Evolution and Innovation in Treating Psoriasis in Pediatric Patients – Dermatology Times

When we talk about evolution in treatment for psoriasis, we have come a long way, April W. Armstrong, MD, MPH, told attendees at the Society for Pediatric Dermatology Pre-AAD Meeting.1

April W. Armstrong, MD, MPH

Armstrong, Chief of the Division of Dermatology at the UCLA Health and the David Geffen School of Medicine, added that through this evolution we are looking for treatments that are effective, convenient and safe. Not too long ago, arsenic was used to treat psoriasis,2 she told attendees. Yes, it killed psoriasis but also killed a lot of other things.

Fortunately, she shared there are now options that are meet the 3 important criteria: safe, effective, and even convenient. For instance, biologics have emerged as a good option for treating psoriasis, especially in adults, Armstrong explained. In general, there are a number of factors she considers when choosing among the biologics, which when grouped include tumor necrosis factor (TNF) inhibitors (ie, etanercept, infliximab, adalimumab, certolizumab), interleukin (IL)-17 inhibitors (ie, ixekizumab, secukinumab, brodalumab, bimekizumab), and IL-23 inhibitors (ie, guselkumab, risankizumab, tildrakizumab, ustekinumab [a IL12/23 inhibitor]).

The IL-17 and IL-23 inhibitors are a good choice for robust psoriasis efficacy. In addition, guselkumab, risankizumab, ustekinumab have been shown to be effective for psoriatic arthritis, while IL-17 inhibitors have been shown to be effective for peripheral and axial psoriatic arthritis. There is evolving evidence for the use of IL-23 inhibitors in psoriatic arthritis of the spine. She cautioned that IL-17 inhibitors should be avoided in patients with a history of inflammatory bowel disease and can be associated with increased risk of oral candidiasis.

Meanwhile, Armstrong noted TNF inhibitors should be avoided in patients with hepatitis B and demyelinating disease. They also are not preferred when there is a history of latent tuberculosis or advanced congestive heart failure. Like the other biologics, TNF inhibitors can be effective for psoriatic arthritis (peripheral and axial) and she added that certolizumab has been great in pregnant patients.

Currently, there arebiologics approved for use in pediatric patients. Ustekinumab which inhibits p40 subunit of IL12/23, has been approved for pediatric plaque psoriasis in patients aged 6 years and older. She pointed to the CADMUS Trial, which found that nearly 70% of patients aged 12 years or older with moderate to severe plaque psoriasis achieved sPGA0/1 (vs 5.4 in the placebo group).3

Secukinumab is approved for pediatric patients aged 6 years and older, she said. She shared results from a study comparing secukinumab versus etanercept in this patient population, noting she especially appreciates head to head comparisons of agents because it speaks to the superiority of one medication over another over a time period. In the study, which was present at the EADV Virtual Congress in 2020, 85% of the patients on secukinumab achieved (and maintained) clear (IGA 0/1) at 52 weeks vs 72% on etanercept.

Approved in pediatric patients 6 years and older for moderate to severe psoriasis, Armstrong said ixekizumab has shown high efficacy when compared with placebo, with 50% of patients achieving PASI 100 by week 12 (vs 2% on placebo).

Bimekizumab, the newest approved biologic for adult patients, has shown fast onset, high efficacy, and robust maintenance of response, Armstrong told attendees. Treatment consists of two 160 mg doses every 4 weeks for the first 16 weeks and then every 8 weeks afterwards. She reminded attendees that labs (ie, tuberculosis, liver enzymes, alkaline phosphatase, and bilirubin) should be checked prior to treatment. Oral candidiasis is the most common adverse event, but she said it is manageable without discontinuation with 100 mg to 200 mg fluconazole for 7 days.

Meanwhile, a phase 2 trial of bimekizumab (NCT04718896) is currently underway to assess safety and efficacy in adolescents with moderate to severe plaque psoriasis.

