Guselkumab resolves enthesitis in most PsA patients

Treatment with the selective interleukin (IL)-23 inhibitor guselkumab results in the clearance of enthesitis for many psoriatic arthritis (PsA) patients, with the resolution maintained through month 12, as shown by pooled data from two phase III trials.

At week 24, resolution rates were markedly different between the guselkumab and placebo groups, in favour of the former, according to a team of investigators led by Dr Dennis McGonagle of the Leeds Biomedical Research Centre, University of Leeds in the UK. 

“Enthesitis resolution was associated with achieving important patient outcomes,” McGonagle said.

Even though patients with more severe inflammation of the entheses had lower rates of resolution, he noted, the beneficial effect of guselkumab on other disease domains was consistent and independent of the presence of enthesitis at baseline.

McGonagle and colleagues synthesized data from 381 patients who have or have not previously taken one or more tumour necrosis factor inhibitors (TNFis; DISCOVER-1) and from 739 biologic-naïve patients (DISCOVER-2). Participants had been assigned to treatment with guselkumab 100 mg every 4 weeks (Q4W) or every 8 weeks (Q8W) or placebo. After 24 weeks, those on placebo switched to guselkumab 100 mg every 4 weeks.

More than half (65 percent) of the overall population had enthesitis, which was assessed using Leeds Enthesitis Index (LEI), at baseline. They exhibited slightly more swollen and tender joints, systemic inflammation, and impaired physical function than patients without enthesitis.

Guselkumab Q4W and Q8W performed better than placebo at clearing pre-existing enthesitis at week 24, with the respective resolution rates of 45 percent, 50 percent, and 29 percent (p=0.0301 for both comparisons). [Rheumatology 2021;doi:10.1093/rheumatology/keab285]

Enthesitis resolution rates continued to rise through week 52, where 58 percent of guselkumab-treated patients combined achieved resolution. These included patients with mild (LEI=1; 70–75 percent), moderate (LEI=2; 69–73 percent), or severe (LEI=3–6; 42–44 percent) enthesitis at baseline.

As previously pointed out, a lot more patients with resolved enthesitis on guselkumab at week 24 achieved minimal disease activity at week 52 as opposed to those with unresolved enthesitis (42 percent vs 17 percent).

The efficacy of biologics approved for PsA in treating enthesitis have been shown in previous studies, although it is difficult to compare due to differences in study designs, measurement tools, and data analyses, according to McGonagle.

“Based on the central role of IL-23 in enthesitis, it is not surprising that results of comparative studies of PsA patients with enthesitis showed both ustekinumab (anti-IL-12/23 agent) and ixekizumab (anti-IL-17 agent acting downstream of IL-23) to be more effective than a TNFi in treating enthesitis,” he said. [Ann Rheum Dis 2017;76:79-87; Semin Arthritis Rheum 2019;48:632-637]

“These limited active comparator data, together with the findings reported here and those recently reported for anti-IL-17 agents, support the central role of the IL-23 and IL-17 pathways in PsA enthesitis pathogenesis and may inform treatment choices for PsA patients with enthesitis,” the investigator added. [Arthritis Res Ther 2019;21:38; Arthritis Res Ther 2019;21:266]

McGonagle highlighted the importance of effectively treating the key PsA manifestation, saying that enthesitis may also be a progenitor of the structural joint damage seen in PsA. “Indeed, the presence and extent of enthesitis have demonstrated positive associations with greater peripheral and axial joint damage, impaired quality of life and function, sleep disturbance, and patient-reported pain.” [Semin Arthritis Rheum 2018;48:35-43; Arthritis Care Res 2017;69:1685-1691; Int J Rheum Dis 2017;20:1212-1218; Arthritis Care Res 2017;69:1692-1699]

Additional studies are warranted, especially those investigating whether targeting the IL-23 p19-subunit is superior to inhibition of TNF and IL-17 in treating PsA patients with enthesitis, according to the investigator.