2024 Key Insights: Psoriasis

As 2024 ends, it is important to step back and reflect on the strides dermatology has made in managing atopic dermatitis (AD) and psoriasis, as these are 2 of the most common inflammatory disorders we manage. At the heart of dermatology is the patient, and integrating patient-reported outcomes (PROs) with clinical assessments is essential to providing truly patient-centered care. Aiming for optimal treatment targets is key to achieving minimal disease activity (MDA) for individuals with these conditions. The notion that “the patient is good enough” is fading along with the final days of 2024. As we look ahead to 2025, patients deserve more than “good enough.” Over the past year, dermatology has embraced MDA as a transformative standard, poised to elevate the quality of life for those with chronic inflammatory skin disorders.

To elevate the standard of care in AD, the Aiming High in Eczema/Atopic Dermatitis (AHEAD) guidelines¹ recommend setting optimal treatment targets for both skin clearance and itch relief. Achieving both targets simultaneously defines MDA. Why is this recommendation so crucial? Data indicate that patients with AD and itch numerical rating scores (NRS) of 2 and 10, even those with high levels of skin clearance (Eczema Area and Severity Index [EASI] 90 or Investigator’s Global Assessment [IGA] 0/1), may experience a 40% to 60% reduction in quality of life.² Meeting both EASI 90 and itch NRS 0/1 thresholds leads to improved outcomes and quality of life, ultimately fulfilling the goal of MDA. This emphasis on dual outcomes is why the recent LEVEL-UP trial, comparing upadacitinib (Rinvoq; AbbVie) with dupilumab (Dupixent; Regeneron and Sanofi), used the composite end point EASI 90+ itch NRS 0/1 as a primary measure, marking it as the most stringent end point in an AD trial to date.³

In the LEVEL UP trial, upadacitinib demonstrated superiority over dupilumab at every time point in patients with moderate to severe AD. During period 1 (0 to 16 weeks), nearly twice as many patients treated with upadacitinib achieved the stringent primary MDA endpoint of EASI 90 & itch NRS 0/1 compared to those treated with dupilumab. In period 2 (16 to 32 weeks), patients who did not achieve EASI 75 on dupilumab by week 16 were allowed to switch directly to upadacitinib (15 mg daily) without a washout period. Remarkably, nearly 70% of these patients reached EASI 75 just 1 month after switching, and the majority achieved EASI 90 with clinically meaningful itch improvement by 4 months post switch. This is a practice-defining study that set a new standard for efficacy in AD.

Adopting higher standards of care for moderate to severe AD requires clinicians to embrace the concept of MDA in real-world practice. A practical way to implement this is by ensuring patients achieve clear or almost clear skin (IGA 0/1) and little to no itch (itch NRS 0/1). If patients are not meeting these benchmarks, clinicians should confidently consider switching therapies.

Moreover, the emergence of advanced systemic therapies for AD—including JAK inhibitors such as upadacitinib and abrocitinib (Cibinqo; Pfizer Inc), as well as biologics like dupilumab, tralokinumab (Adbry; LEO Pharma), and lebrikizumab (Ebglyss; Eli Lilly and Company)—offers effective alternatives to traditional immunosuppressive agents such as systemic corticosteroids. The American Academy of Dermatology guidelines⁴ for AD management support this approach, recommending against the use of systemic corticosteroids, except for short-term use as a bridge to another approved systemic therapy, as they no longer align with modern standards of care.^5,6

Innovations in psoriasis therapeutics have significantly advanced the standard of care, particularly with biologics that achieve optimal skin clearance with fewer doses per year—such as risankizumab (Skyrizi; AbbVie), requiring only 4 doses annually, guselkumab (Tremfya; Janssen) with 6 doses, and bimekizumab (Bimzelx; UCB) with 8 doses. The practice-defining IMMpulse study further elevated the standard by demonstrating the superiority of risankizumab over oral apremilast (Otezla; Amgen) in patients with moderate plaque psoriasis. These results encourage dermatologists to consider risankizumab earlier in the treatment pathway, even for patients with moderate disease, particularly for patients who desire optimal outcomes. Another ongoing, head-to-head study is BE BOLD, comparing bimekizumab , an anti–IL-17, vs risankizumab, an anti–IL-23, in patients with active psoriatic arthritis (PsA). However, a recent population-based study from the US has shown that patients receiving IL-23 inhibitors are at lower risk of developing inflammatory arthritis or psoriatic arthritis than those receiving IL-17 and tumor necrosis factor (TNF) inhibitors.⁷ Looking ahead to 2025, my vision for dermatology providers is to “take back ownership” of PsA by managing all aspects of psoriasis—skin and joints. Advances in systemic therapies have positioned dermatologists to embrace this holistic approach. With that in mind, let’s reflect on 3 key psoriasis narratives that defined 2024.

