Achievement of treatment targets and maintenance of response with upadacitinib in patients with moderate-to-severe rheumatoid arthritis in real-world practice: 1-year outcomes from the UPHOLD observational study

Abstract

Background: Upadacitinib (UPA), an oral Janus kinase inhibitor, has shown efficacy with an acceptable safety profile in rheumatoid arthritis (RA) clinical trials.

Objective: To assess the real-world effectiveness and safety of UPA in adults with moderate-to-severe RA in the UPHOLD observational study.

Methods: Co-primary endpoints were: (i) proportion of patients achieving disease activity score in 28 joints using C-reactive protein (DAS28[CRP]) remission (< 2.6) at 6 months; and (ii) proportion of those patients maintaining remission at 12 months. Additional analyses included proportions of patients achieving and maintaining DAS28(CRP) low disease activity (LDA; ≤ 3.2), other composite measures of disease activity, and subgroup analyses by therapy strategy and prior treatment. Treatment-emergent adverse events (TEAEs) in the full analysis set (FAS; patients receiving ≥ 1 UPA dose) were reported through August 10, 2023. Co-primary and selected secondary endpoints were analyzed by modified non-responder imputation (mNRI) in modified (m)FAS1 (FAS patients who completed 6 months of treatment and had DAS28[CRP] data available, and those who discontinued before 6 months) and mFAS2 (mFAS1 patients who achieved remission at 6 months, completed 12 months of treatment, and had DAS28[CRP] data available, and those who discontinued between 6 and 12 months); and as observed (AO) in patients with non-missing data.

Results: Of 1719 participants, 1717 were enrolled; 1701 comprised the FAS. Overall, 400/1719 (23.3%) patients discontinued before 12 months. Of mFAS1 patients, 499 (mNRI: 499/1074 [46.5%]; AO: 499/902 [55.3%]) achieved DAS28(CRP) remission at 6 months; of mFAS2 patients, 269 (mNRI: 269/340 [79.1%]; AO: 269/317 [84.9%]) maintained remission at 12 months. DAS28(CRP) remission or LDA rates were consistent regardless of whether UPA was initiated and maintained as monotherapy or combination therapy. Similar responses were observed across prior treatment subgroups. Among selected TEAEs of special interest, herpes zoster and serious infection occurred at 3.12 and 2.62 events/100 patient-years, respectively. No new safety signals were identified.

Conclusions: UPA demonstrated real-world effectiveness in moderate-to-severe RA, with approximately half of patients achieving DAS28(CRP) remission at 6 months and most maintaining remission through 12 months. The real-world benefit-risk profile of UPA remains favorable and is consistent with phase 3 clinical trial data.

Trial registration: NCT04497597.

Keywords: Effectiveness; Real-world; Rheumatoid arthritis; Safety; Upadacitinib.

Fig. 1

Patient disposition Note: Some patients may have discontinued the study treatment but remained in the study and completed the 6- or 12-month follow-up for baseline and safety assessments. Premature discontinuation refers to patients who discontinued the study before the specified timepoint AE adverse event, DAS28(CRP) disease activity score in 28 joints using C-reactive protein, D/C discontinuation, FAS full analysis set, f/u follow-up, LOE lack of efficacy, mFAS modified FAS

Fig. 2

Achievement (A, B) and maintenance (C, D) of DAS28(CRP) remission (< 2.6) and LDA (≤ 3.2) (mNRI and AO) Error bars represent 95% confidence intervals ^amFAS1: All patients within the FAS who completed 6 months of UPA 15 mg treatment and had DAS28(CRP) data available (n = 902) or who discontinued treatment for any reason before month 6 (n = 172). ^bNumber of patients in mFAS1 with non-missing data. ^cmFAS2: All patients within mFAS1 who achieved remission at 6 months and completed 12 months of UPA 15 mg treatment and had DAS28(CRP) data available (n = 317), or who discontinued treatment for any reason between 6 and 12 months (n = 23). ^dNumber of patients in mFAS2 with non-missing data. ^eAll patients within mFAS1 who achieved LDA at 6 months and completed 12 months of UPA 15 mg treatment and had DAS28(CRP) data available (n = 395), or who discontinued the study between 6 and 12 months (n = 41). ^fNumber of patients within mFAS1 who achieved LDA at 6 months and completed 12 months of UPA 15 mg treatment and had DAS28(CRP) data available, or who discontinued the study between 6 and 12 months with non-missing data AO as observed, DAS28(CRP) disease activity score in 28 joints using C-reactive protein, FAS full analysis set, LDA low disease activity, mFAS modified FAS, mNRI modified non-responder imputation, RA rheumatoid arthritis, UPA upadacitinib

Fig. 3

Disease activity by DAS28(CRP), CDAI, and SDAI at baseline, 6 months, and 12 months (AO) Note: The proportion of patients who achieved each level of disease activity was calculated using the number of patients with non-missing data for the disease activity score as the denominator. The sum of the proportions may not total 100.0% due to rounding DAS28(CRP) remission: < 2.6; LDA: 2.6 ≤ DAS28(CRP) ≤ 3.2; MDA: 3.2 < DAS28(CRP) ≤ 5.1; HDA: > 5.1. CDAI remission: ≤ 2.8; LDA: 2.8 < CDAI ≤ 10.0; MDA: 10.0 < CDAI ≤ 22.0; HDA: > 22.0. SDAI remission: ≤ 3.3; LDA: 3.3 < SDAI ≤ 11.0; MDA: 11.0 < SDAI ≤ 26.0; HDA: > 26.0 AO as observed, BL baseline, CDAI clinical disease activity index, DAS28(CRP) disease activity score in 28 joints using C-reactive protein, HDA high disease activity, LDA low disease activity, MDA moderate disease activity, REM remission, SDAI simplified disease activity index

Fig. 4

EAERs of TEAEs in patients with moderate-to-severe RA treated with UPA 15 mg Note: Safety was evaluated by assessing all TEAEs (AEs occurring after the first dose of study drug and up to 30 days after the last dose of study drug) occurring in the FAS up to the data cutoff date of August 10, 2023. There were no reported events of gastrointestinal perforation ^aReasonable possibility. ^bExcluding herpes zoster and active tuberculosis. ^cIncludes cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. ^dIncludes VTE, other venous thrombosis, and arterial thromboembolic events (VTE: n = 12; arterial occlusive disease: n = 1; PVT: n = 2). ^eIncludes DVT (n = 4) and PE (n = 8) AE adverse event, CI confidence interval, D/C discontinuation, DVT deep vein thrombosis, E event, EAER exposure-adjusted event rate, FAS full analysis set, MACE major adverse cardiovascular events, NMSC non-melanoma skin cancer, PE pulmonary embolism, PVT portal vein thrombosis, PY patient-years, RA rheumatoid arthritis, TEAE treatment-emergent adverse event, UPA upadacitinib, VTE venous thromboembolic events