrug antibodies may be one reason for the secondary failure of biologic agents for PsA, Dr. Ritchlin and his coauthors wrote in their paper on management of PsA after failure of one TNF inhibitor. Other areas to consider in evaluating failure, they wrote, are compliance and time of dosing, and financial barriers.

Low long-term persistence of second-line biologics for patients with PsA was demonstrated in a national cohort study utilizing the French health insurance database, Dr. Ritchlin noted at the research meeting. 

The French study covered almost 3,000 patients who started a second biologic after discontinuing a TNF inhibitor during 2015-2020. Overall, 1-year and 3-year persistence rates were 42% and 17%, respectively.

Dr. Liao disclosed research grant funding from AbbVie, Amgen, Janssen, Leo, Novartis, Pfizer, Regeneron, and Trex Bio. Dr. Ritchlin reported no disclosures.

WASHINGTON – Multiple biologic failure in a minority of patients with psoriasis may have several causes, from genetic endotypes and immunologic factors to lower serum drug levels, the presence of anti-drug antibody levels, female sex, and certain comorbidities, Wilson Liao, MD, said at the annual research symposium of the National Psoriasis Foundation.

“Tough-to-treat psoriasis remains a challenge despite newer therapies ... Why do we still have this sub-population of patients who seem to be refractory?” said Dr. Liao, professor and associate vice chair of research in the department of dermatology at the University of California, San Francisco, who coauthored a 2015-2022 prospective cohort analysis that documented about 6% of patients failing two or more biologic agents of different mechanistic classes.

“These patients are really suffering,” he said. “We need to have better guidelines and treatment algorithms for these patients.”

A significant number of patients with psoriatic arthritis (PsA), meanwhile, are inadequate responders to tumor necrosis factor (TNF) inhibition, Christopher T. Ritchlin, MD, PhD, professor of medicine in the division of allergy/immunology and rheumatology and the Center of Musculoskeletal Research at the University of Rochester (N.Y.), said during another session at the meeting.

The long-term “persistence,” or usage, of first-line biologics in patients with PsA – and of second-line biologics in patients who failed one TNF-inhibitor – is low, but the literature offers little information on the reasons for TNF-inhibitor discontinuation, said Dr. Ritchlin, who coauthored a perspective piece in Arthritis & Rheumatology on managing the patient with PsA who fails one TNF inhibitor.

Dr. Ritchlin and his coauthors were asked to provide evidence-informed advice and algorithms, but the task was difficult. “It’s hard to know what to recommend for the next step if we don’t know why patients failed the first,” he said. “The point is, we need more data. [Clinical trials] are not recording the kind of information we need.”
 

Anti-drug antibodies, genetics, other factors in psoriasis

Research shows that in large cohorts, “all the biologics do seem to lose efficacy over time,” said Dr. Liao, who directs the UCSF Psoriasis and Skin Treatment Center. “Some are better than others, but we do see a loss of effectiveness over time.”

A cohort study published in 2022 in JAMA Dermatology, for instance, documented declining “drug survival” associated with ineffectiveness during 2 years of treatment for each of five biologics studied (adalimumab [Humira], ustekinumab [Stelara], secukinumab [Cosentyx], guselkumab [Tremfya], and ixekizumab [Taltz]).

“There have been a number of theories put forward” as to why that’s the case, including lower serum drug levels, “which of course can be related to anti-drug antibody production,” he said.

He pointed to two studies of ustekinumab: One prospective observational cohort study that reported an association of lower early drug levels of the IL-12/23 receptor antagonist with lower Psoriasis Area and Severity Index (PASI) scores, and another observational study that documented an association between anti-drug antibody positivity with lower ustekinumab levels and impaired clinical response.

“We also now know ... that there are genetic endotypes in psoriasis, and that patients who are [HLA-C*06:02]-positive tend to respond a little better to drugs like ustekinumab, and those who are [HLA-C*06:02]-negative tend to do a little better with the TNF inhibitors,” Dr. Liao said. The human leukocyte antigen (HLA) allele HLA-C*06:02 is associated with susceptibility to psoriasis.

In a study using a national psoriasis registry, HLA-C*06:02-negative patients were 3 times more likely to achieve PASI90 status in response to adalimumab, a TNF-alpha inhibitor, than with ustekinumab treatment. And in a meta-analysis covering eight studies with more than 1,000 patients with psoriasis, the median PASI75 response rate after 6 months of ustekinumab therapy was 92% in the HLA-C*06:02-positive group and 67% in HLA-C*06:02-negative patients.

The recently published cohort study showing a 6% rate of multiple biologic failure evaluated patients in the multicenter CorEvitas Psoriasis Registry who initiated their first biologic between 2015 and 2020 and were followed for 2 or more years. Investigators looked for sociodemographic and clinical differences between the patients who continued use of their first biologic for at least 2 years (“good response”), and those who discontinued two or more biologics of different classes, each used for at least 90 days, because of inadequate efficacy.

Of 1,039 evaluated patients, 490 (47.2%) had good clinical response to their first biologic and 65 (6.3%) had multiple biologic failure. All biologic classes were represented among those who failed multiple biologics. The first and second biologic classes used were attempted for a mean duration of 10 months – “an adequate trial” of each, Dr. Liao said.

In multivariable regression analysis, six variables were significantly associated with multiple biologic failure: female sex at birth, shorter disease duration, earlier year of biologic initiation, prior nonbiologic systemic therapy, having Medicaid insurance, and a history of hyperlipidemia. The latter is “interesting because other studies have shown that metabolic syndrome, of which hyperlipidemia is a component, can also relate to poor response to biologics,” Dr. Liao said.

The most common sequences of first-to-second biologics among those with multiple biologic failure were TNF inhibitor to IL-17 inhibitor (30.8%); IL-12/23 inhibitor to IL-17 inhibitor (21.5%); TNF inhibitor to IL-12/23 inhibitor (12.3%); and IL-17 inhibitor to IL-23 inhibitor (10.8%).

The vast majority of patients failed more than two biologics, however, and “more than 20% had five or more biologics tried over a relatively short period,” Dr. Liao said.
 

Comorbidities and biologic failure in psoriasis, PsA

In practice, it was said during a discussion period, biologic failures in psoriasis can be of two types: a primary inadequate response or initial failure, or a secondary failure with initial improvement followed by declining or no response. “I agree 100% that these probably represent two different endotypes,” Dr. Liao said. “There’s research emerging that psoriasis isn’t necessarily a clean phenotype.”

