Update on pathogenesis of psoriasis subsets by Johann Gudjonsson

Psoriasis is a chronic inflammatory skin disease affecting over 25 million people worldwide, typically starting in adolescence and persisting throughout life. The condition varies widely in clinical presentation and is associated with significant emotional and psychosocial difficulties, including high rates of depression, anxiety, and suicidal ideation. It is also linked to several comorbidities, such as psoriatic arthritis, cardiovascular disease, metabolic syndrome, multiple sclerosis, and Crohn's disease.  Psoriasis exists on a spectrum of diseases rather than a single phenotype. It is also considered a cytokine-driven disease involving three main self-sustaining cytokine profiles: type 1 and type 2 interferon responses, IL-17A and IL-17F responses, and the IL-36 axis. Chronic plaque psoriasis, characterized by an IL-17 dominant autoimmune inflammatory pattern, represents one end of the spectrum. Paradoxical psoriasis is a phenomenon observed in about 5% of patients on anti-TNF agents, where the treatment meant to alleviate psoriasis symptoms instead worsens them, often leading to complex clinical presentations like eczema, sarcoid granuloma annulare and lichen planus. The elevated levels of interferon-α-2, interferon β-1, IL-22, and interferon-gamma in paradoxical psoriasis indicate a significant influx of plasmacytoid dendritic cells contributing to the condition. Pustular psoriasis, driven primarily by IL-36 axis, manifests in plaque psoriasis and normal skin. Pathogenic mechanism: epidermal autoinflammatory response triggered by significant neutrophil influx due to elevated levels of chemokines (CXCL1, CXCL2, CXCL8). In generalized pustular psoriasis, these chemokines increase 20-50-fold, signifying substantial neutrophil presence in affected skin. Pustular Psoriasis is driven by IL-1 cytokines, particularly IL-36, and the disease is activated downstream of various pro-inflammatory cytokines such as IL-1, IL-17, and TNF-α. IL-36, when exposed to neutrophil proteases, becomes highly active, leading to a cycle of inflammation that attracts more neutrophils

The acral forms of Psoriasis exhibit a significant challenge in treatment due to their similar appearance. Researchers identified 3 distinct phenotypes: Palmoplantar pustular psoriasis, Palma plantar psoriasis, and dyshidrotic eczema, which often look alike in clinical settings. The cytokine IL-17A varied across patients, likely contributing to inconsistent treatment responses. IL-17A, TNF, and IL-36 cytokines are pivotal in the disease's presence and severity. These cytokine responses occur in specific layers of the skin's epidermis: interferon in the basal layer and IL-17A, TNF, and IL-36 in the supraspinous layer.

