FormalPara Key Summary Points

Why carry out this study?

Treatment guidelines for psoriatic arthritis (PsA) recommend aiming for remission or low disease activity (LDA), which can be assessed using validated measures such as Disease Activity in Psoriatic Arthritis and Psoriatic Arthritis Disease Activity Score LDA/remission or the states of minimal/very low disease activity (MDA/VLDA).

The aim of this analysis was to evaluate the proportions of patients who achieved the states of LDA/remission and MDA/VLDA while receiving upadacitinib up to week 56 using data from the SELECT-PsA 1 and SELECT-PsA 2 studies.

What was learned from the study?

In the SELECT-PsA 1 and 2 randomized, controlled trials, more patients receiving upadacitinib 15 mg compared with placebo achieved LDA and remission, regardless of the target used to assess disease control. Responses with upadacitinib were similar to those seen with adalimumab.

With upadacitinib treatment, disease control is feasible in patients with PsA, with sustained results for 56 weeks.

Introduction

Psoriatic arthritis (PsA) is a systemic inflammatory musculoskeletal disease that exists on a spectrum of disease with psoriasis [1,2,3]. Patients with PsA can be impacted by disease activity across multiple domains, including peripheral arthritis, axial disease, enthesitis, dactylitis, skin and nail involvement, inflammatory bowel disease, and uveitis, as well as a variety of cardiovascular, psychological, and metabolic comorbidities [2, 3]. Current treatment guidelines recommend a treat-to-target approach aiming for remission (REM) or alternatively for low disease activity (LDA) [1, 3]; however, assessment of PsA disease activity is challenging due to its variable clinical manifestations and differences in rates of favorable outcomes depending on scoring methods used [1]. The key methods to assess REM and LDA in PsA include Disease Activity in Psoriatic Arthritis (DAPSA) LDA/REM, Psoriatic Arthritis Disease Activity Score (PASDAS) LDA/REM, and minimal/very low disease activity (MDA/VLDA) [4].

Upadacitinib is an oral, reversible Janus kinase (JAK) inhibitor with selectivity for JAK1 over JAK2, JAK3, and tyrosine kinase 2. As of 2021, upadacitinib has received regulatory approval for the treatment of PsA by the European Medicines Agency and the Pharmaceuticals and Medical Devices Agency, along with other regulatory agencies. Upadacitinib (15 mg or 30 mg administered once daily [QD]) is being investigated for the treatment of patients with PsA and an inadequate response or intolerance to non-biologic and biologic disease-modifying antirheumatic drugs (nb/bDMARDs) in the phase 3 SELECT-PsA 1 and SELECT-PsA 2 studies, respectively. In both of these studies, upadacitinib was effective in improving the signs and symptoms of PsA, with responses maintained over 56 weeks of treatment [5,6,7,8]. In SELECT-PsA 1, upadacitinib 15 mg and 30 mg achieved non-inferiority versus adalimumab for American College of Rheumatology 20% response criteria at week 12 [5]. Here, we report the proportions of patients who achieved the states of LDA/REM and MDA/VLDA while receiving upadacitinib up to week 56 using data from the SELECT-PsA 1 and SELECT-PsA 2 studies [5,6,7,8].

Methods

Trial Design

This was a post hoc analysis of 24-week and 56-week disease activity data from the SELECT-PsA 1 (NCT03104400) and SELECT-PsA 2 (NCT03104374) randomized, controlled, phase 3 trials. The designs of the trials have been previously described in detail [5, 7]. In brief, both were multicenter, double-blind, placebo- (and active- [adalimumab] in the case of SELECT-PsA 1) controlled trials of an initial 24-week duration, followed by an additional 32 weeks of blinded treatment (weeks 24–56), and subsequent long-term extension [5,6,7,8].