The option of focusing on comorbidities in the face of biologic failure was another point of discussion. “Maybe the next biologic is not the answer,” a meeting participant said. “Maybe we should focus on metabolic syndrome.”

“I agree,” Dr. Liao said. “In clinic, there are people who may not respond to therapies but have other comorbidities and factors that make it difficult to manage [their psoriasis] ... that may be causative for psoriasis. Maybe if we treat the comorbidities, it will make it easier to treat the psoriasis.”

Addressing comorbidities and “extra-articular traits” such as poorly controlled diabetes, centralized pain, anxiety and depression, and obesity is something Dr. Ritchlin advocates for PsA. “Centralized pain, I believe, is a major driver of nonresponse,” he said at the meeting. “We have to be careful about blaming nonresponse and lack of efficacy of biologics when it could be a wholly different mechanism the biologic won’t treat ... for example, centralized pain.”

As with psoriasis, the emergence of antidrug antibodies may be one reason for the secondary failure of biologic agents for PsA, Dr. Ritchlin and his coauthors wrote in their paper on management of PsA after failure of one TNF inhibitor. Other areas to consider in evaluating failure, they wrote, are compliance and time of dosing, and financial barriers.

Low long-term persistence of second-line biologics for patients with PsA was demonstrated in a national cohort study utilizing the French health insurance database, Dr. Ritchlin noted at the research meeting. 

The French study covered almost 3,000 patients who started a second biologic after discontinuing a TNF inhibitor during 2015-2020. Overall, 1-year and 3-year persistence rates were 42% and 17%, respectively.

Dr. Liao disclosed research grant funding from AbbVie, Amgen, Janssen, Leo, Novartis, Pfizer, Regeneron, and Trex Bio. Dr. Ritchlin reported no disclosures.

WASHINGTON – In psoriatic disease, psoriatic arthritis (PsA) remains one of the greatest unmet needs, with the transition from cutaneous psoriasis poorly understood, diagnosis challenging, and therapeutic accomplishments trailing far behind advances for skin disease. However, leading researchers in rheumatology and dermatology believe that they’re turning the corner toward a day when therapies are phenotype-targeted and diagnosis can be made early and treatment begun well before inflammation worsens and pain and joint damage ensue.

“The challenge right now is that we don’t understand the discrete and overlapping endotypes that underlie the phenotypes or domains” of PsA, said Christopher Ritchlin, MD, MPH, professor of medicine in the division of allergy/immunology and rheumatology and the Center of Musculoskeletal Research at the University of Rochester (N.Y.), who spoke about PsA at the annual research symposium of the National Psoriasis Foundation.

A deep dive into the tissue

Dr. Ritchlin is among those rheumatology clinician-researchers who advocated early on for a “domain” approach to the diagnosis and management of PsA – that is, consideration of the key domains of peripheral arthritis, axial disease, enthesitis, dactylitis, and skin and nail psoriasis.

The approach is an especially important part of treatment recommendations from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. But while interventions can be tailored to some extent to these domains, or phenotypes, there are limitations without an understanding of the different pathophysiology and mechanisms driving the heterogeneity in tissue involvement.

Dr. Ritchlin draws inspiration from pulmonology, which subtyped asthma into various phenotypes (for example, eosinophilic, allergic, intrinsic, exercise-induced) and “drilled down” on understanding underlying mechanisms to guide more specific treatment. Similar phenotype-endotype research has been done for chronic obstructive pulmonary disease, he said at the meeting, pointing to a phase 3 randomized controlled trial, published in the New England Journal of Medicine, that found dupilimab (Dupixent) was effective for patients with COPD who had type 2 inflammation as indicated by elevated eosinophil counts.

“It’s a beautiful example of how to define an endotype from a phenotypic biomarker and then use a specific intervention to improve outcomes,” Dr. Ritchlin said. “We need to do this for psoriasis and PsA.”

The ELLIPSS project will utilize the host of -omics tools and technologies (for proteomics, metabolomics, and genomics, for instance) that are making it increasingly possible to dissect the heterogeneity of single diseases and achieve more precision with treatments.

Researchers will collect blood samples and skin and/or synovial tissue biopsies from cohorts of patients with psoriasis and PsA who are treatment naïve as well as patients who are treated with a biologic or DMARD (looking at responders and non-responders). They’ll also study a cohort of psoriasis patients who may be “on a transition pathway” for PsA based on risk factors such as family history, nail psoriasis, scalp psoriasis, and body surface area greater than 5%.

Patients in all cohorts will represent distinct synovio-entheseal domains of PsA and the heterogeneity of psoriasis (for example, plaque, general, pustular, palmoplantar) and will be followed longitudinally.

With regards to PsA, one goal is to “find new pathways in the joint, then find surrogate markers in the blood that we can use to help mark particular subphenotypes [that will be identified through deep phenotyping],” Dr. Ritchlin said in an interview after the meeting. “This will lead us hopefully to a more precision-based approach.”

The ELLIPSS team joins other researchers who have been studying rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in an earlier iteration of the AIM program, and that will continue this work. Research on RA has thus far elucidated T-cell subsets in the rheumatoid synovium, as well as interactions of mesenchymal cells with the endothelium, for instance, and led to the identification of key molecules such as granzyme A that weren’t previously known to be involved in RA pathogenesis, Dr. Ritchin said in the interview. The current AIM work also includes Sjögren’s disease.
 

Finding biomarkers, diagnostic signatures

The psoriasis-PsA team has the advantage today of being able to utilize a new technology called spatial transcriptomics, which takes transcriptomics (RNA) from the single-cell level to the tissue level, enabling a look at how disease is affecting cellular organization/tissue architecture, gene activity, and cellular signaling within tissues. “It’s a huge advance in technology,” said Dr. Ritchlin. “We can actually see how the cells are interacting in the synovium [and other tissues].”

A paper published in Science Immunology and discussed at the NPF meeting demonstrates the power of special transcriptomics for learning about the skin. Dr. Scher, Dr. Ritchlin, first authors Rochelle L. Castillo, MD, and Ikjot Sidhu, MS, and other co-investigators reported a “dynamic re-organization of the immune milieu and fibroblasts in PsO lesional and non-lesional skin,” the presence of B cells in lesioned skin, and cellular organization/ecosystems that vary occurring according to clinical severity, among other findings.

