Current data and expert opinions on the therapeutic goal of remission

The management of inflammatory rheumatic diseases has improved significantly in recent years with the development of targeted treatments [1]. But how realistic is achieving remission today? The following report provides a summary of current data and the assessments of various experts on the therapeutic goal of remission in rheumatoid arthritis, psoriatic arthritis and spondyloarthritis.

The chronic inflammatory rheumatic diseases rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondyloarthritis (AS) are painful and severely impair the quality of life of those affected. Without proper treatment, the conditions can cause permanent joint damage and lead to disability [2-4]. Because of the heterogeneous nature of the disease, the management of RA, PsA, and AS is complex and often requires several different treatment approaches [4-6]. In addition to tumor necrosis factor inhibitors.
(TNFi), the selective Janus kinase inhibitor (JAKi) upadacitinib (UPA) can also be used in Switzerland in all three indications [7, 8]. The ultimate goal of therapy is to achieve remission – a state in which the disease is completely inactive or so inactive that the patient no longer notices it [5, 6, 9].

More than one in four RA patients with UPA in remission [10]

In RA, achievement of remission in clinical trials is often defined by a 28-Joint Disease Activity Score (DAS28) < 2.6 [11]. DAS28-CRP < 2.6 remission was achieved by 29% of RA patients treated with UPA (15 mg, 1 x daily) and methotrexate (MTX) for 12 weeks in the randomized phase III SELECT-COMPARE trial who had previously had an inadequate response to MTX. Under adalimumab (ADA) and MTX, the remission rate was 18%, and under placebo (PBO) and MTX, it was 6% (both P ≤ 0.001) [10]. After 156 weeks, 32% of patients in the UPA + MTX arm and 22% of patients in the ADA + MTX arm were in remission (P < 0.001) [12].

Also, with UPA as monotherapy, 28% of RA patients with inadequate response to MTX achieved DAS28-CRP < 2.6 remission at 14 weeks in the randomized phase III SELECT-MONOTHERAPY trial, compared with 8% of patients receiving MTX monotherapy (P ≤ 0.0001) [13]

Remission in RA achievable even after TNFi failure [14]

A post-hoc subgroup analysis of 568 TNFi-IR patients from the Phase III studies SELECT-BEYOND, SELECT-CHOICE and SELECT-COMPARE [10, 15, 16] presented at the American College of Rheumatology (ACR) Convergence shows that UPA can also achieve remission in RA patients who have had an inadequate response to or are intolerant of treatment with a TNFi (TNFi-IR): After 12 weeks, 30.1%, 30.4% and 28.3% of patients treated with UPA (15 mg, 1 x daily) in the three studies had achieved DAS28-CRP remission ( Figure 1 ). At 24 weeks, it was 34.9%, 46.8%, and 32.1% of patients, respectively [14].

Figure 1: Remission rates (DAS28-CRP < 2.6) in RA patients on upadacitinib (15 mg, 1 x daily) who previously had an inadequate response to or were intolerant of a TNFi in a post hoc subgroup analysis of the phase III SELECT-BEYOND, SELECT-CHOICE, and SELECT-COMPARE trials. Adapted from [14].

Safety profile of UPA in RA [17]

Integrated safety analysis of five SELECT studies in which 3834 RA patients were treated with UPA for a total of more than 4000 patient-years showed a comparable safety profile of UPA (15 mg, 1 x daily) and ADA in terms of serious infections, malignancies, major adverse cardiovascular events (MACE), and venous thromboembolism (VTEs), but revealed an increased incidence of herpes zoster and elevation of creatine phosphokinase levels with UPA on [17].

Improved remission rates in PsA with UPA vs. PBO. [18]

In clinical studies on PsA, the Minimal Disease Activity (MDA) criteria, which cover the entire spectrum of psoriatic disease, and the Disease Activity in Psoriatic Arthritis (DAPSA) score, which exclusively reflects joint involvement, are used to assess whether a patient is in remission [19].

