FormalPara Key Summary Points

Why carry out this study?

Psoriatic arthritis (PsA) has a major impact on a patient’s health-related quality of life, an important component when evaluating treatment response.

We evaluated whether the Janus kinase inhibitor upadacitinib improved patient-reported outcomes (PROs) in PsA patients with inadequate responses to biologic disease-modifying anti-rheumatic drugs from the phase 3 SELECT-PsA 2 trial.

What was learned from the study?

Significant and clinically meaningful (e.g., improvements ≥ minimal clinically important difference) in PROs were reported with upadacitinib at 12 weeks, which were maintained through 56 weeks.

PRO scores ≥ normative values were reported with upadacitinib, indicating that such a goal is achievable in this patient population.

Introduction

Psoriatic arthritis (PsA) is a multisystem, heterogeneous inflammatory disease that may present with multiple clinical manifestations, including plaque psoriasis, arthritis, dactylitis, enthesitis, and axial skeleton involvement [1]. The burden of disease is substantial, with significant negative impacts on health-related quality of life (HRQOL), physical and emotional functioning, ability to perform daily activities, and work productivity [2, 3]. Current treatment options for PsA include disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate; biologic DMARDs (bDMARDs), including tumor necrosis factor (TNF), Interleukin (IL)-12/23, IL-23, and IL-17A inhibitors; and targeted synthetic DMARDs, such as Janus kinase (JAK) inhibitors [4,5,6]. Despite the recent increase in available advanced therapies for PsA, a significant number of patients still fail to achieve adequate disease control, resulting in substantial HRQOL impairments, which are reported in patient surveys, and highlighting a continued need for novel and effective treatment options.

Upadacitinib is an oral, reversible JAK inhibitor engineered for increased selectivity for JAK1 over other members of the JAK family (JAK2, JAK3, and tyrosine kinase 2 [TYK2]) [7]. Upadacitinib is approved in Europe for patients with PsA and ankylosing spondylitis with inadequate responses or intolerance to DMARDs and conventional therapy, respectively, and in the United States and Europe for patients with moderate-to-severe rheumatoid arthritis with inadequate responses or intolerance to methotrexate, based on the findings from eight separate phase 3 clinical trials [8,9,10,11,12,13,14,15,16,17]. In the phase 3 SELECT-PsA 2 trial, upadacitinib 15 or 30 mg once daily (QD) provided significant improvements in clinical manifestations of PsA, such as musculoskeletal (peripheral arthritis, enthesitis, dactylitis, and axial) symptoms and psoriasis, in patients who were refractory to bDMARDs compared with placebo [15].

Patient-reported outcomes (PROs) assess the impact of disease from a patient perspective and are recommended as one of the core components in the evaluation of treatment responses in randomized controlled trials (RCTs) in PsA [18]. We present here analyses from the SELECT-PsA 2 RCT that compare reported improvements in PROs with both doses of upadacitinib versus placebo, which are clinically meaningful as well as scores that meet or exceed normative values.

Methods

Study design and patients

Detailed study information has been previously reported [15]. SELECT-PsA 2 (NCT03104374) is a phase 3, placebo-controlled, multicenter RCT in patients ≥ 18 years of age with a clinical diagnosis of PsA with symptom onset ≥ 6 months prior to screening and active disease at baseline who fulfilled the Classification Criteria for PsA (CASPAR), and had a diagnosis or documented history of plaque psoriasis, and inadequate responses or intolerance to ≥ 1 bDMARD treatment (bDMARD-IR). Patients were excluded if they had prior exposure to JAK inhibitors or current treatment with ≥ 2 non-bDMARDs.

Patients were randomized 2:2:1:1 to receive oral upadacitinib 15 mg QD, upadacitinib 30 mg QD, or placebo switched to either upadacitinib 15 mg once daily (QD) or upadacitinib 30 mg QD at week 24. Treatment in the randomized controlled portion of the trial was 24 weeks, with blinding to 56 weeks and an open-label extension up to 5 years. Background treatment with nonsteroidal anti-inflammatory drugs, corticosteroids, and ≤ 2 non-bDMARDs was allowed, but not required, with rescue therapy permitted at week 16 and optimization of background therapy after week 36.

The trial was approved by the independent ethics committees or institutional review boards at all study sites and conducted in accordance with the Declaration of Helsinki and consistent with International Conference on Harmonisation Good Clinical Practice and Good Epidemiology Practices, along with all applicable local regulatory requirements. All patients provided written approval before enrollment, and patient data were de-identified and complied with patient confidentiality requirements.