Dr. Scher is using the tool for his NPF-funded diagnostic test research and as part of his work at NYU Langone for the ELLIPPS project. Among his goals: To “discover new cell populations in the microenvironment and study how they interact with each other, then compare those cells between psoriasis and PsA patients to first understand if they’re any different,” he explained after the meeting. Researchers can then investigate the synovial tissue, comparing cell populations and interactions in both compartments and looking for any shared markers/cytokines/proteins, he said.

Multiomics research, meanwhile, is showing that a test for early PsA detection could potentially combine clinical parameters with integrated multi-omic markers into a “diagnostic signature” of sorts.

At the meeting, Vinod Chandran, MD, PhD, a rheumatologist at the University of Toronto who also has an NPF PsA diagnostic test grant, said that his multi-omics analysis of blood samples from patients with psoriasis and PsA has identified signatures with a “high discriminatory value” and that certain metabolic pathways appear to play “a central role in the development and differentiation of PsA.” (Validation in other cohorts and economic analyses are ongoing, Dr. Chandran said. Low-cost alternatives that can be applied broadly in the clinic will need to be pursued, Dr. Scher said.)

Eyes on combination therapy

“The likelihood that all patients will respond to one biologic is very low in PsA, so we’ve been thinking about combination therapy for some time,” Dr. Ritchlin said at the meeting. “I think [dual inhibition] is coming.”

Safety has been the concern, but a phase 2 trial published this year compared a combination of IL-23 and TNF inhibition (guselkumab [Tremfya] plus golimumab [Simponi]) with monotherapy of both biologics in patients with ulcerative colitis and showed that the combination safely drove synergistic restoration of a normal epithelium and mucosal healing, he said.

A phase 2 trial in PsA, designed by Dr. Ritchlin and Dr. Scher and named AFFINITY, will study the safety and efficacy of the same combination of IL-23 and TNF blockade, compared with guselkumab (IL-23 inhibition) alone. The trial is currently completing enrollment of patients who have failed one or two anti-TNF agents.

In the meantime, combination therapy is being employed in clinics for “PsA patients who’ve been channeled through multiple biologics and are still not responding ... when [physicians] feel they’re forced to, not right away,” Dr. Ritchlin said in an interview after the meeting. “As we get a better understanding [through clinical trials], it might be something you’ll see earlier in the treatment process.”

It is wise, Dr. Ritchlin said, to devote more time to addressing “extra-articular traits” (for example, obesity, diabetes, uveitis, colitis, centralized pain) and treatable lifestyle/behavioral risk factors (for example, smoking, exercise, nutrition, adherence to therapy, social support) that can contribute to PsA and treatment nonresponse. He calls this the “treatable traits” strategy.

In practice, “there’s a big focus on inflammation and immune dysfunction, but the problem is, there are other factors involved in nonresponse, and I think ‘treatable traits’ gets to those,” Dr. Ritchlin said after the meeting. Rheumatologists and dermatologists lack time and alliances to address these issues, but “if we can find ways to do it, I think we’ll have improved outcomes.”

Dr. Ritchlin, Dr. Chandran, and Dr. Liao reported no relevant disclosures. Dr. Scher reported ties to Janssen, Pfizer, Sanofi, UCB, and Bristol-Myers Squibb.

WASHINGTON – In psoriatic disease, psoriatic arthritis (PsA) remains one of the greatest unmet needs, with the transition from cutaneous psoriasis poorly understood, diagnosis challenging, and therapeutic accomplishments trailing far behind advances for skin disease. However, leading researchers in rheumatology and dermatology believe that they’re turning the corner toward a day when therapies are phenotype-targeted and diagnosis can be made early and treatment begun well before inflammation worsens and pain and joint damage ensue.

“The challenge right now is that we don’t understand the discrete and overlapping endotypes that underlie the phenotypes or domains” of PsA, said Christopher Ritchlin, MD, MPH, professor of medicine in the division of allergy/immunology and rheumatology and the Center of Musculoskeletal Research at the University of Rochester (N.Y.), who spoke about PsA at the annual research symposium of the National Psoriasis Foundation.

A deep dive into the tissue

Dr. Ritchlin is among those rheumatology clinician-researchers who advocated early on for a “domain” approach to the diagnosis and management of PsA – that is, consideration of the key domains of peripheral arthritis, axial disease, enthesitis, dactylitis, and skin and nail psoriasis.

The approach is an especially important part of treatment recommendations from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. But while interventions can be tailored to some extent to these domains, or phenotypes, there are limitations without an understanding of the different pathophysiology and mechanisms driving the heterogeneity in tissue involvement.

Dr. Ritchlin draws inspiration from pulmonology, which subtyped asthma into various phenotypes (for example, eosinophilic, allergic, intrinsic, exercise-induced) and “drilled down” on understanding underlying mechanisms to guide more specific treatment. Similar phenotype-endotype research has been done for chronic obstructive pulmonary disease, he said at the meeting, pointing to a phase 3 randomized controlled trial, published in the New England Journal of Medicine, that found dupilimab (Dupixent) was effective for patients with COPD who had type 2 inflammation as indicated by elevated eosinophil counts.

“It’s a beautiful example of how to define an endotype from a phenotypic biomarker and then use a specific intervention to improve outcomes,” Dr. Ritchlin said. “We need to do this for psoriasis and PsA.”

The ELLIPSS project will utilize the host of -omics tools and technologies (for proteomics, metabolomics, and genomics, for instance) that are making it increasingly possible to dissect the heterogeneity of single diseases and achieve more precision with treatments.

Researchers will collect blood samples and skin and/or synovial tissue biopsies from cohorts of patients with psoriasis and PsA who are treatment naïve as well as patients who are treated with a biologic or DMARD (looking at responders and non-responders). They’ll also study a cohort of psoriasis patients who may be “on a transition pathway” for PsA based on risk factors such as family history, nail psoriasis, scalp psoriasis, and body surface area greater than 5%.

Patients in all cohorts will represent distinct synovio-entheseal domains of PsA and the heterogeneity of psoriasis (for example, plaque, general, pustular, palmoplantar) and will be followed longitudinally.

With regards to PsA, one goal is to “find new pathways in the joint, then find surrogate markers in the blood that we can use to help mark particular subphenotypes [that will be identified through deep phenotyping],” Dr. Ritchlin said in an interview after the meeting. “This will lead us hopefully to a more precision-based approach.”

