The year 2021 saw additional advances and refinements in the treatment of psoriatic arthritis (PsA), a heterogeneous condition that in the past has lagged behind rheumatoid arthritis (RA) in therapeutic progress. But improved understanding of the pathogenesis of PsA has allowed more targeted, safer, and more effective treatment approaches. In particular, data have begun to emerge from head-to-head and comparative studies of the newer agents and for difficult-to-treat disease manifestations, with the goal of helping clinicians choose among the increasing available options.
Guselkumab (Tremfya)
In a presentation at the 2021 European League Against Rheumatism (EULAR) virtual congress, guselkumab showed high rates of efficacy among PsA patients who had previously been treated unsuccessfully with tumor necrosis factor (TNF) inhibitors.
Guselkumab is a monoclonal antibody that targets the p19 subunit of interleukin (IL)-23, and was shown in two pivotal phase III trials to be effective for PsA. The medication has been approved for the treatment of PsA and severe plaque psoriasis.
In the additional phase IIIb COSMOS trial, 285 patients with PsA who had active disease, and had previously either failed or had not tolerated TNF inhibitor therapy, were randomized to subcutaneous guselkumab, 100 mg or placebo every 8 weeks.
At week 24, 44.4% of patients receiving guselkumab had 20% improvements on the criteria of the American College of Rheumatology (ACR20) compared with 19.8% of those given placebo (P<0.001), reported Laura C. Coates, MBChB, PhD, of the University of Oxford in England.
Improvements with guselkumab were observed as early as week 4, at which time ACR20 responses were seen in 19% of patients in the guselkumab group versus only 4.2% of the placebo group.
A post-hoc analysis of the two phase III trials (DISCOVER-1 and DISCOVER-2) showed that guselkumab was beneficial in resolving enthesitis in patients with PsA.
Enthesitis is inflammation at the site of tendon, ligament, or joint capsule insertion into bone, and affects more than half of patients with PsA.
Among more than 1,100 patients enrolled in the two trials, 65% had enthesitis at baseline. At week 24, 45% of patients who received guselkumab, 100 mg every 4 weeks, had resolution of their enthesitis as did 50% of those given the monoclonal antibody every 8 weeks compared with 29% of those on placebo (P=0.0301 for both dosages).
After week 24, when the placebo patients switched to guselkumab, 100 mg every 4 weeks, rates of enthesitis resolution continued to rise, reaching 58% by week 52.
Ustekinumab (Stelara)
A prospective observational cohort study in a real-world setting compared the efficacy of ustekinumab with that of TNF inhibitors among 868 patients with longstanding PsA, and found no significant differences.
Ustekinumab inhibits the p40 subunit on the IL-12 and 23 cytokines. In two phase III trials, this agent showed efficacy for both skin and joint manifestations of PsA, and it was approved in 2013.
However, few data are available comparing the efficacy of different biologics in real-world use, which can differ from what is observed in clinical trials.
In a propensity-score adjusted analysis, the odds ratio for achieving remission on the clinical Disease Activity Index for Psoriatic Arthritis by 6 months with ustekinumab treatment was 0.73 (95% CI 0.46-1.15) versus TNF inhibitors. In addition, the OR for reaching a state of minimal disease activity was 0.87 (95% CI 0.61-1.25).
A second study compared the risks of serious infections requiring hospitalization among patients with PsA or psoriasis being treated with ustekinumab versus other biologics or small-molecule therapies.
Most previous studies of the safety of the various biologic and small-molecule agents currently used in PsA have compared the newer agents with conventional disease-modifying antirheumatic drugs or corticosteroids. As with efficacy, few data are available on the comparative safety of the new medications.
The study compared risks for serious hospitalized infections in patients on TNF inhibitors, agents that block IL-17, IL23, or IL12/23, and small targeted molecules such as JAK inhibitors and the PDE-4 inhibitor apremilast (Otezla).
The study included more than 123,000 patients enrolled in the MarketScan or Optum databases during the years 2009 to 2017. Compared with ustekinumab, rates of hospitalized infections were consistently higher for the other agents, with hazard ratios such as 1.66 (95% CI 1.34-2.06) for adalimumab and 1.42 (95% CI 1.02-1.96) for apremilast.
