Patient-Reported Outcomes of Upadacitinib Versus Abatacept in Patients with Rheumatoid Arthritis and an Inadequate Response to Biologic Disease-Modifying Antirheumatic Drugs: 12-Week Results of a Phase 3 Trial

Background In previous clinical trials, patients with active rheumatoid arthritis (RA) treated with upadacitinib (UPA) have improved patient-reported outcomes (PROs). This post hoc analysis of SELECT-CHOICE, a phase 3, double-blind, randomized clinical trial evaluated the impact of UPA vs abatacept (ABA) with background conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) on PROs in patients with RA who have inadequate response or intolerance to biologic DMARDs (bDMARD-IR). Methods: Patients in SELECT-CHOICE received UPA (oral 15 mg once daily) or ABA (intravenous). PROs evaluated included Patient Global Assessment of Disease Activity (PtGA) by visual analog scale (VAS), patient’s assessment of pain by VAS, Health Assessment Questionnaire Disability Index (HAQ-DI), duration and severity of morning stiffness, 36-Item Short Form Health Survey (SF-36), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Work Productivity and Activity Impairment (WPAI), and EQ-5D 5-Level (EQ-5D-5L) index score. Least squares mean (LSM) changes from baseline to week 12 were based on an analysis of covariance model. Proportions of patients reporting improvements ≥ minimal clinically important differences (MCID) were compared using chi-square tests. Results: Data from 612 patients were analyzed (UPA, n=303; ABA, n=309). Mean age was 56 years and mean disease duration was 12 years. Thirty-two percent received >1 bDMARD and 72% received concomitant methotrexate at baseline. At week 12, UPA treatment showed signicantly greater improvements than ABA treatment in PtGA, pain, HAQ-DI, morning stiffness severity, EQ-5D-5L, WPAI activity impairment domain, and 3/8 SF-36 domains and physical component summary (PCS) scores (P<0.05). Signicantly more UPA- vs ABA-treated patients reported improvements ≥ MCID in HAQ-DI (74% vs 64%) and SF-36 PCS (79% vs 66%) and 4/8 domain scores (P<0.05). The proportions of patients achieving MCID in the remaining PROs were similar between groups. Conclusions: In this study, treatment with UPA or ABA resulted in clinically meaningful improvements in PROs at week 12 in patients with active RA. UPA treatment elicited greater improvements in key domains of physical functioning, pain, and general health, and earlier improvements in HAQ-DI compared with ABA.


Introduction
Patients with rheumatoid arthritis (RA) frequently experience pain, fatigue, and impaired physical functioning that may impact their health-related quality of life (HRQOL) and ability to work and participate in daily activities (1)(2)(3)(4). Relief of pain is an important treatment outcome for patients and a primary reason for seeking medical care (2). The restrictions on patients' daily work and social activities due to symptom burden has a signi cant impact on their nancial and social well-being (2,4,5). With a signi cant burden on HRQOL, treatment decisions are recommended as a shared decision between the patient and physician (6). Guidelines recommend conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), such as methotrexate (MTX), as a rst-line treatment strategy and biologic DMARDs (bDMARDs) like abatacept (ABA), anti-TNF inhibitors, or Janus kinase (JAK) inhibitors as second-line therapy options (6). Unfortunately, up to 43% of patients do not respond to rst line csDMARD therapy and as many as two-thirds who receive bDMARDs have an inadequate response (bDMARD-IR) after one year of therapy (7,8). Thus, this population is di cult to adequately treat and, as such, exhibit marked increases in healthcare resource utilization; bDMARD-IR patients experienced up to 7-fold increases in hospital length of stay, admissions, and emergency department visits as compared with patients that responded to bDMARD therapy (7).
Discordance between healthcare provider and patient perceptions of disease exist (9,10), especially in patients continuing to experience pain despite in ammation being controlled (11) or by those continuing to experience fatigue despite achieving remission (12). To fully understand the disease burden and bene ts of treatment from the perspective of patients with RA, it is important to include PROs as part of clinical trials and evaluation of treatment e cacy. This is especially true for patients with inadequate response to csDMARDs (csDMARD-IR) and bDMARD-IR. Treatment with upadacitinib (UPA), an oral JAK inhibitor, has resulted in clinically meaningful improvements in patient-reported outcomes (PROs), including in key components of pain, fatigue, and physical functioning (13)(14)(15). Improvements in PROs have been observed with UPA as monotherapy (16) and in combination with MTX (13,15). Improvements were equivalent to or greater than with anti-TNF inhibitor adalimumab (14). In patients with inadequate response or intolerance to MTX, UPA treatment signi cantly improved patient-reported pain and physical functioning (13,14). In a head-to-head comparison with adalimumab, ABA (a T cell costimulator) demonstrated improved patient-reported outcomes (17,18). ABA is commonly prescribed as a second-line bDMARD for the treatment of RA, and comparisons of ABA to JAK inhibitors is limited (19)(20)(21)(22). The use of JAK inhibitors is expected to noticeably increase due to their overall e cacy in RA, especially when compared to biologic therapies and their ease of administration (ie, oral) (19). Further research is needed to guide treatment decisions, particularly from the patients' perspective. This post hoc analysis evaluated the impact and bene ts of treatment with oral UPA versus intravenous (IV) ABA on PROs at week 12 in a head-to-head comparison in patients with active RA and bDMARD-IR in SELECT-CHOICE (23).