The ELLIPSS team joins other researchers who have been studying rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in an earlier iteration of the AIM program, and that will continue this work. Research on RA has thus far elucidated T-cell subsets in the rheumatoid synovium, as well as interactions of mesenchymal cells with the endothelium, for instance, and led to the identification of key molecules such as granzyme A that weren’t previously known to be involved in RA pathogenesis, Dr. Ritchin said in the interview. The current AIM work also includes Sjögren’s disease.
 

Finding biomarkers, diagnostic signatures

The psoriasis-PsA team has the advantage today of being able to utilize a new technology called spatial transcriptomics, which takes transcriptomics (RNA) from the single-cell level to the tissue level, enabling a look at how disease is affecting cellular organization/tissue architecture, gene activity, and cellular signaling within tissues. “It’s a huge advance in technology,” said Dr. Ritchlin. “We can actually see how the cells are interacting in the synovium [and other tissues].”

A paper published in Science Immunology and discussed at the NPF meeting demonstrates the power of special transcriptomics for learning about the skin. Dr. Scher, Dr. Ritchlin, first authors Rochelle L. Castillo, MD, and Ikjot Sidhu, MS, and other co-investigators reported a “dynamic re-organization of the immune milieu and fibroblasts in PsO lesional and non-lesional skin,” the presence of B cells in lesioned skin, and cellular organization/ecosystems that vary occurring according to clinical severity, among other findings.

Dr. Scher is using the tool for his NPF-funded diagnostic test research and as part of his work at NYU Langone for the ELLIPPS project. Among his goals: To “discover new cell populations in the microenvironment and study how they interact with each other, then compare those cells between psoriasis and PsA patients to first understand if they’re any different,” he explained after the meeting. Researchers can then investigate the synovial tissue, comparing cell populations and interactions in both compartments and looking for any shared markers/cytokines/proteins, he said.

Multiomics research, meanwhile, is showing that a test for early PsA detection could potentially combine clinical parameters with integrated multi-omic markers into a “diagnostic signature” of sorts.

At the meeting, Vinod Chandran, MD, PhD, a rheumatologist at the University of Toronto who also has an NPF PsA diagnostic test grant, said that his multi-omics analysis of blood samples from patients with psoriasis and PsA has identified signatures with a “high discriminatory value” and that certain metabolic pathways appear to play “a central role in the development and differentiation of PsA.” (Validation in other cohorts and economic analyses are ongoing, Dr. Chandran said. Low-cost alternatives that can be applied broadly in the clinic will need to be pursued, Dr. Scher said.)

Eyes on combination therapy

“The likelihood that all patients will respond to one biologic is very low in PsA, so we’ve been thinking about combination therapy for some time,” Dr. Ritchlin said at the meeting. “I think [dual inhibition] is coming.”

Safety has been the concern, but a phase 2 trial published this year compared a combination of IL-23 and TNF inhibition (guselkumab [Tremfya] plus golimumab [Simponi]) with monotherapy of both biologics in patients with ulcerative colitis and showed that the combination safely drove synergistic restoration of a normal epithelium and mucosal healing, he said.

A phase 2 trial in PsA, designed by Dr. Ritchlin and Dr. Scher and named AFFINITY, will study the safety and efficacy of the same combination of IL-23 and TNF blockade, compared with guselkumab (IL-23 inhibition) alone. The trial is currently completing enrollment of patients who have failed one or two anti-TNF agents.

In the meantime, combination therapy is being employed in clinics for “PsA patients who’ve been channeled through multiple biologics and are still not responding ... when [physicians] feel they’re forced to, not right away,” Dr. Ritchlin said in an interview after the meeting. “As we get a better understanding [through clinical trials], it might be something you’ll see earlier in the treatment process.”

It is wise, Dr. Ritchlin said, to devote more time to addressing “extra-articular traits” (for example, obesity, diabetes, uveitis, colitis, centralized pain) and treatable lifestyle/behavioral risk factors (for example, smoking, exercise, nutrition, adherence to therapy, social support) that can contribute to PsA and treatment nonresponse. He calls this the “treatable traits” strategy.

In practice, “there’s a big focus on inflammation and immune dysfunction, but the problem is, there are other factors involved in nonresponse, and I think ‘treatable traits’ gets to those,” Dr. Ritchlin said after the meeting. Rheumatologists and dermatologists lack time and alliances to address these issues, but “if we can find ways to do it, I think we’ll have improved outcomes.”

Dr. Ritchlin, Dr. Chandran, and Dr. Liao reported no relevant disclosures. Dr. Scher reported ties to Janssen, Pfizer, Sanofi, UCB, and Bristol-Myers Squibb.

WASHINGTON – In psoriatic disease, psoriatic arthritis (PsA) remains one of the greatest unmet needs, with the transition from cutaneous psoriasis poorly understood, diagnosis challenging, and therapeutic accomplishments trailing far behind advances for skin disease. However, leading researchers in rheumatology and dermatology believe that they’re turning the corner toward a day when therapies are phenotype-targeted and diagnosis can be made early and treatment begun well before inflammation worsens and pain and joint damage ensue.

“The challenge right now is that we don’t understand the discrete and overlapping endotypes that underlie the phenotypes or domains” of PsA, said Christopher Ritchlin, MD, MPH, professor of medicine in the division of allergy/immunology and rheumatology and the Center of Musculoskeletal Research at the University of Rochester (N.Y.), who spoke about PsA at the annual research symposium of the National Psoriasis Foundation.

A deep dive into the tissue

Dr. Ritchlin is among those rheumatology clinician-researchers who advocated early on for a “domain” approach to the diagnosis and management of PsA – that is, consideration of the key domains of peripheral arthritis, axial disease, enthesitis, dactylitis, and skin and nail psoriasis.

The approach is an especially important part of treatment recommendations from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. But while interventions can be tailored to some extent to these domains, or phenotypes, there are limitations without an understanding of the different pathophysiology and mechanisms driving the heterogeneity in tissue involvement.

Dr. Ritchlin draws inspiration from pulmonology, which subtyped asthma into various phenotypes (for example, eosinophilic, allergic, intrinsic, exercise-induced) and “drilled down” on understanding underlying mechanisms to guide more specific treatment. Similar phenotype-endotype research has been done for chronic obstructive pulmonary disease, he said at the meeting, pointing to a phase 3 randomized controlled trial, published in the New England Journal of Medicine, that found dupilimab (Dupixent) was effective for patients with COPD who had type 2 inflammation as indicated by elevated eosinophil counts.