Another important treatment to consider is the tyrosine kinase 2 (Tyk2) inhibitor deucravacitinib, Armstrong told attendees. Currently, deucravacitinib is approved by the US Food and Drug Administration as an oral medication for the treatment of moderate to severe plaque psoriasis in adults. She shared data demonstrating Psoriasis Area and Severity Index (PASI) 75, PASI 90, and Static Physician's Global Assessment (sPGA) 0/1 response sustained through 3 years for patients on the agent, which she added is really impressive.

The tolerability is really where it shines, Armstrong told attendees. It has rates of diarrhea and nausea similar to placebo, and there are low rates of acne and zoster, she explained, but overall the discontinuation rates was lowest for patients on deucravacitinib when compared with patients on placebo or apremilast.

Before initiating treatment, Armstrong noted patients should be evaluated for tuberculosis and baseline liver and hepatitis serologies should be checked in patients with known or suspected liver disease. However, ongoing monitoring is only needed if the patient has liver disease or unmanaged triglycerides.

Im very excited about the possible extension to our pediatric population in the future, Armstrong said. She detailed a phase 3 trial (NCT04772079) is currently underway for pediatric patients with moderate to severe plaque psoriasis looking at safety and efficacy in that patient population. The study is looking at 2 doses across 2 cohorts based on ages (4 to 12 and 12 to 18 years).

The oral phosphodiesterase 4 (PDE4) inhibitor apremilast is also a new medication that has shown efficacy in pediatric patients, according to Armstrong. It currenly is approved for adults regardless of severity, she said. She shared results of a placebo-controlled study of patients with moderate to severe plaque psoriasis aged 6 to 17 years that found almost one-third were clear or almost clear at week 16 (vs 11% for placebo).

Armstrong briefly noted 2 innovative products in the pipeline. JNJ-77242113 is an oral therapeutic peptide selectively targeting IL-23R, she told attendees.4 DC-806 allosterically blocks the same biochemical step as the anti-IL-17 antibodies.

In the topical category, Armstrong pointed to tapinarof and roflumilast as novel non-steroidal agents. Tapinarof, currently approved for adult patients, is an aryl hydrocarbon receptor (AhR) agonist that reduces TH17 cytokines; increases antioxidant activity via Nrf2 pathway; increases filaggrin, loricrin, and involucrin, and decreases Th2 cytokines. The PSOARING 1 study found that 40% of patients on tapinarof 1% cream daily achieved PASI 75 by week 12. Armstrong added that when tapinarof is stopped, patients are able to maintain clear/almost clear status for about 4 months. My opinion is it is probably similar to or stronger than a class 3 topical steroid, she told attendees. Armstrong is hopeful it will become available for pediatric patients in the near future.

Roflumilast is a PDE4 inhibitor approved for patients aged 6 years and older, Armstrong said. Overall it is quite well tolerated. In my opinion, it is probably similar to a class 3 topical steroid, she said. She uses it in clinical practice, but there are some tricks to make sure your patient has access to it, and knowing which local pharmacies are used to working with it.

References

1. Armstrong A. Updates in Psoriasis Management and New Therapeutics. Presented at: 36th Annual Pre-AAD Meeting of the Society for Pediatric Dermatology; March 7, 2024. San Diego, California.

2. Sarfraz R. H16 Arsenic to biologics: psoriasis treatment through the ages. British Journal of Dermatology. 2023; 188(Supplement 4. ljad113.298

3. Landells I, Marano C, Hsu MC, et al. Ustekinumab in adolescent patients age 12 to 17 years with moderate-to-severe plaque psoriasis: results of the randomized phase 3 CADMUS study. J Am Acad Dermatol. 2015;73(4):594-603. doi:10.1016/j.jaad.2015.07.002

4. Bissonnette R, Pinter A, Ferris LK, et al. An Oral Interleukin-23-Receptor Antagonist Peptide for Plaque Psoriasis. N Engl J Med. 2024;390(6):510-521. doi:10.1056/NEJMoa2308713

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Evolution and Innovation in Treating Psoriasis in Pediatric Patients - Dermatology Times

Generative AI, Free Speech, & Public Discourse: Why the Academy Must Step Forward | TechPolicy.Press – Tech Policy Press

On Tuesday, Columbia Engineering and the Knight First Amendment Institute at Columbia University co-hosted a well-attended symposium, Generative AI, Free Speech, & Public Discourse. The event combined presentations about technical research relevant to the subject with addresses and panels discussing the implications of AI for democracy and civil society.