Outcomes

Multiplicity-controlled secondary PRO endpoints included changes from baseline at week 12 in Health Assessment Questionnaire-Disability Index (HAQ-DI; minimal clinically important difference [MCID]: ≥ 0.35-unit decrease; normative value: ≤ 0.25 units) [19, 20], Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F; MCID: ≥ 4-point increase; normative value: ≥ 40.1 points) [21, 22], 36-Item Short Form Health Survey (SF-36) physical component summary (PCS) score (MCID: ≥ 2.5-point increase; normative value: ≥ 50 points) [23,24,25], and change from baseline at week 16 in Self-Assessment of Psoriasis Symptoms (SAPS) (range: 0–110, with higher scores indicating worse patient-reported psoriasis symptoms) [26]. Additional PROs evaluated included Patient Global Assessment of Disease Activity (PtGA) and patient pain (0–10 numerical rating scale [NRS]; MCID: ≥ 1-point decrease; normative value: ≤ 2 points [PtGA]) [27,28,29], SF-36 mental component summary (MCS; MCID: ≥ 2.5-point increase; normative value: ≥ 50 points) [23,24,25] and domains (MCID: ≥ 5-point increase) [23, 24], EuroQoL 5-Dimension 5-Level index score (EQ-5D-5L; MCID: ≥ 0.05-unit increase; normative value: ≥ 0.915) [30, 31], Bath Ankylosing Spondylitis Disease Activity Index (BASDAI: MCID: ≥ 1.1-point decrease) and morning stiffness (mean of BASDAI questions 5 and 6; MCID: ≥ 1-point decrease) [32], BASDAI 50, Work Productivity and Activity Impairment (WPAI) [33, 34], and itch (SAPS question 2; 0–10 NRS, with higher scores indicating worse itch).

SF-36 PCS and MCS scores were norm-based with a mean value of 50 and standard deviation of 10; SF-36 domains were scored from 0 to 100 with higher scores indicating better HRQOL [23,24,25]. BASDAI assessments were assessed in patients with presence of psoriatic spondylitis at baseline determined by the investigator (34% of total population). The WPAI activity impairment domain was assessed in all patients, while presenteeism, overall work impairment, and absenteeism domains only in those employed at baseline [33, 34]. SAPS consists of an 11-item patient self-assessment of psoriasis symptoms that includes questions on severity of pain, itching, redness, scaling, flaking, bleeding, burning, stinging, tenderness, pain due to skin cracking, and joint pain in the areas affected by psoriasis [26].

Following baseline assessments, PtGA, pain, and HAQ-DI were assessed starting at week 2; other PROs at week 12 (except SAPS, which started at week 16).

Statistical methods

Analyses were performed using the full analysis set population, including all randomized patients who received ≥ one dose of study drug. Demographic and baseline characteristics are summarized with descriptive statistics (mean, standard deviation for continuous endpoints, and n [%] for categorical endpoints). For analysis of changes from baseline, within-group least squares (LS) means and 95% confidence intervals (CI) at weeks 12, 24, and 56; and between-group nominal p values at weeks 12 and 24 were based on mixed-effect model repeated measurement (MMRM) analysis using an unstructured variance–covariance matrix, including treatment, visit, treatment-by-visit interaction, and the stratification factor current DMARD use (yes/no) as fixed factors and baseline measurement as a continuous fixed covariate. MMRM analysis used observed longitudinal data up to the respective time point prior to study drug premature discontinuation, with as-observed data reported. Spidergrams were used to illustrate changes from baseline in SF-36 domain scores from 0 to 100 for each treatment group against a combined baseline population and US normative values age- and gender-matched matched to the protocol population [35].

The proportions of patients reporting BASDAI 50, improvements ≥ MCID and scores ≥ normative values at weeks 12 and 24 were evaluated using non-responder imputation for missing responses. Persistence of improvements ≥ MCID from weeks 12 to 56 was determined using as-observed data. The number needed to treat (NNT) to obtain 1 additional MCID response at weeks 12 and 24 for each upadacitinib dose compared with placebo was defined as the reciprocal of the response rate difference between upadacitinib and placebo, with missing responses imputed using non-responder imputation. p values were calculated using Cochran–Mantel–Haenszel test adjusting for the main stratification factor of current DMARD use (yes/no). Statistical significance defined as p < 0.05 was nominal for non-multiplicity-controlled endpoints.

