Guselkumab Improves Skin Disease Activity, Baseline Arthritis in TNF-IR PsA

In patients with psoriatic arthritis (PsA) and intolerance or inadequate response to tumor necrosis factor inhibitors (TNF-IR), guselkumab decreased levels of effector cytokines linked to the interleukin-23 (IL-23)/IL-17 pathway, according to a study published in Arthritis Research and Therapy.¹ These included those associated with baseline arthritis and skin symptoms.

Georg Schett, MD

Credit: Friedrich Alexander University Erlangen-Nürnberg

Although TNF are often prescribed for patients with inadequate response to conventional treatments, 40% of patients do not achieve a 20% improvement in the American College of Rheumatology criteria (ACR20) response at the 6-month mark. Additionally, previous research has shown the efficacy and persistence of treatment declines with additional TNF treatment.²

“Treatments targeting alternative pathways have been evaluated and shown to be efficacious in TNF-experienced patients, suggesting that this population may benefit from therapies with different mechanisms of action,” wrote Georg Schett, MD, Department of Internal Medicine 3, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Germany, and colleagues.

Guselkumab, a high-affinity, fully human monoclonal antibody IL-23 inhibitor, has demonstrated significant efficacy in patients with active PsA. In the phase 3b COSMOS trial specifically, the drug was further shown to effectively reduce disease signs and symptoms in patients with TNF-IR.³

Drawing from data from the COSMOS trial, 189 patients with TNF-IR PsA were randomized 2:1 to receive guselkumab at weeks 0, 4, then every 8 weeks (Q8W), or receive placebo before to guselkumab Q8W at week 24 (n = 96) with the possibility of early intervention at week 16. Of these participants, 100 patients in the guselkumab group and 50 in the placebo group were included in the biomarker cohort. Serum cytokines of interest included TNFα, interferon ɣ (IFNɣ), IL-10, IL-6, T helper 17 (Th17) effector cytokines IL-17A, IL-17F, and IL-22, and C-reactive protein (CRP). The aforementioned levels, as well as guselkumab pharmacodynamics, were then compared with matched healthy controls.

At week 24, investigators evaluated associations between baseline biomarker levels and baseline disease activity and clinical response. Disease activity was measured using the Psoriasis Area and Severity Index (PASI), 28-joint disease activity score using CRP (DAS28-CRP), and the percentage of body surface area (BSA) affected by psoriasis. Clinical response was determined through ACR20 response.

At baseline, the TNF-IR cohort had higher serum levels of IL-6, IL-17A, IL-17F, IL-22, IL-10, TNFα, and IFNɣ. Baseline CRP, serum amyloid A (SAA), and IL-6 were linked to baseline DAS28-CRP. Similarly, IL-17A and IL-17F levels were linked to both baseline PASI score and psoriasis BSA. However, swollen or tender joint counts at baseline were not associated with baseline biomarker levels.

For those in the biomarker cohort, 44% of patients receiving guselkumab achieved ACR20 response at week 24 compared with 20% in the placebo group (P <.01). Patients in the guselkumab cohort exhibiting higher baseline IL-22 and INFɣ were more likely to achieve ACR20 response compared with non-responders.

At the 24-week mark, patients receiving guselkumab had significant decreases in CRP, IL-17A, IL-17F, IL-22 and SAA levels compared with patients in the placebo cohort. IL-17F and IL-22 levels did not differ significantly in patients treated with guselkumab compared with matched health controls at week 24.

Investigators noted potential limitations including the incongruence between serum and tissue levels of cytokines and acute phase proteins. Evaluating tissue would deepen the knowledge of disease pathogenesis and potentially clarify the mechanism of action of guselkumab in the joints.

“These results provide further support for the important role of the IL-23/IL-17 pathway in PsA pathogenesis and expand our knowledge of guselkumab pharmacodynamic effects in patients with TNFi-IR PsA,” investigators concluded.

References

1. ^{Schett G, Chen W, Gao S, et al. Effect of guselkumab on serum biomarkers in patients with active psoriatic arthritis and inadequate response to tumor necrosis factor inhibitors: results from the COSMOS phase 3b study. Arthritis Res Ther. 2023;25(1):150. Published 2023 Aug 16. doi:10.1186/s13075-023-03125-4}
2. ^{Glintborg B, Ostergaard M, Krogh NS, Andersen MD, Tarp U, Loft AG, et al. Clinical response, drug survival, and predictors thereof among 548 patients with psoriatic arthritis who switched tumor necrosis factor alpha inhibitor therapy: results from the Danish Nationwide DANBIO Registry. Arthritis Rheum. 2013;65(5):1213–23.}
3. ^{Coates LC, Gossec L, Theander E, Bergmans P, Neuhold M, Karyekar CS, et al. Efficacy and safety of guselkumab in patients with active psoriatic arthritis who are inadequate responders to tumour necrosis factor inhibitors: results through one year of a phase IIIb, randomised, controlled study (COSMOS). Ann Rheum Dis. 2022;81(3):359–69.}