Speaker- Reinhart Speeckaert

In treating immune-mediated dermatological disorders, the standard approach has traditionally started with topicals, phototherapy, and antibiotics and eventually moved to systemic immunosuppressants. The method increases efficacy as treatment escalates but also has a higher risk of side effects. With the introduction of biologics, there is now a treatment option that offers high efficacy and fewer side effects. The primary challenge is their cost. Additionally, JAK inhibitors (JAKi) are emerging as a replacement for systemic immunosuppressants. These inhibitors are effective but carry slightly more side effects than biologics. However, cost remains a significant barrier to accessing optimal treatment. While biologics are reimbursed for certain skin disorders, broader coverage is needed for other conditions. The ongoing development of targeted treatments holds promise for the future. 

Understanding skin immunity is crucial to identify the most appropriate drug for a patient. For example, the T-helper (Th17) pathway should be considered in cases of hyperkeratosis. The immune response begins with the innate system, where cells attack and signal through mechanisms such as the inflammasome, chemokines, and cytokines. It then progresses to the adaptive immune response, where antigen-presenting cells introduce the antigen to the adaptive immune system. This progression ensures a coordinated and effective immune response.

In discussing the innate immune response, it's crucial to highlight the role of neutrophils, especially in conditions like psoriasis. Neutrophils, in high numbers (around 5 billion in the blood), are highly agile cells that quickly migrate into tissues. Despite their short lifespan, they play a pivotal role in autoimmunity, particularly by forming neutrophil extracellular traps (NETs). NETs are structures formed by neutrophils, consisting of chromatin wrapped with a high concentration of antimicrobial proteins. These nets are released into the extracellular environment to target pathogens. However, this process can also expose self-antigens, which can trigger autoimmune reactions. For instance, histones released during NET formation have been linked to lupus development. In patients receiving anti-tumor necrosis factor (anti-TNF) therapy, lupus may develop due to deregulated NETosis. Furthermore, autoantibodies such as anti-myeloperoxidase (anti-MPO) and anti-Proteinase 3 (anti-PR3), associated with vasculitis, can also arise from this process, illustrating the significant role of neutrophils and NETs in various autoimmune disorders. 

Cathelicidin LL-37 (LL37) is recognized as a key antigen in psoriasis, playing a significant role in NET formation. Though complex and often less discussed, the innate immune response is crucial in many skin conditions. Broad-acting treatments like steroids are effective because they target various innate immune cells. Additionally, conventional immunosuppressants, Phosphodiesterase 4 (PDE4) inhibitors, and Tyrosine Kinase 2 (TIK2) inhibitors impact the innate immune system. Specific treatments, such as Dapsone and some biologics, can target neutrophils and other innate cells, though the more comprehensible adaptive immune response often overshadows them. The adaptive immune system can be categorized into three main responses: TH1, which targets cancer cells and viruses; TH17, which defends against fungi and Candida; and TH2, which counters parasites. Overactive TH1 reactions can lead to conditions like vitiligo and alopecia areata, while an overactive TH17 pathway results in hyperkeratosis and pustules, as seen in psoriasis. An exaggerated TH2 response weakens the skin barrier, leading to atopic dermatitis. Understanding the roles of TH1, TH17, TH2, and follicular T helper cells (which stimulate B cells in blistering diseases) enables clinicians to choose treatments more effectively. With this knowledge, they can select more targeted therapies that offer fewer side effects, providing improved outcomes for patients with various skin conditions. 

In psoriasis, the TH17 pathway is a key player. Conventional immunosuppressants, while broad-acting, are less effective and come with more side effects. More targeted options, like PDE4 and TYK2 inhibitors, focus on the TH17 pathway, offering better safety but still falling short of the effectiveness seen with biologics. Biologics directly target the TH17 pathway, specifically the interleukin17 (IL-17) cytokine family. Among these, IL-17A and IL-17F have similar functions, though IL-17F is weaker. IL-17C and IL-17E intersect the TH17 and TH2 pathways, connecting psoriasis to conditions like asthma or allergic rhinitis. The therapeutic landscape includes TNF blockers, which only work effectively when the TH17 pathway is downregulated. The realization led to more targeted treatments, like IL-17A blockers, IL-17AF blockers (like bimekizumab), and IL-17 receptor blockers. IL-23 blockers, meanwhile, act by preventing the differentiation and maintenance of helper TH17 cells. The key difference between IL-17 and IL-23 blockers is their effects on the bowel and joints. IL-17 is produced by innate immune cells, such as gamma delta T cells and type 3 innate lymphoid cells, independent of IL-23, particularly in the intestine and synovial tissue. It explains why IL-17 blockers can sometimes trigger inflammatory bowel disease while IL-23 blockers do not. IL-17 is also crucial for defending against Candida and maintaining bowel mucosa integrity, distinguishing its role from IL-23. 