First, p19-specific IL-23 biologics are the most widely prescribed class of advanced psoriasis treatments by dermatologists, yet little was previously understood about their molecular differences. A recent study⁸ has shown that the efficacy of these biologics correlates with their molecular structure. Specifically, a larger epitope surface area (risankizumab > guselkumab > tildrakizumab [Ilumya; Sun Pharmaceutical]) is associated with higher binding affinity and a lower dissociation rate (koff), resulting in a more stable antibody-p19/IL-23 complex. This stability translates to superior clinical outcomes, with higher skin clearance (Psoriasis Area and Severity Index [PASI] 90 and PASI 100) response rates observed over both short- and long-term treatment periods. This discovery provides a molecular explanation for the efficacy of p19-specific biologics. Looking ahead, innovation in the IL-23 space includes promising developments. Ongoing phase 3 trials are evaluating JNJ-2113 (Icotrokinra; Protagonist Therapeutics), an oral cyclic peptide that inhibits the IL-23 receptor, for psoriasis. Additionally, extended halflife technology is being applied to create an IL-23 monoclonal antibody with potentially improved dosing schedules. These advancements represent exciting opportunities to further refine IL-23-targeted therapies.

Second, in 2024, bimekizumab completed its first full year of availability for psoriasis. A key advancement was the publication⁹ detailing the molecular basis of its dual inhibition of IL-17A and IL-17F, which underpins its clinical efficacy. Bimekizumab demonstrated the ability to elevate response thresholds, including achieving PASI-100, and showed potential for very rapid skin clearance.¹⁰ Late in 2024, bimekizumab was also approved for PsA. Clinical trial data from the BE COMPLETE and BE VITAL studies highlighted its effectiveness in patients with prior inadequate response or intolerance to TNFα inhibitors. At week 16, American College of Rheumatology response criteria (ACR) 20/50/70 responses were 67%, 43%, and 27%, respectively. These rates improved by week 52, reaching 68%, 52%, and 36%, respectively.¹¹ Additionally, 44% of patients achieved a version of MDA at week 16, increasing to 47% by week 52. The stringent composite end point of ACR 50 + PASI 100 was achieved by 34% at week 16 and 47% at week 52, demonstrating the potential of innovative targeted therapies like bimekizumab to set new standards of care for both psoriasis and PsA.

Third, the next-generation oral TYK2 inhibitor for psoriasis and PsA, zasocitinib (formerly TAK-279; Takeda), is in phase 3 trials. This molecule is over 1.7 million-fold more selective for the TYK2 JH2 domain over the JAK1 JH2 domain (compared with 87-fold for deucravacitinib [Sotyktu; Bristol Myers Squibb]), and its plasma concentration exceeds the TYK2 half-maximal inhibitory concentration (IC50) for a full 24 hours (compared to 3 hours for deucravacitinib) inhibiting 91% of TYK2 signaling daily (compared to 24% for deucravacitinib).¹² In the phase 2b clinical trial, 30 mg zasocitinib once daily achieved 46% PASI 90 and 33% PASI 100 responses at week 12.¹³ For PsA, 27% of patients achieved ACR50 and approximately 30% MDA at week 12.^13,14

Lastly, dermatologists should note that oral upadacitinib is FDA-approved for PsA,¹⁵ demonstrating ACR 20/50/70 response rates at week 12 with the 15 mg daily dose ranging from 57% to 71%, 32% to 38%, and 9% to 16%, respectively. Notably, upadacitinib, in addition to AD, is FDA-approved for 7 immune-mediated disorders, and is currently being studied for alopecia areata, vitiligo, and hidradenitis suppurativa, underscoring the versatility of JAK inhibitors as anti-inflammatory agents. While the focus here has been on systemic therapies, it is important to note the significant advances in nonsteroidal topicals in psoriasis with roflumilast (Zoryve; Arcutis Biotherapeutics) and tapinarof (Vtama; Dermavant Sciences). Roflumilast, in particular, has emerged as a highly potent, effective, tolerable, and safe topical that can reduce Th1, Th2, Th22, and Th17 inflammatory cytokines, explaining roflumilast’s ability to effectively treat AD, psoriasis, and seborrheic dermatitis, along with other roflumilast-responsive dermatoses.

The MDA principle is not only raising the standard of care in AD, psoriasis, and PsA, but is also likely to influence the management of other inflammatory skin conditions such as chronic hand eczema. As we move into 2025, one thing is clear: The true beneficiaries are the patients. With an unprecedented array of advanced and targeted therapies now available, it is incumbent upon clinicians to adapt their thinking and treatment strategies to integrate these transformative medications into everyday clinical practice, ultimately improving patient outcomes and quality of life.