Patients with prior inadequate response or intolerance to ≥ 1 nbDMARD (nbDMARD-IR; SELECT-PsA 1) or ≥ 1 bDMARD (bDMARD-IR; SELECT-PsA 2) were randomized to receive oral upadacitinib 15 mg QD, upadacitinib 30 mg QD, or placebo switched (1:1) to either upadacitinib 15 mg or 30 mg QD at week 24 (both studies), or subcutaneous adalimumab 40 mg every other week (SELECT-PsA 1 only) [5, 7]. From week 16, all patients who qualified for rescue therapy (i.e., did not achieve ≥ 20% improvement in tender joint count in 68 joints [TJC68] and swollen joint count in 66 joints [SJC66] compared with baseline at weeks 12 and 16) were permitted to have background medication(s) initiated or adjusted. From week 36, patients who had not achieved ≥ 20% improvement in TJC68 and SJC66 compared with baseline at two consecutive visits discontinued study drug and were considered non-responders.

Patients

Patients were aged ≥ 18 years with a diagnosis of active PsA, fulfilled the classification criteria for PsA [9], had historic or current plaque psoriasis, and had SJC ≥ 3 of 66 and TJC ≥ 3 of 68 at baseline [5, 7].

Ethics Declaration

Both trials were conducted according to the International Conference on Harmonization guidelines and the principles of the Declaration of Helsinki of 1964 and its later amendments. All patients provided written informed consent. The trial protocols were approved by the relevant independent ethics committees and institutional review boards of all participating institutions (previously published) and were sponsored by AbbVie, which provided upadacitinib, adalimumab, and placebo. All authors have provided their approval for this version to be published.

Assessments

Outcome measures included the proportions of patients achieving LDA and REM (assessed according to the following scores: DAPSA ≤ 14 / ≤ 4, respectively, and PASDAS ≤ 3.2 / ≤ 1.9, respectively), as well as MDA and VLDA. DAPSA score is a composite score based on the sum of five variables: SJC66, TJC68, Patient’s Assessment of Pain (0–10 numeric rating scale [NRS]), Patient's Global Assessment of Disease Activity (PtGA; 0–10 NRS), and high-sensitivity C-reactive protein (hsCRP) test [10]. PASDAS is a composite disease activity measure, which was calculated using the following formula: 0.18 √(Physician's Global Assessment) + 0.159 √(PtGA) − 0.253 √(short form 36-physical component summary) + 0.101 ln (SJC66 + 1) + 0.048 ln (TJC68 + 1) + 0.23 ln (Leeds Enthesitis Index [LEI] + 1) + 0.37 ln (tender dactylitis count + 1) + 0.102 ln (hsCRP + 1) + 2 × 1.5 [1, 11]. MDA and VLDA were determined based on patients meeting five and seven components, respectively, out of the following seven components: TJC68 ≤ 1; SJC66 ≤ 1; Psoriasis Area Severity Index (PASI) ≤ 1 or body surface area-psoriasis (BSA-Ps) ≤ 3%; Patient’s Assessment of Pain ≤ 1.5 (0–10 NRS); PtGA ≤ 2 (0–10 NRS); Health Assessment Questionnaire-Disability Index (HAQ-DI) score ≤ 0.5; and tender entheseal points (LEI) ≤ 1 [10].

Statistical Analyses

Analyses were performed on all randomized patients who had received ≥ 1 dose of trial drug, excluding patients in the upadacitinib 30 mg group. For binary outcomes, non-responder imputation (NRI) was used for handling missing data, where patients with missing data at the specified week or those who prematurely discontinued the trial drug were considered as non-responders. For MDA and VLDA, the NRI with additional rescue handling was used, where those who were rescued at week 16 were considered non-responders. For the primary outcome analysis, pairwise comparisons between upadacitinib doses and placebo or adalimumab were conducted using the Cochran–Mantel–Haenszel test adjusting for main stratification factors. The proportion of patients achieving MDA at week 24 with upadacitinib versus placebo was adjusted for multiplicity control.

Results

Patients

A total of 1069 patients from SELECT-PsA 1 and 317 patients from SELECT-PsA 2 were included in the analysis. Patient demographics and clinical characteristics have been published previously [5, 7] and were largely similar across the treatment groups in the two studies (Supplementary Table 1, Supplementary Material).