Results

A total of 642 patients were randomized; 641 patients received at least one dose of study drug (placebo, n = 212; upadacitinib 15 mg, n = 211; upadacitinib 30 mg, n = 218) [15]. Baseline PROs, demographics, disease characteristics, and disease severity were generally similar across treatment arms (Table 1).

Table 1 Baseline demographics and characteristics
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Improvement from baseline in PROs

Compared with placebo, significant improvements from baseline to weeks 12 and 24 were reported with upadacitinib 15 and 30 mg across all PROs (p < 0.05, nominal except for week 12 multiplicity controlled endpoints of HAQ-DI, FACIT-F, SF-36 PCS, and SAPS, Table 2), with exception of WPAI absenteeism, assessed only in those patients working outside the home (n = 100 [placebo], 120 [upadacitinib 15 mg], and 119 [upadacitinib 30 mg];.p ≥ 0.08). Mean improvements were maintained or further improved through week 56 (Table 2). Greater improvements from baseline in PtGA, pain, and HAQ-DI were reported as early as week 2 with both doses of upadacitinib compared with placebo, with statistically significant improvements based on nominal p values (Fig. 1). In patients receiving placebo who were switched to upadacitinib 15 or 30 mg at week 24, rapid improvements in PtGA, pain, HAQ-DI, and FACIT-F were reported with similar responses at week 56 to those originally randomized to upadacitinib (Fig. 1).

Table 2 LS mean change (95% CI) from baseline in PRO scores at weeks 12, 24, and 56 (MMRM)
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Fig. 1
figure 1

Mean changes from baseline in PtGA, pain, HAQ-DI, and FACIT-F through 56 weeks (MMRM). a PtGA. b Pain. c HAQ-DI. d FACIT-F. CI confidence interval, FACIT-F Functional Assessment of Chronic Illness Therapy-Fatigue, HAQ-DI Health Assessment Questionnaire-Disability Index, LS least squares, MMRM Mixed-Effect Model Repeated Measurement, PBO placebo, PtGA Patient Global Assessment of Disease Activity, UPA upadacitinib

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Significant improvements from baseline in all SF-36 domain scores were reported with both doses of upadacitinib compared to placebo at week 12 (nominal p ≤ 0.01 for all domains), which continued to week 24 (Table 2, Fig. 2, and Fig. S1 in the electronic supplementary material). BASDAI 50 responses were reported by significantly more patients receiving upadacitinib 15 or 30 mg at weeks 12 (20 and 29%) and 24 (32 and 35%) than placebo (7 and 4%) (nominal p < 0.05). Additionally, a greater percentage of patients reported resolution of itch with both doses of upadacitinib versus placebo at weeks 16 and 24, with 31 and 47% of patients reporting itch resolution at week 24 with upadacitinib 15 and 30 mg, respectively, compared with 6–9% with placebo (Fig. S2 in the electronic supplementary material). Improvements with upadacitinib were maintained through week 56.

Fig. 2
figure 2

Week 12 SF-36 domain scores in comparison to age- and gender-matched normative values (MMRM). p values nominal. A/G age-gender adjusted, BL baseline, BP bodily pain, DMARD disease-modifying anti-rheumatic drug, GH general health MH mental health, MMRM Mixed-Effect Model Repeated Measurement, PBO placebo, PF physical functioning, RE role-emotional, RP role-physical, SF social functioning, SF-36 36-Item Short Form Health Survey, UPA upadacitinib, VT vitality

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Clinically meaningful improvements in PROs

At week 12, a significantly greater proportion of patients receiving either dose of upadacitinib compared with placebo reported improvements ≥ MCID across all PROs (including all eight SF-36 domains) (all nominal p ≤ 0.01) with exception of SF-36 MCS score with upadacitinib 30 mg, which numerically, but not statistically, exceeded placebo (Fig. 3). The highest proportion of patients reporting improvements ≥ MCID with upadacitinib were in PtGA (71 and 77% with 15 and 30 mg, respectively, vs. 46% placebo) and pain (68 and 76%, respectively, vs. 46% placebo) (Fig. 3). A significantly greater proportion of patients reported clinically meaningful improvements at week 2 with both doses of upadacitinib versus placebo (nominal p ≤ 0.01) in PtGA (15 mg: 70%, 30 mg: 72%, placebo: 52%), pain (15 mg: 67%, 30 mg: 69%, placebo: 50%), and HAQ-DI (15 mg: 32%, 30 mg: 42%, placebo: 19%). NNTs to achieve one additional response ≥ MCID ranged from 3.2 to 7.3 and 2.6 to 6.9 with upadacitinib 15 mg and 30 mg, respectively, across evaluated PROs (Fig. 3). Similar results were reported at week 24 (Fig. S3 in the electronic supplementary material). Among patients receiving upadacitinib reporting improvements ≥ MCID at week 12, ≥ 80% reported continued or further improved responses at week 56 across most PROs (Fig. S4 in the electronic supplementary material).