While a range of topics were covered across three keynotes, a series of seed funding presentations, and two panelsone on empirical and technological questions and a second on legal and philosophical questionsa number of notable recurring themes emerged, some by design and others more organically:

This event was part of one partnership amongst others in an effort that Columbia University president Manouche Shafik and engineering school dean Shih-Fu Chang referred to as AI+x, where the school is seeking to engage with various other parts of the university outside of computer engineering to better explore the potential impacts of current developments in artificial intelligence. (This event was also a part of Columbias Dialogue Across Difference initiative, which was established as part of a response to campus conflict around the Israel-Gaza conflict.) From its founding, the Knight Institute has focused on how new technologies affect democracy, requiring collaboration with experts in those technologies.

Speakers on the first panel highlighted sectors where they have already seen potential for positive societal impact of AI, outside of the speech issues that the symposium was focussed on. These included climate science, drug discovery, social work, and creative writing. Columbia engineering professor Carl Vondrick suggested that current large language models are optimized for social media and search, a legacy of their creation by corporations that focus on these domains, and the panelists noted that only by working directly with diverse groups can their needs for more customized models be understood. Princeton researcher Arvind Narayanan proposed that domain experts play a role in evaluating models as, in his opinion, the current approach of benchmarking using standardized tests is seriously flawed.

During the conversation between Jameel Jaffer, Director of the Knight Institute, and Harvard Kennedy School security technologist Bruce Schneier, general principles for successful interdisciplinary work were discussed, like humility, curiosity and listening to each other; gathering early in the process; making sure everyone is taken seriously; and developing a shared vocabulary to communicate across technical, legal, and other domains. Jaffer recalled that some proposals have a lot more credibility in the eyes of policymakers when they are interdisciplinary. Cornell Tech law professor James Grimmelman, who specializes in helping lawyers and technologists understand each other, remarked that these two groups are particularly well-equipped to work together, once they can figure out what the other needs to know.

President Shafik declared that if a responsible approach to AIs impact on society requires a +x, Columbia (surely along with other large research universities) has lots of xs. This positions universities as ideal voices for the public good, to balance out the influence of the tech industry that is developing and controlling the new generation of large language models.

Stanfords Tatsunori Hashimoto, who presented his work on watermarking generative AI text outputs, emphasized that the vendors of these models are secretive, and so the only way to develop a public technical understanding of them is to build them within the academy, and take on the same tasks as the commercial engineers, like working on alignment fine-tuning and performing independent evaluations. One relevant and striking finding by his group was that the reinforcement learning from human feedback (RLHF) process tends to push models towards the more liberal opinions common amongst highly-educated Americans.

The engineering panel developed a wishlist of infrastructure resources that universities (and others outside of the tech industry) need to be able to study how AI can be used to benefit and not harm society, such as compute resources, common datasets, separate syntax models so that vetted content datasets can be added for specific purposes, and student access to models. In the second panel, Camille Franois, a lecturer at the Columbia School of International and Public Affairs and presently a senior director of trust & safety at Niantic Labs, highlighted the importance of having spaces, presumably including university events such as the one at Columbia, to discuss how AI developments are impacting civil discourse. On a critical note, Knight Institute executive director Katy Glenn Bass also pointed out that universities often do not value cross-disciplinary work to the same degree as typical research, and this is an obstacle to progress in this area, given how essential collaboration across disciplines is.

