Viewpoint about biologic agents for psoriasis: are they immunosuppressants or immunomodulators?

Introduction

Psoriasis is a common chronic, systemic, immune-mediated disease with prominent skin and joint manifestations that is associated with several comorbidities, including cardiovascular disease, metabolic syndrome, and depression. ¹ Although the exact mechanism of the immune response and the etiology of the disease are not fully understood, many treatment options are available to manage this painful and often debilitating disease. The most promising management option for psoriasis is biologic therapy.

Advances in knowledge of the pathogenesis of psoriasis over the past 20 years have driven the development of highly effective targeted biologic therapies that modulate the immune system and control inflammation, thereby transforming the treatment landscape of psoriasis. ²

Twelve biologics are currently marketed for the management of psoriasis. These include tumor necrosis factor alpha (TNF-α) inhibitors (etanercept, adalimumab, infliximab, certolizumab pegol), interleukin (IL)-12/23 inhibitors (ustekinumab), IL-17 inhibitors (secukinumab, ixekizumab, brodalumab, bimekizumab), and IL-23 inhibitors (tildrakizumab, guselkumab, risankizumab). ¹ Contrary to conventional systemic therapies, namely cyclosporine, methotrexate, and dimethyl fumarate (DMF), which are associated with broad suppression of the immune system, cumulative organ toxicities, and potentially severe adverse effects, biologic agents are precise therapies that selectively target important mediators of psoriasis pathogenesis. For this reason, biologic agents might be used continuously with favorable long-term safety. ¹

Nevertheless, there is some confusion in the healthcare community regarding the classification of biologic agents used to treat psoriasis as immunosuppressants or immunomodulators. In our opinion, these biologic agents should be categorized as immunomodulators instead of their common categorization as immunosuppressants (which include drugs such as methotrexate, cyclosporine, DMF, and azathioprine). This narrative review aimed to define biologic agents used to treat psoriasis as immunomodulators.

Search Strategy

The search terms were as follows: immunosuppression, immunomodulation, psoriasis, biologics, methotrexate, cyclosporine, immune system, TNF-α inhibitors, etanercept, adalimumab, infliximab, certolizumab pegol, IL-12/23 inhibitors, ustekinumab, IL-17 inhibitors, secukinumab, ixekizumab, brodalumab, bimekizumab, IL-23 inhibitors, tildrakizumab, guselkumab, risankizumab, Pharmacokinetics, intraindividual variability, interindividual variability, intracellular, extracellular, and safety profile. The search was performed using NCBI, PubMed, and JAMA.

Differentiating immunomodulators from immunosuppressants

Immunosuppressants comprise a class of drugs used to suppress cell-mediated and humoral immune responses. These agents increase the susceptibility to infection and cancer. However, immunomodulators comprise a class of drugs that target and modify the immune system through both activation and suppression of specific cellular pathways. The current literature distinguishes immunomodulators from immunosuppressants using two main criteria.

Immunosuppressive agents used to treat psoriasis exert their pharmacological effects by targeting intracellular pathways and inhibiting multiple components of the immune response simultaneously. ³ For example, cyclosporine, a classical immunosuppressant, enters the cytoplasm of T cells and binds to cyclophilin, forming a cyclosporine/cyclophilin complex that prevents the calcineurin-mediated de-phosphorylation of nuclear factor of activated T cells and transcription of cytokine genes, including IL-2 and IL-4. The pharmacological mechanism of action of cyclosporine highlights how immunosuppressants target intracellular pathways and illustrates their broad inhibitory effects on many downstream effectors and pathways involved in producing an immune response. Another example is methotrexate, which acts as an anti-inflammatory agent and immunosuppressant by reducing T cell activation as well as other non-specific components of the immune system. ⁴ Conversely, biologics used to treat psoriasis work by regulating extracellular pathways in a targeted manner, thereby modulating targeted extracellular pathways involving cytokines such as TNF-α, IL-23, IL-12/23, IL-17RA, and IL-17A. In contrast to immunosuppressants, biologics do not induce extensive inhibition of the immune response as extracellular cytokines, nor are their receptors solely targeted. Second, immunomodulators can be distinguished from immunosuppressants through their differing pharmacokinetics. Specifically, immunosuppressive agents display significant intra- and interindividual variability, whereas immunomodulators exhibit more predictable and less individually variable pharmacokinetic properties. ⁵ Again, cyclosporine, a classic example of a powerful immunosuppressant has historically been highly variable in intra- and interindividual pharmacokinetic parameters such as absorbance and clearance, making its use in renal transplant patients often challenging. ⁶ Biologics like certolizumab, bimekizumab, risankizumab, adalimumab, and brodalumab have no significant variation in their pharmacokinetics amongst different patients, making their pharmacokinetics highly predictable. ⁷ Biologics such as guselkumab, ixekizumab, ustekinumab, infliximab, tildrakizumab, and etanercept have different pharmacokinetic parameters (such as clearance rate) based on the age, weight, or comorbidities of patients. ⁷ However, when these factors are considered, the pharmacokinetics of these biologics are predictable and invariable among individuals within the same cohort (e.g., patients taking guselkumab display linear pharmacokinetics within the same body weight cohort). Therefore, the pharmacokinetics of biologic agents used to treat psoriasis are predictable, especially when a patient’s weight, age, and comorbidities are considered. Thus, this definition also classifies biologics used for psoriasis as immunomodulators opposed to immunosuppressants because these biologic agents display limited individual pharmacokinetics variability. It is worth noting that the pharmacokinetic variability of these biologic agents have not been studied in patients with renal or hepatic impairments, and special considerations regarding pharmacokinetic variability could exist in patients with specific anti-biologic antibodies. ⁷

Clinical implications of proper biologic drug class categorization

The distinction between biologics being immunomodulators or immunosuppressants is important because patients and physicians need to be aware that biologics do not increase the risk of severe immunosuppression and susceptibility to serious infection and cancer. Although biologics have a well-known safety profile, patients have frequently expressed reservations regarding the use of biologic therapy because of a multitude of reasons including fear and anxiety regarding possible immunosuppressive side effects. ⁸ Consequently, the healthcare community must be proactive in properly categorizing and separating biologics from classic immunosuppressants to increase patients’ willingness to adhere to biologic treatments that are likely to improve their health. Distinguishing immunosuppressants from immunomodulators could prompt patients using biologics to ask for more information regarding risks and to be more receptive to clinical evidence. Although the risk of serious infection is possible following biologic therapy, this is associated with the modulation of specific pathways by biologics opposed to systemic immunosuppression. This is the case for TNF inhibition and potential tuberculosis reactivation. It is also the case for IL-17 inhibition during treatment with biologics such as secukinumab, ixekizumab, brodalumab, and bimekizumab, which also increase the risk of mucocutaneous Candida infection because of the important role of IL-17 in protective antifungal immunity. ⁹

Conclusion

Classifying the 12 biologic agents currently marketed for the treatment of psoriasis as immunomodulators based on their extracellular location of action and low pharmacokinetic variability is important for enhancing patient and physician understanding of the risks associated with these agents. Although more robust methods of classifying biologic agents based on their risks might be possible in the future, as we begin to depart from the peak of the COVID-19 pandemic, it is important to classify them as immunomodulators, a drug categorization less harmful and separate from immunosuppressants.