In rheumatology, especially concerning axial spondyloarthritis, IL-17 blockade has proven effective, whereas IL-23 inhibitors have not shown the same efficacy. However, the situation regarding axial psoriatic arthritis is less clear. While the conditions share similarities with spondyloarthritis, early studies suggest that IL-23 blockers may also work in axial psoriatic arthritis, though more research is needed to confirm this. This is a relatively new development in recent years.

Immunology remains a complex and often challenging field due to the intricate web of driving and inhibiting cytokines, which can lead to paradoxical effects or immune shifts. For example, transforming growth factor beta (TGF-β) and IL-4 inhibit interferon-gamma (IFN-γ), but when present together, they neutralize each other rather than inhibiting IFN-γ. This dynamic helps explain why certain drugs, such as dupilumab, can trigger paradoxical reactions like alopecia areata, yet in patients with high IgE levels; the condition might improve. Selecting the right drug for a patient becomes even more complicated without a precise understanding of their immune profile. The feedback mechanisms within cytokine pathways further complicate this process, as early cytokines like TNF can influence the entire immune response. The concept of upstream and downstream cytokine targeting holds some truth—upstream interventions tend to act slower, last longer, and cause fewer side effects due to redundancy. In comparison, downstream actions work faster but may lead to more side effects. For instance, bimekizumab, an IL-17AF inhibitor, reduces IL-17A, IL-17F, and even IL-23, illustrating how the immune system operates as both a hierarchy and a feedback loop. Whether you visualize it as an inflammatory "tower" or "loop," disrupting a key cytokine can lead to the collapse of the inflammatory process.

When choosing the right drug for the right patient, several factors must be considered, including age, disease severity, comorbidities, treatment history, and other autoimmune conditions. Studies have been conducted, including work published by the Belgian group, outlining treatment strategies for comorbidities. For instance, in cases of inflammatory bowel disease, IL-17 blockers should be avoided. In patients with Human immunodeficiency syndrome (HIV), careful consideration is needed, especially if the disease is active. However, most treatments (except certain conventional immunosuppressants) can be used when the virus is controlled. Screening for tuberculosis (TB) and demyelinating diseases is crucial for anti-TNF therapies. The use of cyclosporine is limited due to the increased cancer risk.

The living EuroGuiDerm guidelines are highly regarded for their annual updates and comprehensive information. In psoriatic arthritis, methotrexate is typically the first-line conventional systemic agent. For Crohn's disease, acitretin may be considered as it does not affect the immune system. In patients with heart failure, cyclosporine should be avoided, and immunosuppression is contraindicated for TB. During pregnancy, both acitretin and methotrexate are not recommended. When discussing biologics and small molecules, the guidelines include a table that outlines the appropriate medications for inflammatory bowel disease (IBD). Consultation with a gastroenterologist is essential when selecting first-line treatments for IBD, and anti-TNF agents should be avoided in heart failure patients. 

Looking ahead, memory T cells play a significant role in skin diseases like psoriasis and vitiligo. Rapid and aggressive treatment is crucial for patients who respond quickly, as they may achieve remission. Future therapies may directly target these memory T cells. There is enthusiasm surrounding bispecific antibodies and small molecules that target two distinct pathways—one for the immune system and another that is location-specific. For example, an anti-desmoglein antibody that targets keratinocytes, combined with an interferon-gamma inhibitor, allows for localized immune modulation. Numerous treatment options are being presented at this congress, with varying degrees of potential success. Selecting the right drug for each patient requires careful consideration of factors such as drug efficacy, disease severity, patient profile, memory response, and comorbidities. Relevant publications can serve as valuable resources for informed decision-making. 

33, European Academy of Dermatology and Venereology Congress, 25-28 September 2024, Amsterdam