“It’s a beautiful example of how to define an endotype from a phenotypic biomarker and then use a specific intervention to improve outcomes,” Dr. Ritchlin said. “We need to do this for psoriasis and PsA.”

The ELLIPSS project will utilize the host of -omics tools and technologies (for proteomics, metabolomics, and genomics, for instance) that are making it increasingly possible to dissect the heterogeneity of single diseases and achieve more precision with treatments.

Researchers will collect blood samples and skin and/or synovial tissue biopsies from cohorts of patients with psoriasis and PsA who are treatment naïve as well as patients who are treated with a biologic or DMARD (looking at responders and non-responders). They’ll also study a cohort of psoriasis patients who may be “on a transition pathway” for PsA based on risk factors such as family history, nail psoriasis, scalp psoriasis, and body surface area greater than 5%.

Patients in all cohorts will represent distinct synovio-entheseal domains of PsA and the heterogeneity of psoriasis (for example, plaque, general, pustular, palmoplantar) and will be followed longitudinally.

With regards to PsA, one goal is to “find new pathways in the joint, then find surrogate markers in the blood that we can use to help mark particular subphenotypes [that will be identified through deep phenotyping],” Dr. Ritchlin said in an interview after the meeting. “This will lead us hopefully to a more precision-based approach.”

The ELLIPSS team joins other researchers who have been studying rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in an earlier iteration of the AIM program, and that will continue this work. Research on RA has thus far elucidated T-cell subsets in the rheumatoid synovium, as well as interactions of mesenchymal cells with the endothelium, for instance, and led to the identification of key molecules such as granzyme A that weren’t previously known to be involved in RA pathogenesis, Dr. Ritchin said in the interview. The current AIM work also includes Sjögren’s disease.
 

Finding biomarkers, diagnostic signatures

The psoriasis-PsA team has the advantage today of being able to utilize a new technology called spatial transcriptomics, which takes transcriptomics (RNA) from the single-cell level to the tissue level, enabling a look at how disease is affecting cellular organization/tissue architecture, gene activity, and cellular signaling within tissues. “It’s a huge advance in technology,” said Dr. Ritchlin. “We can actually see how the cells are interacting in the synovium [and other tissues].”

A paper published in Science Immunology and discussed at the NPF meeting demonstrates the power of special transcriptomics for learning about the skin. Dr. Scher, Dr. Ritchlin, first authors Rochelle L. Castillo, MD, and Ikjot Sidhu, MS, and other co-investigators reported a “dynamic re-organization of the immune milieu and fibroblasts in PsO lesional and non-lesional skin,” the presence of B cells in lesioned skin, and cellular organization/ecosystems that vary occurring according to clinical severity, among other findings.

Dr. Scher is using the tool for his NPF-funded diagnostic test research and as part of his work at NYU Langone for the ELLIPPS project. Among his goals: To “discover new cell populations in the microenvironment and study how they interact with each other, then compare those cells between psoriasis and PsA patients to first understand if they’re any different,” he explained after the meeting. Researchers can then investigate the synovial tissue, comparing cell populations and interactions in both compartments and looking for any shared markers/cytokines/proteins, he said.

Multiomics research, meanwhile, is showing that a test for early PsA detection could potentially combine clinical parameters with integrated multi-omic markers into a “diagnostic signature” of sorts.

At the meeting, Vinod Chandran, MD, PhD, a rheumatologist at the University of Toronto who also has an NPF PsA diagnostic test grant, said that his multi-omics analysis of blood samples from patients with psoriasis and PsA has identified signatures with a “high discriminatory value” and that certain metabolic pathways appear to play “a central role in the development and differentiation of PsA.” (Validation in other cohorts and economic analyses are ongoing, Dr. Chandran said. Low-cost alternatives that can be applied broadly in the clinic will need to be pursued, Dr. Scher said.)

Eyes on combination therapy

“The likelihood that all patients will respond to one biologic is very low in PsA, so we’ve been thinking about combination therapy for some time,” Dr. Ritchlin said at the meeting. “I think [dual inhibition] is coming.”

Safety has been the concern, but a phase 2 trial published this year compared a combination of IL-23 and TNF inhibition (guselkumab [Tremfya] plus golimumab [Simponi]) with monotherapy of both biologics in patients with ulcerative colitis and showed that the combination safely drove synergistic restoration of a normal epithelium and mucosal healing, he said.

A phase 2 trial in PsA, designed by Dr. Ritchlin and Dr. Scher and named AFFINITY, will study the safety and efficacy of the same combination of IL-23 and TNF blockade, compared with guselkumab (IL-23 inhibition) alone. The trial is currently completing enrollment of patients who have failed one or two anti-TNF agents.

In the meantime, combination therapy is being employed in clinics for “PsA patients who’ve been channeled through multiple biologics and are still not responding ... when [physicians] feel they’re forced to, not right away,” Dr. Ritchlin said in an interview after the meeting. “As we get a better understanding [through clinical trials], it might be something you’ll see earlier in the treatment process.”

It is wise, Dr. Ritchlin said, to devote more time to addressing “extra-articular traits” (for example, obesity, diabetes, uveitis, colitis, centralized pain) and treatable lifestyle/behavioral risk factors (for example, smoking, exercise, nutrition, adherence to therapy, social support) that can contribute to PsA and treatment nonresponse. He calls this the “treatable traits” strategy.

In practice, “there’s a big focus on inflammation and immune dysfunction, but the problem is, there are other factors involved in nonresponse, and I think ‘treatable traits’ gets to those,” Dr. Ritchlin said after the meeting. Rheumatologists and dermatologists lack time and alliances to address these issues, but “if we can find ways to do it, I think we’ll have improved outcomes.”

Dr. Ritchlin, Dr. Chandran, and Dr. Liao reported no relevant disclosures. Dr. Scher reported ties to Janssen, Pfizer, Sanofi, UCB, and Bristol-Myers Squibb.

WASHINGTON – A series of three higher-than-approved induction doses of the interleukin-23 inhibitor risankizumab in patients with psoriasis – and no further subsequent dosing – led to an “unprecedented” level of complete skin clearance at week 52 in a small study investigating whether high-dose IL-23 inhibition can target resident memory T cells and thereby induce long-term remission, Andrew Blauvelt, MD, MBA, reported at the annual research symposium of the National Psoriasis Foundation.