Fig. 3
figure 3

Proportion of patients reporting improvements ≥ MCID and NNTs in PROs at week 12 (NRI). a PROs excluding SF-36. b SF-36 PCS, MCS, and domains. *p ≤ 0.01 and †p ≤ 0.001 versus placebo. p values nominal. aReported only for patients with investigator-determined psoriatic spondylitis at baseline. bMean of BASDAI questions 5 and 6. NNT not calculated for non-significant results for upadacitinib versus placebo. MCID definitions: ≥ 1-point decrease (PtGA, pain, and morning stiffness), ≥ 0.35-unit decrease (HAQ-DI), ≥ 4-point increase (FACIT-F), ≥ 0.05-unit increase (EQ-5D-5L), ≥ 1.1-point decrease (BASDAI), ≥ 2.5-point increase (SF-36 PCS and MCS), and ≥ 5-point increase (SF-36 domains). BASDAI Bath Ankylosing Spondylitis Disease Activity Index, BP bodily pain, EQ-5D-5L EuroQoL 5-Dimension 5-Level index score, FACIT-F Functional Assessment of Chronic Illness Therapy-Fatigue, GH general health, HAQ-DI Health Assessment Questionnaire-Disability Index, MCID minimal clinically important difference, MCS mental component summary, MH mental health, NA not available, NNT number needed to treat, NRI non-responder imputation, PBO placebo, PCS physical component summary, PF physical functioning, PRO patient-reported outcome, PtGA Patient Global Assessment of Disease Activity, RE role-emotional, RP role-physical, SF social functioning, SF-36 36-Item Short Form Health Survey, UPA upadacitinib, VT vitality

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Scores ≥ normative values in most PROs were reported by a significantly greater proportion of patients with both doses of upadacitinib versus placebo at week 12 (nominal p < 0.05; Fig. 4), with responses maintained at week 24 (Fig. S5 in the electronic supplementary material). At week 12, the proportion of patients receiving upadacitinib 15 mg and 30 mg reporting scores ≥ normative values were 25% and 32%, respectively, in PtGA versus 9% with placebo; 28% and 31%, respectively, in HAQ-DI versus 12% with placebo; and 29% and 35%, respectively, in FACIT-F versus 17% with placebo (Fig. 4a).

Fig. 4
figure 4

Proportion of patients reporting PRO scores ≥ normative values at baseline and week 12 and age- and gender-matched normative values in SF-36 domains (NRI). a PROs excluding SF-36 domains. b SF-36 domains. *p < 0.05, †p ≤ 0.01, and ‡p ≤ 0.001 versus placebo. p values nominal. The percentage at 12 weeks might or might not include the same patients that achieved that outcome at baseline. BL baseline, BP bodily pain, EQ-5D-5L EuroQoL 5-Dimension 5-Level index score, FACIT-F Functional Assessment of Chronic Illness Therapy-Fatigue, GH general health, HAQ-DI Health Assessment Questionnaire-Disability Index, MCS mental component summary, MH mental health, NRI non-responder imputation, PBO placebo, PCS physical component summary, PF physical functioning, PtGA Patient Global Assessment of Disease Activity, PRO patient-reported outcome, RE role-emotional, RP role-physical, SF social functioning, SF-36 36-Item Short Form Health Survey, UPA upadacitinib, VT vitality

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Discussion

In this post hoc analysis of the phase 3 SELECT-PsA 2 study of PsA patients refractory or intolerant to bDMARDs, upadacitinib treatment provided significant and clinically meaningful improvements across a broad range of PROs after 12 and 24 weeks compared with placebo. In PtGA, pain, and HAQ-DI, these were reported as early as 2 weeks after treatment initiation. With upadacitinib, significantly greater percentages of patients reported PRO scores ≥ normative values, reflective of a population without inflammatory arthritis. Additionally, NNTs ≤ 10, considered economically and clinically meaningful [36], were calculated based on improvements ≥ MCID with upadacitinib at weeks 12 and 24 across all PROs. Improvements in these PROs were maintained through week 56.

