Interleukin Targeted Therapies for Psoriatic Arthritis

Psoriatic arthritis (PsA) can lead to reduced quality of life and significant morbidity. Treatment often requires tumor necrosis factor (TNF) antagonists; however, not all patients respond fully to these agents. Thus, research has focused on interleukin-17 (IL-17) and IL-17 receptor (IL-17R) targeted therapies as treatment options for PsA.

Wang and colleagues¹ at the University of California Davis School of Medicine reviewed the role of IL-17 and IL-17R in the pathogenesis of PsA, as well as the clinical evidence for IL-17 and IL-17R targeted therapeutics. They published their findings in the European Journal of Rheumatology.

Roles of IL-17 and IL-17R in PsA
IL-17 plays multiple roles in the pathogenesis of PsA and psoriasis. "It is known to act on keratinocytes and synovial cells to produce pro-inflammatory mediators, bridging the innate and adaptive immune systems to sustain chronic inflammation," the researchers write.

At the clinical level, IL-17 has also been shown to correlate with disease activity as IL-17 and IL-17 producing cells have been found in the serum, psoriatic lesions, and within the synovial fluid of PsA patients. Furthermore, synovial fibroblasts isolated from PsA patients contain greater IL-17R expression than those from osteoarthritis (OA) patients.

IL-17 blockade for PsA
Various biologics that target either IL-17 or IL-17R are currently being studied to evaluate efficacy in psoriasis and PsA, including secukinumab, ixekizumab, and brodalumab. Each biologic medication has slightly different specificities targeting the IL-17 pathway.

Secukinumab is a fully human anti-IL-17A monoclonal antibody. In a phase III study, it was significantly more effective than placebo in improving the signs and symptoms of PsA, along with patient-reported physical functioning and quality of life. There was also a significant reduction in radiographic progression in the treatment group compared with the placebo group, as well as improvements in the severity of plaque and nail psoriasis. This biologic medication was the first anti-IL-17 based therapy to receive FDA approval for treatment of PsA in January 2016.

Ixekizumab is a humanized anti-IL-17A monoclonal antibody. It was studied in active PsA in a recent 24-week phase III trial (SPIRIT-P1), comparing subcutaneous ixekizumab to subcutaneous adalimumab or placebo in PsA patients who were naive to biologic DMARDs. Significantly more patients receiving ixekizumab achieved a greater ACR20 response as compared to placebo, and treatment also reduced radiographic progression of joint damage. This trial has been extended by 3 years to allow for longer-term assessment of safety and efficacy.

Brodalumab is a fully human IL-17R monoclonal antibody. It has been evaluated in PsA patients in a placebo-controlled phase II study. At week 12 of treatment, patients receiving brodalumab demonstrated significantly higher rates of improvement in ACR20 than the placebo group. While reports of suicidal thoughts and behavior were seen in some clinical trial patients taking the drug, a critical review of the trial data did not reveal a causal relationship between brodalumab use and suicidality. The FDA has since approved brodalumab for moderate to severe psoriasis with a Boxed Warning on suicidal ideation and behavior.

IL-23 blockade for PsA
Recent research on the IL-23/IL-17 axis has provided a better understanding of the pathogenesis of many types of inflammatory arthritis. A biologic blockade of IL-23, ustekinumab, has been well-studied in the setting of psoriasis but not extensively studied in the setting of PsA. A phase II trial showed improvement in ACR20 response rates for patients with PsA, as well as significant improvement in skin disease, enthesitis, dactylitis, and physical functioning. However, a higher dose was required to treat PsA than that used for treating psoriasis.

A phase III PSUMMIT 1 trial showed similar improvements in PsA patients who were anti-TNF-experienced. A PSUMMIT-2 phase III trial demonstrated that ustekinumab induces long-term significant improvement in the joint, enthesitis/dactylitis, and skin symptoms of active PsA. These findings supported FDA approval of this biologic medication for the treatment of active PsA as of September 2013.

Disclosures:

The authors declared that this study has received no financial support.

References:

1. Wang EA, Suzuki E, Maverakis E, Adamopoulos IE. Targeting IL-17 in psoriatic arthritis. Eur J Rheumatol. Published online Nov. 10, 2017. DOI: 10.5152.eurjrheum.2017.17037