Purpose Safety and efficacy of allogeneic integrin α10β1-selected MSCs (integrin α10-MSCs) have been shown in two post-traumatic osteoarthritis (OA) equine models. The aim of this study is to evaluate safety, tolerability and preliminary efficacy of allogeneic integrin α10-MSCs in human symptomatic knee OA. Methods In a first-in-human prospective multicentre phase I/IIa dose escalation study, 24 patients (41-75 years, Kellgren-Lawrence grade II-III knee OA) were treated with a single intra-articular injection of 4, 8 or 16 million integrin α10-MSCs. Safety and tolerability were assessed by adverse events, electrocardiography, vital signs, and physical and laboratory examinations. Clinical outcome was measured by visual analogue scale (VAS) for pain and Knee injury and Osteoarthritis Outcome Score (KOOS). Structural outcomes were assessed by X-ray and MRI. The total follow-up period was 24 months for the highest dose and 18 months for the lower doses. Results The most frequently reported study drug-related adverse events were injection site pain, joint swelling and injection site movement impairment. All doses showed sustained improvements in pain and function, whereas the 16 million dose cohort showed earlier effects. The 16 million dose cohort also showed a reduction in bone marrow lesions, signs of an improved cartilage quality by T2* relaxation time, and a stable medial minimum joint space width. Conclusions This study demonstrated safety and efficacy of intra-articular injection of integrin α10-MSCs for the treatment of mild to moderate knee OA. At a dose of 16 million integrin α10-MSCs, a potentially quick and long-lasting therapeutic effect, supportive of disease-modification, was evident.

Objectives Evaluate the risks and benefits of upadacitinib 15 mg vs adalimumab in rheumatoid arthritis (RA) patients with an inadequate response to methotrexate based on cardiovascular (CV) risk.Methods In SELECT-COMPARE, patients received upadacitinib 15 mg, placebo or adalimumab 40 mg every other week, with background methotrexate. This post hoc analysis assessed patients with lower (age <65 years; no CV risk factors) and higher CV risk (age ≥65 years and/or ≥1 CV risk factor). Safety and efficacy outcomes were compared between upadacitinib and adalimumab over the short term (~6 months) and long term (5 years) based on CV risk.Results The study included 211 lower-risk patients (upadacitinib, n=129; adalimumab, n=82) and 767 higher-risk patients (upadacitinib, n=522; adalimumab, n=245). Rates of malignancy excluding nonmelanoma skin cancer (NMSC), major adverse cardiovascular event and venous thromboembolism were comparable between upadacitinib and adalimumab in both risk groups but numerically higher in the higher-risk group. Upadacitinib showed higher rates of herpes zoster versus adalimumab in both risk groups and numerically higher rates of serious infection and NMSC in the higher-risk group. Upadacitinib demonstrated consistently better efficacy outcomes, including 28-joint Disease Activity Score (C reactive protein) <2.6, Clinical Disease Activity Index remission and Boolean remission at 6 months, which were generally maintained through 5 years.Conclusions Regardless of baseline CV risk, upadacitinib demonstrated comparable safety to adalimumab, except for higher rates of herpes zoster in both CV risk groups and NMSC and serious infections in the higher-risk group. Upadacitinib consistently showed better clinical and functional outcomes than adalimumab. The benefit–risk profile of upadacitinib in RA patients was favourable, independent of CV risk category, in both short and long term.

Psoriatic arthritis (PsA) is a progressive, systemic inflammatory disease. It can lead to serious joint damage and disability, increased cardiovascular risk and reduced quality of life. Six experts met to develop the recommendations for the management of PsA in Australia. The final recommendations are approved by all panel members. Management and treatment recommendations have been made under six subheadings: Recommendations for non-steroidal anti-inflammatory drugs and glucocorticoids; Disease-modifying treatment; Screening and monitoring; Family planning; Symptom treatment and extra-articular manifestations; Comorbidities and lifestyle considerations. Our recommendations for the management of PsA in Australia draw heavily on the established global guidelines. These recommendations aim to assist clinicians to make informed, patient-centric choices when delivering treatment to people with PsA.

Objective To evaluate the long-term sustainability of response to the Janus kinase inhibitor upadacitinib among patients with rheumatoid arthritis and an inadequate response or intolerance to biological disease-modifying antirheumatic drugs (bDMARD-IR) in the SELECT-BEYOND phase 3 trial.Methods Patients on background conventional synthetic DMARDs (csDMARDs) were treated once daily with upadacitinib 15 mg or placebo. Patients who completed the week 24 visit could enter a long-term extension of up to 5 years. The sustainability of response was assessed based on achievement of Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and Disease Activity Score 28-joint count using C-reactive protein (DAS28 (CRP)) targets and evaluated up to week 260 in all patients receiving the approved upadacitinib 15 mg dose, including those randomised to upadacitinib 15 mg and those who switched from placebo to upadacitinib 15 mg at week 12.Results In this bDMARD-IR population, 45% (n=104/229) and 79% (n=172/219) of patients treated with upadacitinib 15 mg plus background csDMARD(s) achieved CDAI remission or CDAI low disease activity (LDA) at any point during the 5-year study, respectively. Of those who achieved CDAI remission/LDA, 25%/43% maintained their initial response through 240 weeks of follow-up after first achieving response. Most patients who lost remission or LDA were able to recapture that response by the cut-off date. Similar overall results were observed for SDAI and DAS28 (CRP). No strong predictors of response were identified.Conclusions Over three-quarters of bDMARD-IR patients achieved CDAI LDA with upadacitinib, and almost half of those maintained LDA through 240 weeks of follow-up. Remission was achieved by nearly half of all patients and maintained in approximately a quarter of those achieving remission.Trial registration number NCT02706847.