Understanding and trying to target resident memory T (Trm) cells has become a hot topic in psoriasis research, with possible importance for psoriatic arthritis as well. The cells, which normally develop within tissues in a pathogen-specific manner and persist after infections resolve, have been found in healed psoriatic skin and are believed to be responsible for recurrences of psoriasis at the same sites previously affected by the disease. Research suggests, moreover, that Trm cells are dependent on IL-23 for their survival, said Dr. Blauvelt, an investigator with the Oregon Medical Research Center, Portland.

Using an approach he has coined “knockout” therapy, 20 adult patients at the center were randomized 1:1 in double-blinded dosing to receive 300 mg or 600 mg of risankizumab (two and four times the standard initial doses, respectively) at 0, 4, and 16 weeks, and were seen every 4-6 weeks in a double-blinded follow-up period. Skin biopsies of lesional and nonlesional skin were collected at weeks 0 and 52 for RNA sequence analysis to evaluate changes in Trm cell number and effector function.

At week 28, almost all patients – 94% – achieved a Psoriasis Area and Severity Index 90 score, and 83% achieved PASI 100. At week 52, of the 18 still-enrolled patients, 69% had PASI 90 scores and 43% maintained PASI 100 scores. “We’re not curing psoriasis, but that is incredible to have 43% still clear 9 months after the last dose,” Dr. Blauvelt said.

The findings are interim results that pool the two doses of risankizumab (Skyrizi). An evaluation of maintenance of efficacy with the 300-mg versus 600-mg doses and results of the skin biopsies will be presented at the 2024 annual meeting of the American Academy of Dermatology, he said. Patients who have not had recurrences are being followed up to week 100 (unblinded).

Skin biopsy findings together with levels of clearance will “add insight as to whether high-dose IL-23 inhibition is associated with higher levels of complete clearance (i.e., PASI 100) over long periods of time, and whether remissions are associated with more profound knock-down of Trm cells,” Dr. Blauvelt wrote in an editorial on Trm cells in psoriasis published in the Journal of Psoriasis and Psoriatic Arthritis.

Risankizumab was approved by the Food and Drug Administration for moderate to severe plaque psoriasis in 2019, and for active psoriatic arthritis in 2022.
 

Impact of IL-23 inhibition

A 2021 study, Dr. Blauvelt noted in his presentation, showed that the IL-23 inhibitor guselkumab (Tremfya) reduced the number of Trm cells in healed psoriatic skin, while the IL-17A inhibitor secukinumab (Cosentyx) did not affect Trm cells.

Other researchers have concluded that local IL-23 is required for the proliferation and retention of Trm cells in the skin, he said, noting also that, as a class, IL-23 blockers “are associated with the longest disease-free intervals” in patients with psoriasis.

Research showing loss of Trm cells in biopsies of cleared skin is “incredibly important,” as is data showing that IL-23 may be “a critical survival factor” for Trm cells, said Christopher Ritchlin, MD, MPH, a rheumatologist and director of the clinical immunology research unit at the University of Rochester (N.Y.) Medical Center, who attended the NPF meeting and was asked to comment on the growing interest in Trm cells. He did not hear Dr. Blauvelt’s presentation but has followed Trm research in psoriasis.

Measuring Trm cells in synovial tissue of patients with psoriatic disease is, in fact, on the agenda of a new research team coled by Dr. Ritchlin that is part of the Autoimmune and Immune-Mediated Diseases Program of the Accelerating Medicine Partnership – a public-private partnership that aims to collect and analyze troves of biological data in order to illuminate the cellular and molecular interactions leading to autoimmune diseases.

“Resident memory T cells have been thought to be cells that are constrained to being resident in the tissue, and while that’s largely true, there’s more recent data showing that they actually can dedifferentiate and go back to the lymph node and then go back to the joint again,” Dr. Ritchlin noted in an interview. “So it’s a more complicated story,” but nonetheless targeting the cells is a concept worth exploring therapeutically.
 

Moving toward a cure?

The high induction doses of risankizumab in Dr. Blauvelt’s phase 2 “knockout” study were well tolerated through week 40, with safety profiles similar overall to those reported in previous studies of risankizumab and “no new safety signals,” Dr. Blauvelt said at the meeting.

(At baseline, patients had a mean disease duration of 21 years, a mean affected BSA of 21, and a mean PASI of 18.5. Seven had prior treatment with biologic medications, though not in the prior 4 months and not with risankizumab.)

In lieu of a cure, which is still possible in the next 10 years, he said, patients are eager for longer-term remission and the ability to break away from established regular dosing. After publication of a phase 1 study of risankizumab, in which a notable number of patients experienced complete skin clearance up to 1 year following a single high dose, “we started getting numerous calls in our [clinical trials] office from patients who said ‘I want to be on that drug that you give once a year,’ ” Dr. Blauvelt said. (The high dosing was not investigated any further in phase 2 and 3 research, he added.)

While the “knockout” study adopts a “hit hard” approach, it is also possible that a strategy to hit both hard and early after disease onset may induce long-term remission and/or cure of the disease. “I’m talking about using the best things first. There are hints that if we treat early, maybe we can keep [psoriasis] from becoming a chronic disease, keep it from ‘setting up shop’ if you will,” he said, noting that the “hit hard, hit early” concept is not unique to dermatology.

During a discussion period, Dr. Blauvelt said that in a future iteration of the “knockout” study, he would like to evaluate risankizumab in patients with disease duration under 12 months. It may also be valuable to look not only at Trm cells, but more broadly at other elements of the tissue architecture before and after treatment.

Among other strategies for achieving long-term remission and/or cure is the expansion of regulatory T cells, which work to “control inappropriate immune responses” and calm inflammation. Defects in the number and function of regulatory T cells are associated with psoriasis and other autoimmune diseases, and it appears in early research from other investigators that low-dose IL-2 can induce the expansion of regulatory T cells and improve psoriasis. “Keep tuned,” Dr. Blauvelt said.

Dr. Blauvelt disclosed ties with numerous pharmaceutical companies. Dr. Ritchlin had no disclosures.

WASHINGTON – A series of three higher-than-approved induction doses of the interleukin-23 inhibitor risankizumab in patients with psoriasis – and no further subsequent dosing – led to an “unprecedented” level of complete skin clearance at week 52 in a small study investigating whether high-dose IL-23 inhibition can target resident memory T cells and thereby induce long-term remission, Andrew Blauvelt, MD, MBA, reported at the annual research symposium of the National Psoriasis Foundation.