Proposals for regulation were made throughout the symposium, a number of which are listed below, but the keynote by Bruce Schneier was itself an argument for government intervention. Schneiers thesis was, in brief, that corporation-controlled development of generative AI has the potential to undermine the trust that society needs to thrive, as chatbot assistants and other AI systems may present as interpersonally trustworthy, but in reality are essentially designed to drive profits for corporations. To restore trust, it is incumbent on governments to impose safety regulations, much as they do for airlines. He proposed a regulatory agency for the AI and robotics industry, and the development of public AI models, created under political accountability and available for academic and new for-profit uses, enabling a freer market for AI innovation.

Specific regulatory suggestions included:

A couple of cautions were also voiced: Narayanan warned that the Liars Dividend could be weaponized by authoritarian governments to crack down on free expression, and Franois noted the focus on watermarking and deepfakes at the expense of unintended harms, such as chatbots giving citizens incorrect voting information.

There was surprisingly little discussion during the symposium of how generative AI specifically influences public discourse, which Jaffer defined in his introductory statement as acts of speaking and listening that are part of the process of democracy and self-governance. Rather, much of the conversation was about online speech generally, and how it can be influenced by this technology. As such, an earlier focus of online speech debates, social media, came up a number of times, with clear parallels in terms of concern over corporate control and a need for transparency.

Hashimoto referenced the notion that social media causes feedback loops that greatly amplify certain opinions. LLMs can develop data feedback loops which may cause a similar phenomenon that is very difficult to identify and unpick without substantial research. As chatbots become more personalized, suggested Vondrick, they may also create feedback on an individual user level, directing them to more and more of the type of content that they have already expressed an affinity for, akin to the social media filter bubble hypothesis.

Another link to social media was drawn in the last panel, during which both Grimmelmann and Franois drew on their expertise in content moderation. They agreed that the most present danger to discourse from generative AI is inauthentic content and behavior overwhelming the platforms that we rely on, and worried that we may not yet have the tools and infrastructure to counter it. (Franois described a key tension between the Musk effect pushing disinvestment in content moderation and the Brussels effect encouraging a ramping up in on-platform enforcement via the DSA.) At the same time, trust and safety approaches like red-teaming and content policy development are proving key to developing LLMs responsibly. The correct lesson to draw from the failures to regulate social media, proposed Grimmelmann, was the danger of giving up on antitrust enforcement, which could be of great value when current AI foundation models are developed and controlled by a few (and in several cases the same) corporations.

One final theme was a framing of the current moment as one of transition. Even though we are grappling with how to adapt to realistic, readily available synthetic content at scale, there will be a point in the future, perhaps even for todays young children, that this will be intuitively understood and accounted for, or at least that media literacy education, or tools (like watermarking) will have caught up.

Several speakers referenced prior media revolutions. Narayanan was one of several who discussed the printing press, pointing out that even this was seen as a crisis of authority: no longer could the written word be assumed to be trusted. Wikipedia was cited by Columbia Engineering professor Kathy McKeown as an example of media that was initially seen as untrustworthy, but whose benefits, shortcomings, and suitable usage are now commonly understood. Franois noted that use of generative AI is far from binary and that we have not yet developed good frameworks to evaluate the range of applications. Grimmelman mentioned both Wikipedia and the printing press as examples of technologies where no one could have accurately predicted how things would shake out in the end.

As the Knight Institutes Glenn Bass stated explicitly, we should not assume that generative AI is harder to work through than previous media crises, or that we are worse equipped to deal with it. However, two speakers flagged that the tech industry should not be the given free rein: USC Annenbergs Mike Ananny warned that those with invested interests may attempt to prematurely push for stabilization and closure, and we should treat this with suspicion; and Princetons Narayanan noted that this technology is producing a temporary societal upheaval and that its costs should be distributed fairly. Returning to perhaps the dominant takeaways from the event, these comments again implied a role for the academy and for the government in guiding the development of, adoption of, and adaptation to the emerging generation of generative AI.

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Generative AI, Free Speech, & Public Discourse: Why the Academy Must Step Forward | TechPolicy.Press - Tech Policy Press