New and emerging therapies for Psoriasis by Lluis Puig

In the last two decades, psoriasis treatment has seen substantial progress, with higher therapeutic goals. Initially, PASI 50 was a significant milestone, but advancements like IL 17 inhibitors have raised the bar to PASI 75, PASI 90, and the pursuit of PASI 100. A recent meta-analysis highlights Bimekizumab (BKZ) as a promising breakthrough for psoriasis treatment, as it targets both IL 17 A and F, crucial cytokines in psoriasis development. This is particularly important as the IL-17F levels were 30 times higher than IL-17A in psoriasis patients, making drugs like BKZ crucial for achieving complete clearance. Compared to other medications like Ixekizumab or Ustekinumab, BKZ has advantages, including its ability to block the signaling of both IL 17A and F through a different receptor, IL 17 receptor A. Moreover, BKZ demonstrates a rapid onset of action, maintains a high response rate (with close to 80 % of patients remaining on PASI 100), and sustains this response for up to five years. Several molecules can block IL-17 A and IL-17 F, including a nanobody made up of three small units called Sonelokimab. This nanobody can block IL-17 F, IL-17A, and 17F simultaneously, and it utilizes albumin to prolong the drug's effective.  A comparison between the sonelokimab and secukinumab reveals similar efficacy in achieving PASI 90 responses, but the nanobody shows a higher numerical response for PASI 100. Notably, the nanobody demonstrates an advantage with a slower decrease in patient response after discontinuation, despite its half-life. Patients swiftly regain their response upon reintroduction of the drug. Similar characteristics are observed in Guselkumab, Risankizumab, and BKZ, suggesting a commonality among these drugs in maintaining response even after withdrawal, indicating remission. Izokibep, a novel IL-17A inhibitor, comprises two IL-17A-specific Affibody domains combined with a single albumin-binding domain. It has excellent tissue penetration and a low incidence of fungal infections in treating psoriatic arthritis and Psoriasis. One common challenge faced by these drugs, including Minikizumab, is the delayed loss of response after drug withdrawal, linked to the reactivation of tissue-resident memory cells. The ECLIPSE trial explored the impact of Guselkumab and Secukinumab treatments on Psoriasis patients. It revealed that diverse tissue-resident memory cell classes and their cytokine responses influenced the time until patient relapse, with a higher proportion of these cells leading to faster relapse. These cells could accumulate in non-lesional sites and were associated with disease duration. Additionally, the study found that IL-23 inhibiting therapy could suppress tissue-resistant memory cells producing IL-17, both in animal models and clinical contexts. Spesolimab and Imsidolimab, drugs block IL in case of generalized postural psoriasis flares although their effectiveness in different indications varies. For palmoplantar pustulosis, existing treatments have generally been ineffective, prompting a need for better outcome measures. IL-30 and 23 blockade, as well as interferon blockade, might be more effective based on limited clinical trial data. Deucravacitinib specifically targets TYK 2, inhibiting the signal transduction of IL-12 and 23 signals. It also demonstrated efficacy in clinical trials, showing a 60% response rate for PASI 75 by week 16, reaching 70% for PASI 95 by week 24. Some patients achieved a PASI 100 response, but relapse occurs in 50% within 12 weeks due to its short half-life. Efficacy plateaus around week 24, with 66% achieving PASI 75, 44% PASI 90, and 20% PASI 100. Zasocitinib and JNJ2113 are promising molecules in treating psoriasis, with high response rates in clinical trials. Orismilast also shows potential for future treatments for psoriasis patients.

How to Select the Right Treatment for Your Patients with Psoriasis? By Hervé Bachelez

Plaque psoriasis is a largely homogeneous condition, mainly linked to the IL-23 and IL-17 pathways. The development of treatments has followed these advances in our understanding of the disease’s pathogenesis. Multiple factors influence treatment choices, with efficacy being a primary concern for physicians and patients. Shared decision-making, influenced by disease localization, comorbidities, practical considerations (such as pregnancy), patient preferences and regulatory constraints, is becoming more prevalent. The “one target fits all” approach has limitations, as seen in drug efficacy meta-analyses. A top group of effective drugs includes IL-23 blockers, bimekizumab, and infliximab, while others like deucravacitinib, certolizumab, and fumarates have intermediate or lower efficacy. These findings highlight the complexity of treatment decisions and the need for a personalized approach. In real-world practice, drug survival is often used as an indicator of treatment efficacy, but it has limitations. Newer drugs with no alternatives tend to have longer survival times, as physicians and patients prefer to continue them. For instance, guselkumab demonstrates high drug survival, with fewer than 10% of patients opting to switch from it after two years. In real-life practice, the main reason for treatment switches is inadequate effectiveness. Other TNF alpha blockers, like ustekinumab and adalimumab, see higher attrition rates, up to 25% within two years. Even newer drugs such as IL-17 blockers like ixekizumab have a substantial proportion of switches. This underscores two key points: IL-23 blockers demonstrate good real-world effectiveness, while even highly effective drugs like secukinumab and ixekizumab have patients who switch due to initial success followed by secondary flare ups. A Danish study compared "super responders," who have a strong response to treatment, with "treatment-refractory" patients, who don't respond to at least two modes of action and three drugs. The findings showed that super responders had fewer female patients compared to the treatment-refractory group. This gender difference is significant as it can affect drug immunization. The treatment-refractory group had a higher proportion of female patients. Super responders also tended to have higher socioeconomic status than the treatment-refractory group. Patients often switch between various treatments and modes of action, creating complex situations, sometimes leaving certain individuals with no effective treatment options. This session explores genotyping biomarkers for psoriasis treatment decisions. Early research links HLA CW6 allele to PASI 90 response with ustekinumab but notes limited practicality. The focus shifts to single-gene models in psoriasis, particularly the CARD 14 gene, a gain-of-function mutant enhancing keratinocyte response to IL-17. This mutation is present in various psoriasis subtypes. IL-23 blockade is effective for patients with CARD 14 mutations. Other single-gene models, like IL-36 receptor antagonist deficiencies, IL-1 receptor antagonist mutations, and DERA syndrome, require specific inhibitors based on the genetic variant. Artificial intelligence, particularly a software called Alpha Missense, is mentioned as a tool to predict the pathogenicity of single gene variants, potentially offering insights into more effective treatment strategies in the future. The importance of artificial intelligence and machine learning in predicting the pathogenicity of genetic variants and the transcriptomic analysis of lesional skin and its role in understanding the inflammatory response. Some psoriasis patients exhibit an upregulation of interferon-stimulated genes in their skin, which might be associated with a better response to JAK inhibitors. The speaker concludes by emphasizing the need for better patient stratification based on individual characteristics and mechanistic scenarios, potentially leading to more precise, personalized treatments in the future.

