Use of IL-23 Inhibitors for the Treatment of Plaque Psoriasis and Psoriatic Arthritis

A Comprehensive Review

Kevin Yang; Allen S. W. Oak; Boni E. Elewski


Am J Clin Dermatol. 2021;22(2):173-192. 

In This Article

Abstract and Introduction


Psoriasis is a common inflammatory skin disease with multiple comorbidities, including psoriatic arthritis and coronary artery disease, that can severely impact an individual's quality of life and daily functioning. In recent years, enhanced understanding of the pathogenesis of psoriasis, especially the role of T helper 17 cells, has resulted in the development of new classes of biologic drugs targeting modulators along its disease pathway. Among these, inhibitors of interleukin-23 (e.g., ustekinumab, guselkumab, tildrakizumab, and risankizumab) have emerged as safe and effective options for the treatment of moderate-to-severe plaque psoriasis; ustekinumab and guselkumab have additionally been approved to treat psoriatic arthritis. Selective interleukin-23 inhibitors require less frequent dosing than interleukin-17 inhibitors and may possess a more favorable risk profile without an increased risk of candidiasis or inflammatory bowel disease. Overall, these highly effective medications are contributing to a rising standard for psoriasis outcomes through resolution of skin lesions and joint manifestations and improvement of patient quality of life.


Psoriasis is a chronic inflammatory disease affecting over 7 million people in the USA with an estimated annual financial burden of over US$112 billion.[1,2] Plaque psoriasis is the most common subtype and classically manifests as erythematous plaques with an overlying micaceous silvery scale on the trunk and extensor surfaces of the extremities; less common subtypes include inverse, guttate, and pustular.[3,4] Nail lesions, such as pitting and onycholysis, may also be seen. Psoriasis is also associated with multiple comorbidities, including cardiovascular disease, metabolic syndrome, psychiatric conditions, malignancy, renal disease, and hepatic disease.[5]

Psoriatic arthritis (PsA) is an inflammatory arthritis that may co-occur in up to a third of patients with psoriasis.[6] Psoriatic arthritis clinically presents with dactylitis, as well as enthesitis of the plantar fascia and Achilles tendon.[7] Psoriatic arthritis usually arises approximately 10 years after the onset of psoriatic lesions. However, it may precede the skin findings in 15% of cases.[7] Psoriatic arthritis may be difficult to distinguish from other inflammatory arthritides, but the morbidity of the disease warrants a low threshold for initiation of therapy.

The pathogenesis of psoriasis stems from dysregulation of the immune system, resulting in chronic inflammation and uncontrolled keratinocyte proliferation. Early studies demonstrated the presence and potential interaction of dendritic cells and T lymphocytes in psoriatic lesions.[8,9] Originally, T helper 1 cells, activated by dendritic cell-produced interleukin (IL)-12, were implicated in psoriasis via production of tumor necrosis factor-α (TNF-α) and interferon-γ; however, these cytokines showed no involvement in regulating keratinocyte proliferation.[10–12] Subsequently, the subset of T helper cells known as T helper 17 (Th17) cells and its production of IL-17 and IL-22 were identified to be central in driving psoriasis.[13–17] In particular, keratinocytes are stimulated to increase chemokine expression that perpetuates recruitment of Th17 cells.[18,19] Upstream of this key component, dendritic cells produce IL-23 to promote differentiation and proliferation of the Th17 cells.[20,21] Interestingly, a novel study reporting single-cell RNA sequencing of psoriatic human epidermis identified elevated populations of proliferative and ion channel genes. In addition, psoriatic epidermis was also found to be enriched for CD1C+CD301A+ myeloid dendritic cells.[22] Similarly, Th17 cells have been heavily associated with the pathogenesis of PsA.[23,24] While incompletely understood, PsA is generally thought to result from migration of dendritic cells out of the skin into the joint space, resulting in chronic inflammation in the synovial fluid.[25,26] Further, IL-22 plays a role in upregulating RANKL to induce osteoclast formation, bone erosion, and new bone formation.[27,28]

Treatment of psoriasis has traditionally focused on suppressing the immune system and keratinocyte proliferation, such as with methotrexate, cyclosporine, and acitretin. With elucidation of the immunological processes underlying psoriasis, biologic drugs have rapidly come to the forefront for targeting of modulators along these pathways, including TNF-α, IL-17, and IL-23. In the last 5 years, seven biologic drugs have been approved by the US Food and Drug Administration (FDA) to treat plaque psoriasis (Table 1). Ustekinumab, approved by the FDA in 2009, targets the p40 subunit shared by IL-23 and IL-12. We include ustekinumab in this review because it is partially an IL-23 inhibitor.

Guselkumab, tildrakizumab, and risankizumab have been approved in the last 3 years with targeting of the p19 subunit of IL-23 (Table 2). At the time of this writing, mirikizumab remains under development. This review evaluates the efficacy and safety of IL-23 inhibitors in the treatment of plaque psoriasis and psoriatic arthritis.