Axial spondyloarthritis (axSpA) is characterised by inflammation of the sacroiliac joints (SIJ) and the spine. Secukinumab (SEC) treatment was clinically efficacious and reduced SIJ bone marrow oedema as detected by magnetic resonance imaging (MRI) in patients (pts) with non-radiographic (nr)-axSpA through 52 weeks in the PREVENT (NCT02696031) study.1To report radiographic progression and the course of inflammation as assessed by X-ray and MRI of SIJ and spine over 2 years in the PREVENT study.Study design and key endpoints have been reported earlier.1 In total, 555 pts were randomised (1:1:1) to receive SEC 150 mg, with (LD) or without loading (NL) doses, or placebo (PBO). Switch to open-label (OL) SEC or standard of care (SoC) was permitted after Week (Wk) 20. All pts (except those who switched to SoC) received OL SEC from Wk 52. Radiographs of the spine and SIJ were collected at baseline (BL) and Wk 104; MR images of the spine and SIJ were collected at BL, Wk 16, 52, and 104. Spinal radiographs were scored using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) and SIJ radiographs according to modified New York criteria (mNYC). Pts whose screening SI joint radiographs fulfilled mNY criteria during the eligibility reading session were excluded from the study. Spinal MR images were assessed for signs of inflammation with the Berlin score. SIJ bone marrow oedema was assessed according to the Berlin Active Inflammatory Lesions Scoring. All images were evaluated in blinded fashion independently by 2 central readers. All data are reported from the Wk 104 reading session and are presented as observed.The vast majority (98%) of pts treated with SEC 150 mg (pooled LD and NL) showed no structural progression, defined as change in total mSASSS score ≤ smallest detectable change (SDC) of 0.76 (80% agreement level) over 2 years. At BL, 62 pts (43 in SEC, 19 in PBO) presented with ≥1 syndesmophyte (≥1 vertebral unit scored by ≥1 reader). Among these pts, 9 in SEC (20.9%) and 7 in PBO (36.8%) groups had developed ≥1 new syndesmophyte by Wk 104. Among 237 SEC and 117 PBO pts without syndesmophytes at BL, only 4 pts on SEC (1.7%) and 4 pts on PBO (3.4%) developed ≥1 new syndesmophyte by Wk 104. SIJ radiographs showed that 88% of pts on SEC and 86% on PBO had no progression in SIJ (defined as change ≤ SDC (0.46) in total mNYC score) by Wk 104. No patient had an increase in total mNYC score of 2 or more. When screening radiographs of eligible pts were scored alongside post-BL images in the final reading campaign, approximately 25% of pts (68/277 and 34/139 pts in the SEC and PBO groups, respectively) were evaluated as mNY-positive at screening (pts were considered mNY-positive if ≥1 reader evaluated them as mNY-positive). Of these, 11/68 pts in the SEC (16.2%) and 5/34 in the PBO (14.7%) groups were evaluated as mNY-negative at Wk 104. In the SEC and PBO groups, 202 (96.7%) and 102 (97.1%) pts who were mNY-negative at screening stayed negative through Wk 104, respectively. Only 7 pts in the SEC (3.3%) and 3 in the PBO (2.9%) groups who were mNY-negative at BL were scored as mNY-positive at Wk 104. In both groups, fewer pts progressed from mNY-negative to mNY-positive than had a change in the opposite direction (from positive to negative), resulting in an overall negative net progression. Spinal inflammation on MRI (Berlin score) was low at BL with a mean of 0.82 in SEC and 1.07 in PBO groups with no meaningful change up to Wk 104 (mean of 0.56, SEC). SEC reduced SIJ bone marrow oedema score versus PBO at Wk 16 and Wk 52 with sustained reduction through Wk 104 in the overall patient population, with greater reduction in pts with BL score >2 (Figure 1).Most pts initially randomised to SEC or PBO showed no radiographic progression through 2 years. There was some discrepancy between SIJ eligibility and efficacy reads. SEC reduced SIJ inflammation (bone marrow oedema) on MRI in pts with active nr-axSpA.[1]Deodhar A, et al. Arthritis Rheumatol. 2021;73:110–20.Juergen Braun Speakers bureau: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Medac, MSD (Schering-Plough), Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, UCB pharma, Eli Lilly, Consultant of: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, UCB, Eli Lilly, Grant/research support from: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, UCB, Eli Lilly, Ricardo Blanco Speakers bureau: AbbVie, Pfizer, Roche, Bristol-Myers, Janssen, UCB pharma, MSD, Eli Lilly, Consultant of: AbbVie, Pfizer, Roche, Bristol-Myers, Janssen, UCB pharma, MSD, Grant/research support from: AbbVie, MSD, Roche, Helena Marzo-Ortega Speakers bureau: AbbVie, Celgene, Janssen, Eli Lilly and Company, Novartis, Pfizer, Takeda, UCB, Consultant of: AbbVie, Celgene, Janssen, Eli Lilly and Company, Novartis, Pfizer, Takeda, UCB, Grant/research support from: Janssen, Novartis, UCB, Lianne S. Gensler Consultant of: Gilead, Eli Lilly, Janssen, Novartis, Pfizer, UCB, Grant/research support from: UCB, Pfizer, Filip van den Bosch Speakers bureau: AbbVie, BMS, Celgene, Galapagos, Janssen, Eli Lilly, Merck, Novartis, Pfizer, UCB, Consultant of: AbbVie, BMS, Celgene, Galapagos, Janssen, Eli Lilly, Merck, Novartis, Pfizer, UCB, Grant/research support from: AbbVie, BMS, Celgene, Galapagos, Janssen, Eli Lilly, Merck, Novartis, Pfizer, UCB, Stephen Hall Speakers bureau: Novartis, Merck, Janssen, Pfizer, Eli Lilly, UCB, Consultant of: Novartis, Merck, Janssen, Pfizer, Eli Lilly, UCB, Grant/research support from: AbbVie, UCB, Janssen, Merck, Hideto Kameda Speakers bureau: Abbvie, Asahi-Kasei, Astellas, BMS, Chugai, Eisai, Eli Lilly, Gilead Sciences, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer, Consultant of: Abbvie, Astellas, Boehringer, Eli Lilly, Gilead Sciences, Janssen, Novartis, Sanofi, UCB, Grant/research support from: Abbvie, Asahi-Kasei, Boehringer, Chugai, Eisai, Mitsubishi-Tanabe, Denis Poddubnyy Speakers bureau: AbbVie, BMS, Lilly, MSD, Novartis, Pfizer, UCB, Consultant of: AbbVie, Biocad, BMS, Eli Lilly, Gilead, MSD, Novartis, Pfizer, Samsung Bioepis, UCB, Grant/research support from: AbbVie, Eli Lilly, MSD, Novartis, Pfizer, Marleen G.H. van de Sande Speakers bureau: Novartis, MSD, Consultant of: Abbvie, Novartis, Eli Lily, Grant/research support from: Novartis, Eli Lilly, Janssen, UCB, Désirée van der Heijde Paid instructor for: Novartis, AbbVie, Bayer, BMS, Cyxone, Eisai, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Lilly, Pfizer, UCB Pharma, and Director of Imaging Rheumatology BV, Tingting Zhuang Shareholder of: Novartis, Employee of: Novartis, Anna Stefanska Shareholder of: Novartis, Employee of: Novartis, Aimee Readie Shareholder of: Novartis, Employee of: Novartis, Hanno Richards Shareholder of: Novartis, Employee of: Novartis, Atul Deodhar Speakers bureau: AbbVie, Boehringer Ingelheim, Eli Lilly, Janssen, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, UCB