Study design and participants
Full details of the study design of SELECT-CHOICE (NCT03086343) were previously reported (23). This study was a Phase 3, double-blind, randomized clinical trial in patients with active bDMARD-IR RA currently receiving background csDMARD therapy. Patients ≥ 18 years of age with moderately to severely active RA for ≥ 3 months on a stable background of csDMARD therapy (≥ 3 months prior to study entry) were randomized double-blind to receive either oral UPA (15 mg once daily) with IV placebo or IV ABA and oral placebo. Both IV placebo and ABA treatments were administered on day 1 and at weeks 2, 4, 8, and 12 at doses of 500, 750, or 1000 mg, depending on patient weight (< 60 kg, 60-100 kg, or > 100 kg, respectively). Concomitant use of ≤ 2 of the following csDMARDs was permitted: MTX, sulfasalazine, hydroxychloroquine, chloroquine, or le unomide; combination of MTX and le unomide was not permitted. Eligible patients had no previous exposure to ABA. Data on the primary and ranked secondary outcomes of this study have been published previously (23). The protocol was approved by independent ethics committee or institutional review board at all study sites. All participants provided written, informed consent prior to enrollment. The registered clinical trial was conducted in accordance with the ethical principles that have their origin in the current Declaration of Helsinki and is consistent with the International Conference on Harmonization Good Clinical Practice and Good Epidemiology Practices, and all applicable local regulatory requirements. All patient data were de-identi ed and complied with patient con dentiality requirements.

Time to Treatment Response
The time to response, as measured by HAQ-DI, was signi cantly shorter for UPA-vs ABA-treated patients (medians: 2 weeks vs 4 weeks, P < 0.01 [data not shown]). The median time to response was not statistically signi cantly different for UPA-versus ABA-treated patients in pain (2 weeks vs 4 weeks).
There was no difference in the median time to response for morning stiffness severity or morning stiffness duration.

