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Options With IL-23 Inhibitors for the Patient With Psoriasis

Options With IL-23 Inhibitors for the Patient With Psoriasis

New and emerging therapies such as biologics continue to improve quality of life and outcomes for patients with psoriasis. Biologics that block IL-23 functions present a unique opportunity to provide long-term, effective treatment.


Though the exact causes are still unknown, psoriasis has been linked to the immune system and genetics.1 Traditional oral systemic medications, such as cyclosporine, methotrexate, and acitretin (Soriatane), target the whole immune system or work to decrease keratinocyte hyperproliferation,2 but some patients do not respond to these treatments or seek a treatment that requires less frequent administration. Similarly, while generally effective,3 phototherapies are time-consuming, can be ineffective for some patients, and require frequent visits to the dermatology office. In addition, topical treatments can slow down excessive cellular reproduction and reduce inflammation,4 but these do not necessarily address an underlying cause for the cutaneous symptoms.

Among the newer therapies available for this immune-mediated disease are biologics, large molecular-weight proteins that target specific components of the immune system. Tumor necrosis factors (TNFs; cell-signaling cytokine involved in inflammation) and interleukins (ILs; leukocyte-produced glycoproteins that regulate immune response) are secretions by dendritic cells and macrophages (eg, IL-12, IL-23) that activate T helper (TH) cells and have an active role in controlling the immune response.5,6 Elevated levels of TNF-α and IL-12 have been expressed in psoriatic lesions,7,8 prompting the introduction of biologic therapies that target those particular components and categorizing psoriasis as a TH1-mediated disease.9 The earliest TNF blocker still available in the market is etanercept (Enbrel), and the earliest IL inhibitor is ustekinumab (Stelara).10 

Ustekinumab was identified as a potential therapy for psoriatic disease and focused on IL-12, a driving factor in TH1 differentiation. IL-12 is a heterodimer composed of a p40 and p35 subunit. Research showed that the p40 subunit of IL-12 also paired with a unique p19 subunit. This new, additional cytokine was classified as IL-23,11 and it was later discovered to play a more central role in psoriasis than IL-12.9 Thus, research shifted from the inhibition of IL-12 to IL-23.

Interestingly, IL-23 regulates TH17 cells, which produce various cytokines including IL-17, the major effector cytokine in psoriatic disease.12 IL-17 production subsequently leads to the proliferation and differentiation of keratinocytes, which then produce proinflammatory cytokines and chemokines.12-14 This cascade shapes the inflammatory response, presumably causing the classic presentation of psoriatic disease. In addition, these inflammatory pathways have been demonstrated in common comorbidities of psoriasis, including cardiovascular disease and obesity.13-17

Several IL-17 inhibitors have been approved by the FDA and are currently available in the market, including brodalumab (Siliq), ixekizumab (Taltz), and secukinumab (Cosentyx).10,18 These therapies have proven incredibly effective in treating the spectrum of psoriatic disease, particularly with a rapid onset of action.19 In addition, secukinumab and ixekizumab are approved for the treatment of ankylosing spondylitis, another inflammatory disease.20 Though they are well tolerated overall, IL-17 inhibitors do display some adverse events, such as increased risk of infection (particularly mucocutaneous candidiasis), inflammatory bowel disease, and suicidal ideation and depression.10

Because of its ability to affect IL-17 production via IL-23 without blocking IL-17 activity, IL-23 inhibitor biologics (Table) may be advantageous in the treatment of psoriasis. These biologics may provide more efficacy, convenience, and safety than other biologics for certain populations of patients with psoriasis.

Table. Biologic therapies that inhibit IL-23

 

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