Understanding and trying to target resident memory T (Trm) cells has become a hot topic in psoriasis research, with possible importance for psoriatic arthritis as well. The cells, which normally develop within tissues in a pathogen-specific manner and persist after infections resolve, have been found in healed psoriatic skin and are believed to be responsible for recurrences of psoriasis at the same sites previously affected by the disease. Research suggests, moreover, that Trm cells are dependent on IL-23 for their survival, said Dr. Blauvelt, an investigator with the Oregon Medical Research Center, Portland.

Using an approach he has coined “knockout” therapy, 20 adult patients at the center were randomized 1:1 in double-blinded dosing to receive 300 mg or 600 mg of risankizumab (two and four times the standard initial doses, respectively) at 0, 4, and 16 weeks, and were seen every 4-6 weeks in a double-blinded follow-up period. Skin biopsies of lesional and nonlesional skin were collected at weeks 0 and 52 for RNA sequence analysis to evaluate changes in Trm cell number and effector function.

At week 28, almost all patients – 94% – achieved a Psoriasis Area and Severity Index 90 score, and 83% achieved PASI 100. At week 52, of the 18 still-enrolled patients, 69% had PASI 90 scores and 43% maintained PASI 100 scores. “We’re not curing psoriasis, but that is incredible to have 43% still clear 9 months after the last dose,” Dr. Blauvelt said.

The findings are interim results that pool the two doses of risankizumab (Skyrizi). An evaluation of maintenance of efficacy with the 300-mg versus 600-mg doses and results of the skin biopsies will be presented at the 2024 annual meeting of the American Academy of Dermatology, he said. Patients who have not had recurrences are being followed up to week 100 (unblinded).

Skin biopsy findings together with levels of clearance will “add insight as to whether high-dose IL-23 inhibition is associated with higher levels of complete clearance (i.e., PASI 100) over long periods of time, and whether remissions are associated with more profound knock-down of Trm cells,” Dr. Blauvelt wrote in an editorial on Trm cells in psoriasis published in the Journal of Psoriasis and Psoriatic Arthritis.

Risankizumab was approved by the Food and Drug Administration for moderate to severe plaque psoriasis in 2019, and for active psoriatic arthritis in 2022.
 

Impact of IL-23 inhibition

A 2021 study, Dr. Blauvelt noted in his presentation, showed that the IL-23 inhibitor guselkumab (Tremfya) reduced the number of Trm cells in healed psoriatic skin, while the IL-17A inhibitor secukinumab (Cosentyx) did not affect Trm cells.

Other researchers have concluded that local IL-23 is required for the proliferation and retention of Trm cells in the skin, he said, noting also that, as a class, IL-23 blockers “are associated with the longest disease-free intervals” in patients with psoriasis.

Research showing loss of Trm cells in biopsies of cleared skin is “incredibly important,” as is data showing that IL-23 may be “a critical survival factor” for Trm cells, said Christopher Ritchlin, MD, MPH, a rheumatologist and director of the clinical immunology research unit at the University of Rochester (N.Y.) Medical Center, who attended the NPF meeting and was asked to comment on the growing interest in Trm cells. He did not hear Dr. Blauvelt’s presentation but has followed Trm research in psoriasis.

Measuring Trm cells in synovial tissue of patients with psoriatic disease is, in fact, on the agenda of a new research team coled by Dr. Ritchlin that is part of the Autoimmune and Immune-Mediated Diseases Program of the Accelerating Medicine Partnership – a public-private partnership that aims to collect and analyze troves of biological data in order to illuminate the cellular and molecular interactions leading to autoimmune diseases.

“Resident memory T cells have been thought to be cells that are constrained to being resident in the tissue, and while that’s largely true, there’s more recent data showing that they actually can dedifferentiate and go back to the lymph node and then go back to the joint again,” Dr. Ritchlin noted in an interview. “So it’s a more complicated story,” but nonetheless targeting the cells is a concept worth exploring therapeutically.
 

Moving toward a cure?

The high induction doses of risankizumab in Dr. Blauvelt’s phase 2 “knockout” study were well tolerated through week 40, with safety profiles similar overall to those reported in previous studies of risankizumab and “no new safety signals,” Dr. Blauvelt said at the meeting.

(At baseline, patients had a mean disease duration of 21 years, a mean affected BSA of 21, and a mean PASI of 18.5. Seven had prior treatment with biologic medications, though not in the prior 4 months and not with risankizumab.)

In lieu of a cure, which is still possible in the next 10 years, he said, patients are eager for longer-term remission and the ability to break away from established regular dosing. After publication of a phase 1 study of risankizumab, in which a notable number of patients experienced complete skin clearance up to 1 year following a single high dose, “we started getting numerous calls in our [clinical trials] office from patients who said ‘I want to be on that drug that you give once a year,’ ” Dr. Blauvelt said. (The high dosing was not investigated any further in phase 2 and 3 research, he added.)

While the “knockout” study adopts a “hit hard” approach, it is also possible that a strategy to hit both hard and early after disease onset may induce long-term remission and/or cure of the disease. “I’m talking about using the best things first. There are hints that if we treat early, maybe we can keep [psoriasis] from becoming a chronic disease, keep it from ‘setting up shop’ if you will,” he said, noting that the “hit hard, hit early” concept is not unique to dermatology.

During a discussion period, Dr. Blauvelt said that in a future iteration of the “knockout” study, he would like to evaluate risankizumab in patients with disease duration under 12 months. It may also be valuable to look not only at Trm cells, but more broadly at other elements of the tissue architecture before and after treatment.

Among other strategies for achieving long-term remission and/or cure is the expansion of regulatory T cells, which work to “control inappropriate immune responses” and calm inflammation. Defects in the number and function of regulatory T cells are associated with psoriasis and other autoimmune diseases, and it appears in early research from other investigators that low-dose IL-2 can induce the expansion of regulatory T cells and improve psoriasis. “Keep tuned,” Dr. Blauvelt said.

Dr. Blauvelt disclosed ties with numerous pharmaceutical companies. Dr. Ritchlin had no disclosures.