Christopher G. Bunick, MD, PhD, is an associate professor of dermatology and translational biomedicine at the Yale University School of Medicine in New Haven, Connecticut. He is Dermatology Times’ 2024 winter editor in chief.

References
1. Silverberg JI, Gooderham M, Katoh N, et al. Combining treat-to-target principles and shared decision-making: International expert consensus-based recommendations with a novel concept for minimal disease activity criteria in atopic dermatitis. J Eur Acad Dermatol Venereol. 2024;38(11):2139-2148. doi:10.1111/jdv.20229
2. Reich K, de Bruin-Weller MS, Deleuran M, et al. Higher levels of response on clinical atopic dermatitis severity measures are associated with meaningful improvements in patient-reported symptom and quality of life measures: integrated analysis of three upadacitinib phase 3 trials. J Eur Acad Dermatol Venereol. Published online February 24, 2023. doi:10.1111/jdv.18995
3. Silverberg JI, Bunick CG, Hong HC, et al. Efficacy and safety of upadacitinib vs dupilumab in adults and adolescents with moderate-to-severe atopic dermatitis: week 16 results of an open-label, randomized, efficacy assessor-blinded head-to-head phase 3b/4 study (Level Up). Br J Dermatol. Published online October 23, 2024. doi:10.1093/bjd/ljae404
4. Davis DMR, Drucker AM, Alikhan A, et al. Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies. J Am Acad Dermatol. 2024;90(2):e43-e56. doi:10.1016/j.jaad.2023.08.102
5. Bunick CG, Vleugels RA, Lebwohl M, et al. Utilization and duration of systemic corticosteroid exposure in atopic dermatitis patients after the introduction of advanced therapies: a population-based study from the United States. Poster presented at: Fall Clinical Dermatology Conference; October 24-27, 2024; Las Vegas, NV.
6. Daniele SG, Eldirany SA, Damiani G, Ho M, Bunick CG. Structural basis for p19 targeting by anti-IL-23 biologics: correlations with short- and long-term efficacy in psoriasis. JID Innov. 2024;4(2):100261. doi:10.1016/j.xjidi.2024.100261
7. Strober B, Soliman AM, Li C, Patel M, Unigwe I, Gisondi P. Risk of developing inflammatory arthritis in patients with psoriasis initiating treatment with biologics: a populationbased analysis. J Am Acad Dermatol. Published online August 27, 2024. doi:10.1016/j.jaad.2024.06.106
8. Daniele SG, Galimberti F, Bunick CG. Structural insights: what makes some IL 23 biologics more effective in psoriasis. J Drugs Dermatol. 2024;23(10):903-904.
9. Adams R, Bunick CG, Lawson ADG, Gomez B, Shaw S. Crystal structure of bimekizumab fab fragment in complex with IL-17F provides molecular basis for dual IL-17A and IL-17F inhibition. J Invest Dermatol. 2024(11):2581-2583. e2. doi:10.1016/j.jid.2024.03.037
10. Abdin R, Gharib R, Bunick CG, Issa NT. Rapid remission of plaque psoriasis with bimekizumab treatment. J Drugs Dermatol. 2024;23(8):694-696. doi:10.36849/JDD.8381
11. Coates LC, Landewé R, McInnes IB, et al. Bimekizumab treatment in patients with active psoriatic arthritis and prior inadequate response to tumour necrosis factor inhibitors: 52-week safety and efficacy from the phase III BE COMPLETE study and its open-label extension BE VITAL. RMD Open. 2024;10(1):e003855. doi:10.1136/rmdopen-2023-003855
12. Mehrotra S, Sano Y, Halkowycz P, et al. Zasocitinib (TAK-279) displays high TYK2 inhibition and no inhibition of JAK1/3 versus licensed inhibitors. Poster presented at: 2024 European Society for Dermatological Research Conference; September 4-7, 2024; Lisbon, Portugal.
13. Armstrong AW, Gooderham M, Lynde C, et al. Tyrosine kinase 2 inhibition with zasocitinib (TAK-279) in psoriasis: a randomized clinical trial. JAMA Dermatol. 2024;160(10):1066-1074. doi:10.1001/jamadermatol.2024.2701
14. Kivitz A, Muensterman E, Kavanaugh A, et al. Efficacy and safety outcomes of TAK-279, a selective oral tyrosine kinase 2 (TYK2) inhibitor, from a randomized, doubleblind, placebo-controlled phase 2b trial in patients with active psoriatic arthritis. Presented at: American College of Rheumatology 2023 Convergence; November 10-15, 2023; San Diego, CA.
15. Building a routine with Rinvoq medication. Rinvoq. 2024. Accessed November 15, 2024. https://www.rinvoq.com/resources/building-rinvoq-medication-routine