Discussion
JAK inhibitors, including UPA, are a newer class of treatment for RA in comparison to other biologics such as abatacept, which have been commonly accepted therapies for patients with RA over the past 20 years.
Understanding the e cacy of newer therapies, especially as they compare to more established ones, is important because nearly half of patients do not adequately respond to rst-line csDMARDs and up to 66% do not adequately respond to second-line biologics (7,8). Thus, these patients represent a population that may be more di cult to treat. The SELECT-CHOICE study is a Phase III trial that is a direct head-to-head comparison of e cacy, safety, and PROs between UPA and ABA in a bDMARD-IR population (23). Primary e cacy data demonstrated that UPA was superior to ABA in the change from baseline in DAS28-CRP and achievement of remission after 12 weeks of treatment (23). As a supplement to the clinical e cacy results, analysis of other secondary endpoints showed that both UPA and ABA demonstrated improvement in PROs, however UPA treatment resulted in more signi cant and clinically meaningful improvements in PROs at 12 weeks when compared with ABA. Differences between the treatments were seen in key domains of physical functioning, pain, and general health with improvements in HAQ-DI observed earlier in UPA-vs ABA-treated patients. In this study, patients treated with UPA achieved signi cantly greater improvements from baseline in PtGA, pain, HAQ-DI, and FACIT-F as compared with ABA. Likewise, SF-36 PCS, 3 SF-36 domains (ie, physical functioning, bodily pain, and general health), and 2 WPAI domains (ie, presenteeism and activity impairment) showed signi cant improvement with UPA vs ABA. Similar improvements were noted for UPA and ABA in other PROs. The improvements in PROs reported with UPA in this study are similar to those improvements seen with UPA previously in csDMARD-IR and bDMARD-IR patient populations and highlight the superiority of UPA vs ABA at week 12 (13)(14)(15)23). Data from SELECT-COMPARE, which compared UPA, placebo, and adalimumab at 12 weeks also demonstrated signi cant improvements with UPA in PtGA, pain, HAQ-DI, morning stiffness severity, FACIT-F, SF-36 PCS, and 6/8 SF-36 domain scores as compared with adalimumab (14). Importantly, SELECT-COMPARE enrolled patients who received csDMARDs contrasts with this study, which enrolled bDMARD-IR patients who represent a di cult-to-treat population with a greater, unmet medical need.
Assessment of PROs in chronic disease is key to understanding patient perspectives and should be included when analyzing study drug e cacy. PROs are useful tools to measure the impact of chronic illness on daily living and work abilities because these also impact healthcare resource utilization and overall economic burden of disease. Likewise, PROs can in uence treatment decisions and provide a more customized approach to disease management, especially when treatments are comparable (35).
When selecting treatments, time to response, route of administration, and quantity of doses taken per day are also important factors to consider as they may greatly affect patient's perception of e cacy and overall treatment adherence (36, 37). Patients with RA frequently experience pain, fatigue, and impaired physical functioning and these may have negative impacts on their HRQOL (1)(2)(3)(4). Fatigue and pain are also associated with reductions in mental well-being and the ability of patients to perform daily activities and maintain employment (4,38,39). In the current study, improvements in physical functioning (HAQ-DI) and severity of morning sickness were observed as early as 2 weeks after treatment initiation with UPA. After 12 weeks of treatment, greater proportions of UPA-vs ABA-treated patients reported clinically meaningful improvements in physical functioning and in 4 of 8 SF-36 domain and PCS scores. The proportion of UPA-vs ABA-treated patients reporting scores ≥ normative values after 12 weeks treatment was signi cantly greater in PtGA, physical functioning, general HRQOL by EQ-5D-5L, and SF-36 PCS and 3 of 8 domain scores (ie, physical functioning, bodily pain, and general health). Similar percentages of patients (over half) treated with UPA or ABA achieved clinically meaningful reductions in work and activity impairment. Likewise, similar percentages of patients treated with UPA or ABA also achieved clinically meaningful reductions in the key symptom of fatigue. Importantly, patients reported shorter median response times to improvements in physical functioning with UPA treatment compared with ABA.
Together, these results suggest that UPA may lead to meaningful improvements in key PROs that are important to patients, including fatigue, pain, physical functioning, and ability to perform work and daily activities.
There are both strengths and limitations to this study. Strengths of the study include the utilization of several validated PROs that re ect the different aspects of the patient experience. To our knowledge, this is the rst clinical study comparing a JAK inhibitor to ABA in a bDMARD-IR population. This study lls the gap by providing important data on patient-perceived e cacy in this population. The use of MCIDs and normative values allow for the data to be clinically meaningful and interpretable for patients and physicians. Blinded and randomized study design allows for unbiased reporting from each patient and mitigates biases due to differences between treatment groups. Limitations of the study include the collection of PROs at xed visits, sometimes weeks apart, with no day-to-day data available. Prolonged recall of such dynamic symptoms may introduce recall bias that could affect patient perceptions of e cacy (40). The PROs presented here were not multiplicity controlled, ranked secondary endpoints, thus all signi cance values are nominal. Imputation of missing data as non-response may lead to an underestimation of the true response rate for each PRO. The time frame of this analysis was relatively short (12 weeks), and e cacy data only extended to 24 weeks, thus additional studies are needed to determine if the patient-reported improvements observed are maintained long-term.

Conclusions
Treatment with UPA or ABA resulted in rapid and clinically meaningful improvements in PROs among bDMARD-IR patients with moderately to severely active RA. Overall, greater improvements in PROs, especially in the key domains of physical functioning, pain, and general health, were observed with treatment with UPA compared with ABA after 12 weeks of treatment. Meaningful improvements in physical functioning were observed more quickly in UPA versus ABA treated patients. Good Epidemiology Practices, and all applicable local regulatory requirements. All patient data were deidenti ed and complied with patient con dentiality requirements.

Consent for publication
Not applicable.
analysis plan development and conducted analysis. MB and GCW contributed to study design and analysis plan review, as well as results interpretation. All authors reviewed and approved the nal manuscript.