Secukinumab (Cosentyx)
In the first head-to-head study comparing the IL-17A inhibitor secukinumab with adalimumab (Humira), secukinumab failed to show superiority to the TNF inhibitor, reported Iain McInnes, MD, PhD, of the University of Glasgow in Scotland at EULAR. In a phase IIIb study that included 853 patients, ACR20 responses were seen in 67.4% of patients randomized to secukinumab and in 61.5% of those given adalimumab, for an odds ratio of 1.30 (95% CI 0.98-1.72, P=0.0719).
Because superiority was not established on the primary endpoint, analyses for secondary endpoints could not be formally tested for statistical significance. Nonetheless, numerically greater responses on the Psoriasis Area and Severity Index (PASI) were observed for secukinumab. A 90% improvement on this index was seen in 65.4% of patients in the secukinumab group versus 43.2% of the adalimumab group (OR 2.49, 95% CI 1.67-3.71).
Tildrakizumab and Risankizumab
The monoclonal antibody tildrakizumab, which inhibits the IL-23 p19 subunit and that is approved for use in psoriasis, also showed benefits for PsA in a phase IIb study.
Tildrakizumab inhibits the IL-23-induced kinase signaling pathway, which results in decreased Th17 cell proliferation and limits the production of inflammatory cytokines such as IL-17 and IL-22 that are upregulated by Th17.
At week 24, 71.4% to 79.5% of patients randomized to one of several doses of tildrakizumab had achieved an ACR20 response, compared with 50.6% of those given placebo (P<0.01). They also had higher ACR50 responses (39.7% to 52.6% vs 24.1%) and ACR70 responses (16.7% to 29.1% vs 10.1%). Greater numbers of patients on tildrakizumab also had significant improvements on the PASI and on the Leeds Enthesitis Index.
The treatment was well tolerated through 52 weeks of follow-up, and the results “support tildrakizumab phase III clinical development in PsA,” the investigators wrote.
Risankizumab, another monoclonal antibody that inhibits IL-23 by binding to its p19 subunit, was evaluated in two phase III clinical trials among patients with PsA who had an inadequate response to either conventional DMARDs or biologics. The results were presented at the 2021 ACR virtual meeting.
A total of 1,400 patients were included in the KEEPSAKE 1 and 2 trial, and were randomized to receive subcutaneous risankizumab, 150 mg, or placebo at baseline and again at weeks 4 and 16.
At week 24, ACR20 responses were seen in 55.5% of patients in the risankizumab group compared with 31.3% of those in the placebo group, for a difference of 24 (95% CI 19-29, P<0.001).
Also at week 24, PASI 90 responses were observed in 53.2% of the risankizumab-treated patients compared with 10% of those on placebo, for a difference of 43.1 (95% CI 37.3-48.8, P<0.001). Significantly higher rates of patients on the active treatment also had resolution of enthesitis and dactylitis, as well as improvements in disability and fatigue.
Upadacitinib (Rinvoq)
The oral JAK inhibitor upadacitinib, approved for use in RA, showed promise as a treatment for PsA in a phase III trial comparing the drug with placebo and adalimumab.
The SELECT-PsA 1 study was conducted at 281 sites and included 1,704 patients who had had an inadequate response or were unable to tolerate nonbiologic DMARDs.
At week 12, ACR20 responses were seen in 70.6% of patients receiving upadacitinib, 15 mg daily, in 78.5% of those given 30 mg daily, in 65% of those receiving subcutaneous adalimumab, 40 mg every other week, and in 36.2% of those given placebo. Both of the upadacitinib doses showed noninferiority to adalimumab, and the 30 mg dose was superior.
Secondary endpoints that showed significantly greater responses versus placebo included changes on the Health Assessment Questionnaire, 75% improvement on the PASI, and on radiographic changes measured by the Sharp-van der Heijde score.
Brepocitinib
The small molecule tyrosine kinase 2/JAK 1 inhibitor brepocitinib was superior to placebo in both joint and skin manifestations of PsA in a phase IIb controlled trial presented at the ACR.
Among 218 patients with active PsA, 66.7% of those randomized to receive 30 mg brepocitinib daily achieved an ACR20 response at week 16 as did 74.6% of those given 60 mg per day compared with 43.3% of those given placebo (P<0.05).
After week 16, all patients were given 30 or 60 mg brepocitinib daily, and by week 52, ACR20 responses were observed in 67.6% of the 30-mg group and 60.9% of the 60-mg group. At that time point, 53.7% of the 30-mg and 46% of the 60-mg group also had PASI 90 responses. Safety was similar to what has been seen with approved JAK inhibitors.