Long-term remissions through disease modification: Are we there yet? By Curdin Conrad

Disease modification means changing the natural course of a condition through treatment to achieve long-term remission or a state where ongoing treatment is unnecessary. The aim is to achieve a cure or long-lasting remission without continued treatment. The speaker highlights psoriasis as a chronic and recurrent condition, highlighting the role of T cells in recurrence. Traditionally, it was believed that T cells migrated between lymph nodes and skin during remission. However, recent research suggests that psoriatic lesions reoccur in the same areas, indicating a potential skin memory phenomenon. The speaker highlights the importance of skin-resident memory T cells in psoriasis, which were discovered through experiments involving the transplantation of T cells onto mice. These memory T cells, which outnumber blood T cells, play a critical role in psoriasis development. CD49 and other markers keep these cells in the skin, and blocking CD49 prevents lesion formation, confirming the importance of skin-resident memory T cells. Even after treatment and clinical remission, residual memory T cells persist in the skin. These cells activate and multiply locally upon a trigger, recruiting more T cells from circulation and causing lesion recurrence. The speaker explores disease modification in psoriasis treatment, focusing on influencing or reversing disease memory to alter its course. A randomized withdrawal trial showed that 50% of the patients who continued guselkumab treatment maintained a PASI-90 response, persisting for up to six months following their last injection. Patients with complete clearance also sustain their response. Early intervention (less than two years of disease duration) predicts better treatment outcomes and the potential for maintaining a response without continuous therapy. IL-23 blockade may eliminate skin memory T cells, especially in non-lesional areas, due to IL-23 receptor expression. Potential removal mechanisms include antibody-dependent cell-mediated cytotoxicity and indirect T-cell elimination due to reduced IL-23 stimulation. A study shows IL-23 is vital for skin memory T cell growth in psoriasis. IL-23 treatment reduces these T cells after around six months, improving outcomes.  Early intervention prevents the accumulation of IL17-producing TRM in previously unaffected, non-lesional psoriasis skin. Yet, eradicating them while inflamed is challenging, as they protect against infections. IL-23 blockade doesn't increase long-term infection risk. In psoriasis, the monocytes undergo epigenetic changes like histone acetylation and DNA methylation, resulting in a "trained" and "tolerized" state of memory immune cells, exhibiting heightened and dampened responses upon encountering a second stimulus, respectively. This memory also affects keratinocyte stem cells, leading to heightened responses upon re-stimulation. The "step-in study", emphasized that early intervention within the first year has better potential for modifying psoriasis, while intervening after five years is less effective in changing the disease's course. This year's analysis on psoriasis highlights that early treatment, particularly with secukinumab, can lead to sustained disease modification by reversing epigenetic changes. Normalization of gene expression takes longer for longstanding, chronic cases, and they retain epigenetic scars. This underscores the importance of early intervention for more effective outcomes and potential therapy cessation.