In the randomized phase III SELECT-PsA-1 trial of 1705 PsA patients who had inadequate response or intolerance to nonbiologic disease-modifying anti-rheumatic drugs (DMARDs), 37% of patients on UPA (15 mg, 1 x daily) met 5 of 7 criteria for MDA at 24 weeks, which can be interpreted as remission. This was achieved by 33% of patients in the ADA arm (40 mg, every 2 weeks) and 12% in the PBO arm (Figure 2) [18]. DAPSA remission (≤ 4 points) had been achieved at this time by 11% of patients on UPA, 10% on ADA, and 3% on PBO (P < 0.05 UPA vs PBO) [20].

As shown in the current analysis of the SELECT-PsA-1 trial, 42% of patients on UPA and 38% of patients on ADA were in MDA remission after 2 years (no significant difference) [21].

Remission possible for PsA patients after biologics failure [20]

That PsA patients can benefit from treatment with UPA even after biologic failure is shown by the results of the randomized phase III SELECT-PsA-2 trial of 641 patients who had inadequate response or intolerance to at least one biologic DMARD [22]. Also in this patient population, the MDA response rate at 24 weeks was more than 22% higher with UPA than with placebo (25% vs 2%; P < 0.05) (Figure 2). In DAPSA remission were 7% of patients treated with UPA and none of those receiving PBO (P < 0.05) [20]. After 3 years, 31.1% of patients treated with UPA showed MDA remission. [23].

The safety profile of UPA in PsA was comparable to that of ADA at 3 years, according to an integrated analysis of both the SELECT-PsA-1 and -2 trials, except for the more frequent occurrence of herpes zoster and opportunistic infections with UPA. Rates of malignancy, MACEs, VTE, and death were comparable under UPA and ADA [24].

Figure 2: MDA and DAPSA remission rates at 24 weeks in PsA patients receiving placebo, upadacitinib, or adalimumab in the randomized phase III SELECT-PsA-1 and SELECT-PsA-2 trials. Post hoc analysis with 1386 patients. * nominal P value < 0.05 (UPA vs. PBO) SELECT-PsA-1: patients who had an inadequate response to or were intolerant of at least 1 nonbiologic DMARD; SELECT-PsA-2: patients who had an inadequate response to or were intolerant of at least 1 biologic DMARD. MDA: minimal disease activity, 5 of 7 criteria met; DAPSA-REM: ≤ 4 points according to Disease Activity in Psoriatic Arthritis; ADA EOW: adalimumab (40 mg, biweekly) PBO: placebo; UPA: upadacitinib QD (15 mg, 1 x daily). Adapted from [20].

UPA in AS achieves significantly higher remission rates than placebo [25, 26].

In AS, achieving an Ankylosing Spondylitis Disease Activity Score (ASDAS) < 1.3 is considered remission in clinical trials. The ASDAS considers back pain, peripheral joint pain and swelling, morning stiffness, and C-reactive protein (CRP) level [27].

At the conclusion of the 14-week double-blind phase of the randomized phase IIb/III SELECT-AXIS 1 trial of 187 AS patients who had previously responded inadequately to nonsteroidal anti-inflammatory drugs (NSAIDs), 16% of patients on UPA (15 mg, 1 x daily) were in ASDAS <1.3 remission. This was not achieved in any patient who received PBO (P < 0.0001) [25]. After 64 weeks, more than one in three patients in the UPA arm had achieved remission [28].

The randomized phase III SELECT-AXIS 2 trial included 420 AS patients who had inadequate response or intolerance to biologics. Here, the ASDAS <1.3 remission rate at 14 weeks was 13% in the UPA arm and 2% in the PBO arm (P = 0.0001) [26]. Also, no new safety signals for UPA were recorded in the two AS studies [25, 26].

Conclusion

As recent study data show, UPA can enable a significant proportion of patients to achieve the therapeutic goal of remission in the three indications RA, PsA and AS – even if they have previously responded inadequately to a biologic [10, 14, 18, 20, 25, 26]. In addition, the safety profile of UPA is comparable to that of ADA in terms of serious infections, MACE, malignancies, and VTE [17, 24-26]. Overall, JAKi shows a favorable benefit-risk profile and, also due to its once-daily oral administration, offers a valuable addition to the treatment repertoire in chronic inflammatory rheumatic diseases [7, 29].

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