Upadacitinib effectiveness and factors associated with minimal disease activity achievement in patients with psoriatic arthritis: preliminary data of a real-life multicenter study

Psoriatic arthritis (PsA) is a chronic systemic inflammatory musculoskeletal disease that affects up to 30% of patients with psoriasis [1‐5]. PsA encompasses various phenotypes, including skin and nail psoriasis, peripheral synovitis, enthesitis, dactylitis, and axial involvement. Managing PsA requires considering all these phenotypes based on the 2021 GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis) recommendations [6].

Despite the available therapies, only approximately one-third of patients achieve and maintain minimal disease activity [7]. Thus, there is a significant need for novel therapies effective on as many disease domains as possible, providing personalized treatment for each patient’s phenotypes.

Two oral Janus Kinase (JAK) inhibitors, tofacitinib, and upadacitinib, have been recently approved for use in PsA, with their therapeutic efficacy consistently demonstrated in randomized controlled trials [8‐11].

Upadacitinib (UPA) is an oral, reversible JAK inhibitor with higher selectivity for JAK1. The SELECT 1–2 trials have reported its efficacy in various PsA domains, along with significant improvements in pain, fatigue, and quality of life. Safety concerns include opportunistic upper respiratory tract infections and Herpes Zoster Virus (HZV) reactivations [8, 9].

Since real-world data regarding UPA treatment in PsA clinical practice are lacking, we conducted a multicenter observational study to assess its effectiveness and safety over 24 weeks in a cohort of patients with both peripheral and axial PsA.

PsA is a chronic immune-mediated musculoskeletal disease that is considered a systemic disease for its heterogenic clinical presentation and for being tightly correlated to several comorbid diseases like cardiovascular, metabolic, infective, psychological, and neoplastic ones [22‐25]. As such, growing evidence shows that disease activity and therapeutic response vary considerably among patients with peripheral and/or axial involvement and with the number and/or type of extra-articular domains involved [25‐30].

Two JAK inhibitors have been recently licensed for use in PsA, following the results of randomized controlled trials (RCTs) that demonstrated their efficacy in several disease domains [8‐11, 31‐35]. However, the discrepancy between RCTs and real-world evidence can be significant, in some cases, given the use of new medications in patients that would not be eligible for phase III studies.

Herein, we reported preliminary results from an ongoing multicenter prospective cohort study that aims to illustrate the real-life efficacy and safety of upadacitinib (UPA) therapy in patients with PsA (UPREAL-PsA study) and determine factors influencing clinical outcomes at 6 months.

Our data show that UPA is effective already at 12 weeks and maintains activity at 24 weeks, both in the composite and in the single domains scores (peripheral, enthesis, and skin ones), in agreement with the results of RTCs.

Notably, UPA demonstrated consistent efficacy in patients with axial involvement up to the 24-week follow-up. In this regard, it should be underlined that there is growing interest in the assessment of axial symptoms in PsA patients, and an interesting debate is ongoing on whether axial-PsA should be considered only axial-SpA with psoriasis or a separate clinical entity [36‐38]. Therefore, we believe that an important added value of our cohort is that patients were defined as having axial PsA when both the CASPAR criteria and the ASAS classification criteria for axial SpA were met [12, 13], and this allowed us to evaluate the benefits of UPA in this unique PsA phenotype.

In comparison to the UPA 15 mg arm of the SELECT 1 RCT [8], our study shows a higher proportion of female patients (68.3% vs. 55.5%), a slightly higher mean age (56.5 ± 11.4 vs. 51.6 ± 12.2), and a longer duration of disease (10.0 ± 8.3 vs. 6.2 ± 7.4 years). Furthermore, our study included a significant proportion of patients who were bio-experienced, which were excluded from the SELECT 1 trial. Lastly, the proportion of patients achieving MDA is comparable between the two studies.

Very recently, another real-life study on the effectiveness of UPA in PsA patients from Germany and Canada was published [39]. The results of this study are similar to those of our own conducted in Italy, and the data from these different populations mutually support each other.

Our study also showed results comparable to a real-life study on the effectiveness of Tofacitinib in PsA [40]. The reduction in DAPSA score at 24 weeks aligns with our study, showing similar outcomes. A notable difference is that none of our patients received steroid therapy during the study.

Of note, patients having a worse global health state at baseline (such as elevated BMI with metabolic comorbidities; debilitating long-lasting PsA such as those with more involved skin and/or higher number of inflamed joints) were also more likely to present higher PsA disease activity at baseline. Interestingly, UPA was effective in reducing clinical activity, as assessed by DAPSA and ASDAS-CRP, in all the patient subgroups, but the results of the multivariate analysis suggested that bio-naïve patients and those with higher CRP at baseline were more likely to achieve the dichotomous MDA response at week 24.

Finally, the regression analysis also showed that males were more likely to achieve MDA at week 24 compared to females. These data corroborate similar recent findings supporting the need for a gender-specific evaluation and therapeutic strategy adjustment in PsA patients [41‐44]. In this regard, it should be emphasized that subjective parameters (i.e., PtGA, VAS pain, TJC, HAQ) tend to be worse than the objective ones (i.e. PhGA, SJC, LEI, PASI, CRP), suggesting that the inadequate response of some subgroups of patients could be related, at least in part, to a negative perception of their global health status and central pain processing mechanisms, i.e. nociplasticity [45].

In this study, the safety profile of UPA was reassuring, based on the limited number of adverse events of any type, the absence of serious adverse events (including thromboembolic or major cardiovascular events), and the low number of patients lost at the 24-week follow-up.

In our opinion, this study has several strengths. First, this is one of the first real-life studies conducted in a large cohort of heterogeneous PsA patients and provides a comprehensive assessment of PsA patients initiating UPA in real-life. Second, we identified clinical and demographic parameters associated with a better response to UPA therapy in a real-life cohort of PsA patients.

We are also aware of the limitations of our study. First, the study is observational, and it has been conducted only in tertiary referral centers in a single country (Italy), thus it may not fully represent the entire spectrum of the disease.Second, due to the ongoing nature of the study and the preliminary nature of the data, the short-term observation period may lead to an underestimation of the incidence of adverse events or patient dropouts. Additionally, it does not allow for the assessment of survival. Third, the proportion of bio-naïve patients with early-stage disease is relatively small: most patients have previously failed at least one b-DMARD, and half of them have failed more than three biological lines, which can affect drug responsiveness. In this context, it is important to note that regulatory restrictions in our country limit the use of JAK inhibitors in bio-naïve patients, and these limitations may introduce a slight bias in the composition of our real-life study cohort. Fourth, we acknowledge that certain confounding factors, such as the use of non-steroidal anti-inflammatory drugs or the dose of methotrexate, were not specifically recorded and therefore not accounted for in our analysis.

The 24-week results from the UPREAL-PsA study confirm the remarkable efficacy and good safety profile of upadacitinib therapy in real-life PsA, with the higher efficacy of UPA demonstrated in males, bio-naïve patients, and those with elevated baseline CRP.