Abstract Background Radiographic progression and course of inflammation over 2 years in patients with non-radiographic axial spondyloarthritis (nr-axSpA) from the phase 3, randomized, PREVENT study are reported here. Methods In the PREVENT study, adult patients fulfilling the Assessment of SpondyloArthritis International Society classification criteria for nr-axSpA with elevated CRP and/or MRI inflammation received secukinumab 150 mg or placebo. All patients received open-label secukinumab from week 52 onward. Sacroiliac (SI) joint and spinal radiographs were scored using the modified New York (mNY) grading (total sacroiliitis score; range, 0–8) and modified Stoke Ankylosing Spondylitis Spine Score (mSASSS; range, 0–72), respectively. SI joint bone marrow edema (BME) was assessed using the Berlin Active Inflammatory Lesions Scoring (0–24) and spinal MRI using the Berlin modification of the AS spine MRI (ASspiMRI) scoring (0–69). Results Overall, 78.9% (438/555) of patients completed week 104 of the study. Over 2 years, minimal changes were observed in total radiographic SI joint scores (mean [SD] change, − 0.04 [0.49] and 0.04 [0.36]) and mSASSS scores (0.04 [0.47] and 0.07 [0.36]) in the secukinumab and placebo-secukinumab groups. Most of the patients showed no structural progression (increase ≤ smallest detectable change) in SI joint score (87.7% and 85.6%) and mSASSS score (97.5% and 97.1%) in the secukinumab and placebo-secukinumab groups. