The disease burden and current treatment landscape
Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease with complex clinical manifestations such as plaque psoriasis, dactylitis and enthesitis. Patients with PsA often experience fatigue, physical function limitations, sleep disturbance, as well as diminished work capacity and social participation. The disease is also associated with several comorbidities including cardiovascular disease, uveitis, autoimmune gut disorders, depression and anxiety. The clinical burden of PsA translates to substantial costs for patients and society that result from direct medical costs, disability and lost productivity.
PsA treatment is highly complex due to the heterogeneity of the disease. Treatment often begins with a trial of conventional synthetic disease modifying antirheumatic dugs (csDMARDs), such as methotrexate or sulfasalazine. For decades, the therapeutic agents used to treat PsA have been employed on the basis of data from patients with rheumatoid arthritis (RA), and have not been adequately evaluated in patients with PsA. Further, conventional DMARDs have adverse effects that often lead to drug discontinuation and are often ineffective at reducing symptoms or radiographic progression in PsA. Encouragingly, the treatment landscape has changed substantially and rapidly in the last decade with multiple therapeutic choices available to address the progressively destructive nature of the disease. Newer therapies in the foray include biologics such as TNF inhibitors, IL-17 inhibitors and IL-12/23 inhibitors, as well as targeted DMARDs such as a Janus kinase (JAK) inhibitors.
Drug profile: upadacitinib’s efficacy and safety
In November 2021, the newest JAK inhibitor, upadacitinib (Rinvoq) by Abbvie, received market authorisation in Singapore for the treatment of ‘active PsA in adult patients who have responded inadequately to, or who are intolerant to one or more DMARDs.’ Upadacitinib is an oral reversible selective JAK inhibitor available in Singapore as a 15mg extended-release oral tablet. Its selectivity for JAK1, compared with other JAK subtypes, provides upadacitinib a degree of disease specificity that differentiates it from tofacitinib, the only other JAK inhibitor currently approved in Singapore for PsA. Although their comparative efficacy and safety in PsA have not been evaluated in head-to-head clinical trials, upadacitinib’s selective JAK1 blockade is postulated to confer a better safety profile, reducing the risk of infection and cytopenia.
The efficacy and safety of upadacitinib in PsA are supported by data from 2 large long-term Phase III trials, SELECT-PsA 1 and SELECT-PsA 2. The trials recruited patients with active PsA (≥3 swollen and ≥3 tender joints) and a prior inadequate response or intolerance to ≥1 non-biologic DMARD. Patients received either once daily upadacitinib 15mg or 30mg, adalimumab 40mg every other week, or a placebo. The primary endpoint for both trials was a 20% improvement in American College of Rheumatology (ACR20) at Week 12. Other secondary endpoints evaluated include achievement of minimal disease activity, pain, fatigue, physical function, musculoskeletal symptoms and quality of life.
Across SELECT-PsA 1 and SELECT-PsA 2, upadacitinib met its primary endpoint of ACR20 at Week 12. Both doses of upadacitinib were significantly superior to placebo in terms of achieving higher ACR20 responses. In SELECT-PsA 1, upadacitinib 15mg and 30mg once daily were also found to be non-inferior to adalimumab at week 12, with superiority demonstrated for upadacitinib 30mg. No new safety signals were identified and upadacitinib’s safety profile was generally consistent with results reported previously in RA trials. A brief overview of the SELECT-PsA clinical program, populations, primary outcomes and safety data are described in the table below.
| Trial | Intervention/ Comparator | Primary Efficacy Outcome | Safety |
| SELECT-PsA 1
N=1,704 Female 53.2% Mean age 50.8y 82% were on ≥1 concomitant non-bDMARD (84% MTX +/- another non-bDMARD) |
Randomized 1:1:1:1 to:
Through to Week 24 At Week 24, placebo patients were switched to UPA 15mg or UPA 30mg. All other treatment arms remained unchanged through to Week 56. |
Primary: At Week 12, ACR20 rates were: 70.6% vs 78.5% vs 65% vs 36.2% for UPA 15mg, UPA 30mg, ADA and placebo respectively
|
|
| SELECT-PsA 2
N=642 Female: 54.3% Mean age: 53.3y 34.6% were on MTX alone at baseline |
Randomized 2:2:1:1 to
|
At Week 12, ACR20 response was achieved in 56.9%, 63.8% and 24.1% of the UPA 15mg, UPA 30mg and placebo arms respectively; p<0.001 for both UPA arms vs placebo |
|
Abbreviations – UPA: upadacitinib, ADA: adalimumab, MTX: methotrexate, TEAE: treatment-emergent adverse events, URTI: upper respiratory tract infection, PBO: placebo, MACE: major adverse cardiovascular event, AE: adverse event
Notably, approximately 31% of patients in the SELECT-PsA 1 (n=534/1,704) and 34% in SELECT-PsA 2 (n=219/640) had axial involvement, a group that is historically more likely to have a higher disease burden and poorer quality of life impairments compared to patients without axial involvement. Further, the trials observed a greater efficacy with upadacitinib 15mg and 30mg once per day versus placebo for clinical manifestations of PsA which include physical function (assessed by HAD-DI) and fatigue (measured by the FACIT-F).
Practice implications and cost-efficacy considerations
A systemic review of real world studies and RCTs by Zardin-Moraes, 2019, estimated that only one-third of PsA patients were able to achieve minimal disease activity (MDA) with the present treatment options. There is thus a pressing clinical need for a range of treatment options in PsA due to disease heterogeneity and its massive negative impact on quality of life, with significant humanistic, clinical and societal burden.
Evidence to date has demonstrated upadacitinib’s efficacy over placebo, and similar efficacy to adalimumab for treating active PsA. Further, the drug also conferred improvements in musculoskeletal symptoms, psoriasis, physical function, pain, fatigue and inhibited radiographic progression. A key limitation in the current body of evidence however rests in the fact that upadacitinib has not been directly compared with any other biological DMARD (bDMARD) for the treatment of PsA. To address this, a company-submitted network meta-analysis has suggested that overall, upadacitinib produced broadly equivalent results compared with the current therapeutic options and is likely to work as well as other bDMARDs in csDMARD-experienced PsA populations and bDMARD-experienced PsA populations.
Its cost efficacy also remains contentious in the broader landscape of alternative bDMARDs. Most recently in January 2022, the UK NICE issued a Final Appraisal Determination outlining its subsidy recommendation of upadacitinib in patients with PsA. NICE’s approval was based on upadacitinib’s commercial arrangement with the NHS and in the context of patients with PsA with three or more tender joints and three or more swollen ligaments, if they have had two csDMARDs and at least one bDMARD, or TNF-alpha inhibitors are contraindicated but would otherwise be considered. NICE’s recommendation ultimately highlights approval of a relatively expensive third-line therapeutic in a treatment landscape faced with a high unmet need. Cost and reimbursement decisions in the local Singapore context has yet to be formally evaluated, but intersectoral support will ultimately be required to support treatment access and improve disease outcomes.