Efficacy

At week 24, achievement of DAPSA LDA ranged from 4–16% in placebo-treated patients and 35–48% in patients receiving upadacitinib 15 mg, while achievement of PASDAS LDA ranged from 2–16% and 33–46%, respectively (Fig. 1A, B; Supplementary Fig. 1A, B). Achievement of DAPSA REM at week 24 ranged from 0–3% with placebo and 7–11% with upadacitinib 15 mg, and achievement of PASDAS REM ranged from 1–3% and 10–14%, respectively (Fig. 1C, D; Supplementary Fig. 1C, D). A significantly higher proportion of patients achieved DAPSA/PASDAS LDA or REM at week 24 in the upadacitinib 15 mg compared with the placebo group (nominal p < 0.05). The percentage of patients achieving DAPSA/PASDAS LDA and REM broadly increased between week 24 and week 56. LDA or REM rates at week 56 were generally similar in patients who were originally randomized to upadacitinib 15 mg compared with those who switched from placebo to upadacitinib 15 mg at week 24. DAPSA/PASDAS LDA and REM rates were numerically greater in nbDMARD-IR patients receiving upadacitinib than in bDMARD-IR patients receiving upadacitinib.

Fig. 1
figure 1

Proportion of patients achieving DAPSA LDA (A), PASDAS LDA (B), DAPSA REM (C), and PASDAS REM (D) at weeks 24 and 56 (NRI). *Nominal p < 0.05 versus PBO. ADA adalimumab, bDMARD biologic disease-modifying antirheumatic drug, DAPSA Disease Activity in Psoriatic Arthritis, EOW every other week, IR inadequate response, LDA low disease activity, nbDMARD non-biologic disease-modifying antirheumatic drug, NRI non-responder imputation, PASDAS Psoriatic Arthritis Disease Activity Score, PBO placebo, QD once daily, REM remission, UPA upadacitinib. At week 24, all patients who had originally been randomized to PBO were switched to UPA 15 mg QD regardless of response

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Significantly greater proportions of patients achieved MDA (Fig. 2A) and VLDA (Fig. 2B) at week 24 with upadacitinib 15 mg versus placebo (p < 0.05). MDA and VLDA rates in the group originally randomized to upadacitinib 15 mg were maintained or increased at week 56. Among patients originally randomized to placebo, the proportions of patients who achieved MDA and VLDA increased after switching to upadacitinib 15 mg at week 24.

Fig. 2
figure 2

Proportion of patients achieving MDA (A) and VLDA (B) at weeks 24 and 56 (NRI). *Nominal p < 0.05 versus PBO. #Statistically significant in the multiplicity-controlled analysis. ADA adalimumab, bDMARD biologic disease-modifying antirheumatic drug, EOW every other week, IR inadequate response, MDA minimal disease activity, nbDMARD non-biologic disease-modifying antirheumatic drug, NRI non-responder imputation, PBO placebo, QD once daily, UPA upadacitinib, VLDA very low disease activity. At week 24, all patients who had originally been randomized to PBO were switched to UPA 15 mg QD regardless of response

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Among patients who achieved MDA with upadacitinib 15 mg or adalimumab at week 24, the proportion of patients achieving TJC68 ≤ 1 and Patient’s Assessment of Pain ≤ 1.5 tended to be lower than that for other MDA components (Fig. 3). The achievement of individual MDA components was broadly similar regardless of whether patients achieved MDA with upadacitinib 15 mg or adalimumab. Conversely, around half of the patients who did not achieve MDA by week 24 still achieved meaningful improvement in skin and enthesitis with upadacitinib 15 mg or adalimumab treatment. Similar trends were observed at week 56 (Fig. 4).

