Psoriasis mechanism of disease: Insights on treatment options

In this installment of Discourses in Dermatology, Dr Jason Hawkes, a medical dermatologist in the greater Sacramento area, sits down with Dr George Han, associate professor and director of clinical trials in the department of Dermatology at the Donald and Barbara Zucker School of Medicine at Hofstra Northwell, to discuss insights on treatment options for psoriasis.

Biologics vs historic systemic immunosuppressants

Dr Hawkes begins the discussion by asking Dr Han to highlight the primary role of biologics and their advantages compared to systemic immunosuppressants that have been used historically.

Dr Han remarks that our understanding of the immunology of psoriasis has grown significantly over time, and in some cases after medications have been developed. It was initially believed that IL-12 was more important than IL-23 in psoriasis while it was later demonstrated that the inverse is true, with some animal studies showing IL-12 inhibition may actually negatively impact psoriasis treatment.

He continues to comment on the ability of biologics to specifically target individual cytokines and antibodies very precisely in the body compared with the ability of small molecules, which target a few amino acid sequence differences among different receptors and cannot be as selective. Patients are often uncomfortable with biologics, wondering why they must inject themselves when they can take a pill that would be much less invasive. He explains that with small molecules, sacrifices must be made because more of the immune system is being blocked; there are more risks to inhibiting a large amount of things as opposed to specifically blocking a cytokine that’s involved in the pathogenesis of psoriasis with a targeted medication.

Dr Han links this idea to TNF alpha inhibitors, which have been in use for almost 20 years. TNF alpha is a cytokine involved in a broad array of immune-mediated diseases; as a result, some of these medications have many indications as they’re ubiquitous across a large number of disease states. However, they block more of the immune system, thus leading to more contraindications. He compares this with the newer classes of biologics now available for psoriasis, which target cytokines like IL-23 and IL-17 that are specific to psoriasis. 

He goes on to explain how he counsels patients who are fearful about negative effects of biologics. He advises them that there are individuals who are born genetically without IL-17 who lead normal lives and may simply be more prone to minor fungal infections, which he finds helps his patients contextualize the effects of taking a biologic.

Key points

• Biologics can target individual cytokines and antibodies precisely in the body
• Small molecules cannot be as selective, thus leading to increased risk as a result of hampered immune systems
• Contextualizing the effects of taking a biologic may help patients who are concerned about taking these medications

Addressing safety concerns around biologics

Dr Hawkes responds to Dr Han’s commentary by reiterating that historical agents used in psoriasis were broad-acting immunosuppressants that worked because they hampered most of the immune system. While they are effective in controlling psoriasis, they come at the cost of collateral damage to the patient.

He believes this has created a paradox when it comes to payers that push strongly to use these broad-acting medications. This tendency communicates indirectly to patients and providers that the newer targeted agents may not be as safe as the older oral medications, and he sees hesitancy to use the newer agents because they’re not traditional but rather are unique molecules created in a lab. He asks Dr Han how he addresses this attitude when it comes to the safety of biologics.

Dr Han confirms that there is a lot of apprehension surrounding biologics, which he posits may come from poorly designed or older studies. However, most of these medications, while newer, now have 3- to 5-year data available. They’re also evolutions of older medicines, which means they’re often more narrowly focused. He adds that IL-12 and IL-23 inhibition emerged in 2009, so there is actually a long track record of targeting these mechanisms.

He recounts recently seeing a patient on etanercept and methotrexate prescribed by their rheumatologist and notes that rheumatologists are often very comfortable with methotrexate. However, he explains that the risk of liver damage and liver fibrosis from methotrexate is different for patients with rheumatoid arthritis than it is for patients with psoriasis. He recounts a study that demonstrated the highest risk was seen in patients with psoriasis, followed by those with psoriatic arthritis, and lastly, those with rheumatoid arthritis.

He feels this demonstrates the importance of communicating with patients that we don’t need to rely on these medications when we have better, more targeted tools available. However, he acknowledges that when it comes to medical economics, there are often different pressures at play.

Key points

• A push from payers to prescribe broad-acting medications may lead to hesitancy in using newer biologic agents
• Most biologics now have 3- to 5-year safety data available 
• Biologics are evolutions of older medicines, which means they’re often more narrowly focused
• Proper counseling of patients is important when it comes to explaining the benefits of biologics

Weighing the benefits of targeted therapies

Dr Hawkes continues the conversation by asking Dr Han if there are clinical scenarios in which these narrowly targeted medications may be problematic when compared to using medications with a broader impact and what may drive him to select a broader-acting biologic over a highly selective one.

Dr Han highlights the sequential development from TNF alpha to IL-17 A and IL-23 inhibitors, noting the increasing effectiveness observed on the skin. Despite achieving high levels of clearance, he emphasizes that no medication is 100% effective all the time, leaving room for improvement in efficacy.

The conversation then shifts to the importance of treating patients to target, aiming for maximum clearance with biologics. Dr Han acknowledges the need for enhancement in efficacy and considers the trade-offs in targeting specific conditions. For instance, IL-23 inhibitors may be effective for psoriasis but might not be the optimal choice for psoriatic arthritis, which is better addressed by TNF alpha and IL-17 inhibitors according to guidelines.

He then delves into the challenges in rheumatology, particularly in assessing joint conditions. Unlike the straightforward evaluation of skin psoriasis with PASI scores, assessing the joints is more complex, and the differentiation between medications becomes more challenging. 

He recalls case reports when ustekinumab came out that showed patients exhibiting unmasking of psoriatic arthritis. He posits what was likely happening was that patients on TNF alpha inhibitors were getting good control of their psoriatic arthritis, but not their skin. When they switched medications, their skin may have improved, but at the cost of pulling efficacy from the joint. He remarks that a clinical scenario like that may drive towards one treatment versus another.

Dr Han goes on to discuss the IL-17 family and considerations about different isoforms, emphasizing the significance of a holistic approach now that we can differentiate and target different aspects of IL-17. He concludes by expressing interest in how these developments will impact clinical practice.

To close the discussion, Dr Hawkes reflects on the implications of a skin bias that emerges as a result of skin being accessible. He acknowledges the challenge of making assumptions and extrapolations about joint health based solely on skin findings. He comments that that the immune environment in joints might differ, requiring a broader suppression of the immune system for patients with psoriatic arthritis.

He concludes by remarking on the need to learn more about the nuances of psoriatic disease and assess selective therapies to balance the benefits and disadvantages of being too broad or too narrow in treatment approaches.

Key points

• Some clinical scenarios may benefit from the use of a broader-acting biologic over a highly selective one
• Patients with psoriatic arthritis may require a more nuanced approach to treatment selection