Guselkumab Effective in Treating Enthesitis in Psoriatic Arthritis


Patients with psoriatic arthritis (PsA) treated with guselkumab resulted in higher percentages of resolved enthesitis by Week 24 and maintained those results through 1 year when compared with a placebo.

Treatment of psoriatic arthritis (PsA) with guselkumab, a selective interleukin-23p19-subunit inhibitor, resulted in higher percentages of resolved enthesitis by Week 24 and maintained those results through 1 year when compared with a placebo, according to a study published in Oxford.1

Enthesitis, an inflammation of tendon, ligament, or joint capsule insertion sites to bone, is present in up to 54% of patients with PsA. As it correlates to disease burden, impaired physical function, lower quality of life, and more active psoriatic arthritis, investigators theorized that being able to resolve this symptom may improve patient outcomes.

“Enthesitis is not only a hallmark of PsA, but may also be a progenitor of the structural joint damage seen in patients with PsA,” explain investigators. “Specifically, biomechanical stress is proposed to trigger the release of cytokines into the synovio-entheseal complex based on a popular model, which then induce an articular inflammatory response.”

Both tumor necrosis factor inhibitors (TNFi) and antibodies to interleukin (IL)-17 or IL-12/23 have been shown to be effective treatment methods for enthesitis. Therefore, biologic therapy is recommended. Guselkumab, a high-affinity, human, anti-IL-23p19-subunit monoclonal antibody, has been previously approved to treat moderate-to-severe PsA.

In these multicenter, randomized, double-blind, placebo-controlled, Phase 3 studies, DISCOVER-1 (NCT03162796) and DISCOVER-2 (NCT03158285), investigators analyzed the use of guselkumab in adults with active PsA despite standard therapies. Standard therapies included conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs), apremilast, and NSAIDs. Investigators examined the efficacy of guselkumab for both preventing and resolving enthesitis, as well as enthesitis at baseline and resolution at 1 year.

In the DISCOVER-1 study, 381 patients exhibited ≥3 tender and ≥3 swollen joints as well as C-reactive protein (CRP) ≥0.3 mg/dL. Approximately 30% of patients were allowed to have taken 1 or 2 TNFi in the past. In the DISCOVER-2 study, investigators examined 739 biologic-naïve patients with ≥5 tender and ≥5 swollen joints and CRP ≥0.6 mg/dL. During the studies, patients were able to continue standard treatments such as NSAIDs, oral corticosteroids, 1 csDMARD, sulfasalazine, hydroxychloroquine, or leflunomide. Eligible participants were screened for laboratory assessments as well as tuberculosis history, testing, and treatment. Additionally, enthesitis was present in 65% of participants.

Patients were randomized into 3 groups and treated with either subcutaneous guselkumab 100mg every 4 weeks (Q4W), guselkumab 100mg at Week 0, Week 4, and then every 8 weeks (Q8W), or initially placebo followed by guselkumab 100mg Q4W at Week 24 (Placebo→Q4W). Participants received treatment through Week 48 in DISCOVER-1, and through Week 100 in DISCOVER-2. Efficacy was examined through Week 52. Baseline demographics and disease characteristics were similar among all groups.

The Leeds Enthesitis Index (LEI) was used to assess enthesitis during both studies. The LEI tool is used to document the absence (0) or presence (1) of entheses in patients with PsA. Investigators evaluated changes in tender LEI sites at baseline and those with enthesitis resolution at Week 24. Patients also evaluated their pain levels based on a 0-10 cm visual analog scale (VAS), a global impression of disease activity, and physical function. Severity of skin disease fell into 4 categories: cleared (0), minimal (1), mild (2), moderate (3), and severe (4). Body surface area affected and severity of symptoms were graded on a scale of 0-4, with 0 meaning none.

Patients significantly resolved enthesitis at Week 24 in the guselkumab groups. Resolution was achieved in 45% (109/243) of participants in the Q4W group and 50% (114/230) in the Q8W group, compared with only 29% (75/255) in the placebo groups. This was maintained through Week 52 in both Q4W and Q8W groups, with 58% reaching resolution and a 64% improvement in LEI entheseal counts (ECs) from baseline. Further, most participants without enthesitis at baseline did not acquire the condition through Week 52: Q4W (89%), Q8W (92%), and placebo groups (81%). At Week 52, 83-87% of patients without enthesitis at baseline who received guselkumab did not develop enthesitis.

“While this suggests that guselkumab may inhibit the development of enthesitis, it may also be due to inherent patient and disease differences between those with and without enthesitis,” warn investigators. “However, as noted, guselkumab was similarly effective in improving joint signs and symptoms, psoriasis, physical function, and physical aspect of Health-related quality of life (HRQoL) in patients with or without enthesitis.”

At baseline, 728 (65%) of DISCOVER-1 and DISCOVER-2 participants had enthesitis, which included 243 patients in the Q4W cohort, 230 in the Q8W cohort, and 255 in the Placebo→Q4W cohort. Of the patients with enthesitis, there were a higher percentage of females, patients with BMI ≥30, more active disease activity, and a longer duration of PsA.

The main limitation to the study is the lack of an active comparator, meaning investigators were not able to determine if targeting the IL-23p19-subunit is superior to inhibition of TNF and IL-17 in treating PsA.

“While patients with more severe enthesitis had lower rates of resolution, the efficacy of guselkumab in improving other disease domains was consistent across patients with or without enthesitis at baseline,” concluded investigators. “The patients with the most severe disease as determined by higher overall LEI scores tended to be female and have a higher BMI, longer disease duration, and normal CRP, potentially pointing towards mechanical factors and chronic pain contributing to entheseal area tenderness that may not be modifiable with biological therapy. This is an important area for further research for appropriate therapy initiation and understanding underlying mechanisms associated with treatment response.”


McGonagle D, McInnes IB, Deodhar A, et al. Resolution of Enthesitis by Guselkumab and Relationships to Disease Burden: 1-Year Results of Two Phase-3 Psoriatic Arthritis Studies [published online ahead of print, 2021 Apr 6]. Rheumatology (Oxford). 2021;keab285. doi:10.1093/rheumatology/keab285

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