Fig. 3
figure 3

Proportion of patients achieving MDA components among upadacitinib- or adalimumab-treated patients who achieved MDA (A) and did not achieve MDA (B) at week 24 (NRI). ADA adalimumab, bDMARD biologic disease-modifying antirheumatic drug, BSA-Ps body surface area-psoriasis, EOW every other week, HAQ-DI Health Assessment Questionnaire-Disability Index, IR inadequate response, LEI Leeds Enthesitis Index, MDA minimal disease activity, nbDMARD non-biologic disease-modifying antirheumatic drug, NRI non-responder imputation, NRS numeric rating scale, PASI Psoriasis Area Severity Index, PtGA Patient’s Global Assessment of Disease Activity, QD once daily, SJC66 swollen joint count in 66 joints, TJC68 tender joint count in 68 joints, UPA upadacitinib

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Fig. 4
figure 4

Proportion of patients achieving MDA components among upadacitinib- or adalimumab-treated patients who achieved MDA (A) and did not achieve MDA (B) at week 56 (NRI). ADA adalimumab, bDMARD biologic disease-modifying antirheumatic drug, BSA-Ps body surface area-psoriasis, EOW every other week, HAQ-DI Health Assessment Questionnaire-Disability Index, IR inadequate response, LEI Leeds Enthesitis Index, MDA minimal disease activity, nbDMARD non-biologic disease-modifying antirheumatic drug, NRI non-responder imputation, NRS numeric rating scale, PASI Psoriasis Area Severity Index, PtGA Patient’s Global Assessment of Disease Activity, QD once daily, SJC66 swollen joint count in 66 joints, TJC68 tender joint count in 68 joints, UPA upadacitinib

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Discussion

This post hoc analysis of data from the SELECT-PsA 1 and SELECT-PsA 2 randomized, controlled trials showed that upadacitinib 15 mg treatment led to desirable states of REM or LDA, which were sustained through 56 weeks.

Guidelines recommend aiming for REM or LDA in PsA [1, 3]. Achieving MDA leads to significantly greater and sustained improvement in quality of life (QoL) [12]. However, REM in PsA is difficult to define, but should be seen as an abrogation of inflammation [3]. Consequently, a range of measures have been used in PsA trials to determine LDA or REM [4, 10]. While DAPSA measures showed higher sensitivity to identify patient-perceived LDA/REM than VLDA/MDA, VLDA/MDA cut-offs were more rigorous and accounted for extra-articular symptoms of PsA such as psoriasis [4, 10, 13]. Patients who achieved MDA or VLDA were also more likely to experience a reduction in radiographic progression, and a positive impact on health-related QoL and work productivity [14]. On the other hand, MDA and PASDAS have been shown to be well correlated between instruments and are highly sensitive and specific for assessing disease activity [4, 10].

Despite the differences between LDA/REM measures in PsA, the results from our analysis suggested that similar proportions of upadacitinib-treated patients achieved LDA/REM at weeks 24 and 56 across the outcome measures assessed. While upadacitinib treatment was associated with greater LDA/REM rates than placebo in both nbDMARD-IR patients and bDMARD-IR patients, the treatment effect of upadacitinib was greater in nbDMARD-IR patients than bDMARD-IR patients, as expected. Regardless of outcome measures, LDA/REM rates were generally similar between patients receiving upadacitinib 15 mg and adalimumab.

Patients who achieved MDA with upadacitinib or adalimumab demonstrated similar clinically important improvements across individual MDA/VLDA components, including improvements in skin symptoms, enthesitis, and physical function. This provides further evidence of disease control with upadacitinib. However, very few patients who achieved MDA experienced clinically important improvement in pain and TJC68 when compared with other MDA/VLDA components. This may be due to the relatively stringent threshold for pain used in the MDA criteria (≤ 1.5 on a 0–1 NRS), and the high number of tender joints present at baseline in both the SELECT-PSA 1 and 2 trials.

The limitations of this study include the post hoc nature of the analysis, with data at week 24 and week 56 not powered to detect differences between upadacitinib and adalimumab. However, these data are taken from two rigorous randomized, controlled trials with a reasonably large patient population, and using the conservative approach of NRI might mitigate any bias favoring the active treatment.

Conclusions

These data show that a greater proportion of patients with PsA treated with upadacitinib 15 mg frequently achieve disease control, measured by LDA or REM, compared with placebo over 56 weeks. Further studies are needed to confirm the link between disease control and long-term QoL for patients.