WASHINGTON – A series of three higher-than-approved induction doses of the interleukin-23 inhibitor risankizumab in patients with psoriasis – and no further subsequent dosing – led to an “unprecedented” level of complete skin clearance at week 52 in a small study investigating whether high-dose IL-23 inhibition can target resident memory T cells and thereby induce long-term remission, Andrew Blauvelt, MD, MBA, reported at the annual research symposium of the National Psoriasis Foundation.

Understanding and trying to target resident memory T (Trm) cells has become a hot topic in psoriasis research, with possible importance for psoriatic arthritis as well. The cells, which normally develop within tissues in a pathogen-specific manner and persist after infections resolve, have been found in healed psoriatic skin and are believed to be responsible for recurrences of psoriasis at the same sites previously affected by the disease. Research suggests, moreover, that Trm cells are dependent on IL-23 for their survival, said Dr. Blauvelt, an investigator with the Oregon Medical Research Center, Portland.

Using an approach he has coined “knockout” therapy, 20 adult patients at the center were randomized 1:1 in double-blinded dosing to receive 300 mg or 600 mg of risankizumab (two and four times the standard initial doses, respectively) at 0, 4, and 16 weeks, and were seen every 4-6 weeks in a double-blinded follow-up period. Skin biopsies of lesional and nonlesional skin were collected at weeks 0 and 52 for RNA sequence analysis to evaluate changes in Trm cell number and effector function.

At week 28, almost all patients – 94% – achieved a Psoriasis Area and Severity Index 90 score, and 83% achieved PASI 100. At week 52, of the 18 still-enrolled patients, 69% had PASI 90 scores and 43% maintained PASI 100 scores. “We’re not curing psoriasis, but that is incredible to have 43% still clear 9 months after the last dose,” Dr. Blauvelt said.

The findings are interim results that pool the two doses of risankizumab (Skyrizi). An evaluation of maintenance of efficacy with the 300-mg versus 600-mg doses and results of the skin biopsies will be presented at the 2024 annual meeting of the American Academy of Dermatology, he said. Patients who have not had recurrences are being followed up to week 100 (unblinded).

Skin biopsy findings together with levels of clearance will “add insight as to whether high-dose IL-23 inhibition is associated with higher levels of complete clearance (i.e., PASI 100) over long periods of time, and whether remissions are associated with more profound knock-down of Trm cells,” Dr. Blauvelt wrote in an editorial on Trm cells in psoriasis published in the Journal of Psoriasis and Psoriatic Arthritis.

Risankizumab was approved by the Food and Drug Administration for moderate to severe plaque psoriasis in 2019, and for active psoriatic arthritis in 2022.
 

Impact of IL-23 inhibition

A 2021 study, Dr. Blauvelt noted in his presentation, showed that the IL-23 inhibitor guselkumab (Tremfya) reduced the number of Trm cells in healed psoriatic skin, while the IL-17A inhibitor secukinumab (Cosentyx) did not affect Trm cells.

Other researchers have concluded that local IL-23 is required for the proliferation and retention of Trm cells in the skin, he said, noting also that, as a class, IL-23 blockers “are associated with the longest disease-free intervals” in patients with psoriasis.

Research showing loss of Trm cells in biopsies of cleared skin is “incredibly important,” as is data showing that IL-23 may be “a critical survival factor” for Trm cells, said Christopher Ritchlin, MD, MPH, a rheumatologist and director of the clinical immunology research unit at the University of Rochester (N.Y.) Medical Center, who attended the NPF meeting and was asked to comment on the growing interest in Trm cells. He did not hear Dr. Blauvelt’s presentation but has followed Trm research in psoriasis.

Measuring Trm cells in synovial tissue of patients with psoriatic disease is, in fact, on the agenda of a new research team coled by Dr. Ritchlin that is part of the Autoimmune and Immune-Mediated Diseases Program of the Accelerating Medicine Partnership – a public-private partnership that aims to collect and analyze troves of biological data in order to illuminate the cellular and molecular interactions leading to autoimmune diseases.

“Resident memory T cells have been thought to be cells that are constrained to being resident in the tissue, and while that’s largely true, there’s more recent data showing that they actually can dedifferentiate and go back to the lymph node and then go back to the joint again,” Dr. Ritchlin noted in an interview. “So it’s a more complicated story,” but nonetheless targeting the cells is a concept worth exploring therapeutically.
 

Moving toward a cure?

The high induction doses of risankizumab in Dr. Blauvelt’s phase 2 “knockout” study were well tolerated through week 40, with safety profiles similar overall to those reported in previous studies of risankizumab and “no new safety signals,” Dr. Blauvelt said at the meeting.

(At baseline, patients had a mean disease duration of 21 years, a mean affected BSA of 21, and a mean PASI of 18.5. Seven had prior treatment with biologic medications, though not in the prior 4 months and not with risankizumab.)

In lieu of a cure, which is still possible in the next 10 years, he said, patients are eager for longer-term remission and the ability to break away from established regular dosing. After publication of a phase 1 study of risankizumab, in which a notable number of patients experienced complete skin clearance up to 1 year following a single high dose, “we started getting numerous calls in our [clinical trials] office from patients who said ‘I want to be on that drug that you give once a year,’ ” Dr. Blauvelt said. (The high dosing was not investigated any further in phase 2 and 3 research, he added.)

While the “knockout” study adopts a “hit hard” approach, it is also possible that a strategy to hit both hard and early after disease onset may induce long-term remission and/or cure of the disease. “I’m talking about using the best things first. There are hints that if we treat early, maybe we can keep [psoriasis] from becoming a chronic disease, keep it from ‘setting up shop’ if you will,” he said, noting that the “hit hard, hit early” concept is not unique to dermatology.

During a discussion period, Dr. Blauvelt said that in a future iteration of the “knockout” study, he would like to evaluate risankizumab in patients with disease duration under 12 months. It may also be valuable to look not only at Trm cells, but more broadly at other elements of the tissue architecture before and after treatment.

Among other strategies for achieving long-term remission and/or cure is the expansion of regulatory T cells, which work to “control inappropriate immune responses” and calm inflammation. Defects in the number and function of regulatory T cells are associated with psoriasis and other autoimmune diseases, and it appears in early research from other investigators that low-dose IL-2 can induce the expansion of regulatory T cells and improve psoriasis. “Keep tuned,” Dr. Blauvelt said.

Dr. Blauvelt disclosed ties with numerous pharmaceutical companies. Dr. Ritchlin had no disclosures.