PROs reflect many important issues that significantly impact patients with PsA, including challenges in mental, physical, and social functioning, pain, fatigue, work-related disability, in addition to psoriatic, axial, and skin disease symptoms. Many of these symptoms and sequelae of disease are represented by the core domains recommended by the GRAPPA-OMERACT working group to be measured in all RCTs to evaluate treatment efficacy [2, 3, 18, 37,38,39,40]. In a recent qualitative interview study of PsA patients recruited through the FORWARD databank, joint pain and stiffness, skin symptoms, fatigue, and physical disability were identified as some of the most salient PsA symptoms [39]. Similarly, pain, fatigue, and poor HRQOL have been identified as some of the highest-ranking outcomes that patients would want treatment to remedy [40]. In an international survey of 1268 patients with PsA, moderate-to-major impairment was reported in 78, 62, and 69% of patients in physical activity, work productivity, and emotional/mental well-being, respectively [37]. In a separate study, approximately 50% of patients reported the social impact of PsA to include negative effects on personal relationships, relationships with family and friends, and engagement in sports and recreational activities [37]. The results presented here demonstrate that upadacitinib has the potential to provide a substantial positive impact on symptoms, domains, and the impact of disease on HRQOL that most affect patients with PsA.

These results also complement the primary clinical findings from SELECT-PsA 2, where significant clinical improvements in musculoskeletal and psoriatic symptoms of PsA were observed with upadacitinib compared with placebo [15]. Additionally, the magnitude of improvements in PROs reported in this RCT in a more heavily treated bDMARD-IR population is similar to those reported by the biologic-naïve population in the parallel phase 3 RCT, SELECT-PsA 1 (NCT03104400) [16, 41]. Further, nominally significant improvements with both upadacitinib doses versus placebo at week 12 were more consistently reported in SELECT-PsA -2 than -1 [41].

Treatment options for patients with PsA who are refractory to bDMARDs are limited. The inhibitors for JAK (tofacitinib), IL-12/23 (ustekinumab), IL-23 (guselkumab), and IL-17A (secukinumab and ixekizumab) have demonstrated efficacy and HRQOL improvements in this patient population and are approved for treatment of PsA [42,43,44,45,46]. Although comparisons between these and the current RCT are difficult owing to differences in treatment mechanisms of action, study designs and patient populations, some observations can be made. Following 12 weeks of tofacitinib 5 or 10 mg BID treatment, statistically significant improvements versus placebo were similarly reported in PtGA, pain, HAQ-DI, SF-36 PCS, FACIT-F, and EQ-5D scores and 4 and 5 SF-36 domains, respectively [42]. NNTs were generally lower with upadacitinib than tofacitinib treatment, reflecting the percentages of patients reporting improvements ≥ MCID with tofacitinib versus placebo did not statistically differ in FACIT-F and 4/8 SF-36 domains [42]. Further, with tofacitinib treatment, the percentages reporting scores ≥ normative values were not significantly different from placebo across the majority of PROs, noting that all patients in the BEYOND protocol were required to have been receiving methotrexate [42]. With secukinumab and ixekizumab, significant improvements at weeks 16 and 24, respectively, were reported across most PROs compared with placebo, similar to upadacitinib [45, 46], and, like upadacitinib, ixekizumab was reported to resolve itch [46].

A limitation of this study was that it was not powered to detect differences between upadacitinib treatment arms and there was no placebo or active comparator after week 24. Additionally, results may not be generalizable beyond the trial patient population.

Conclusions

Patients with active PsA who had failed ≥ one bDMARD reported significant and clinically meaningful improvements in PROs with upadacitinib 15 or 30 mg QD through 24 weeks, maintained or further improved through 56 weeks. Clinically meaningful responses in PtGA, pain, and HAQ-DI were reported as early as week 2 with both doses of upadacitinib with NNTs ≤ 10 at weeks 12 and 24. Further, significantly more patients receiving upadacitinib reported scores ≥ normative values across all evaluated PROs. In summary, these results highlight the potential for upadacitinib to provide substantial improvement in HRQOL and other important patient-reported outcomes in patients with PsA.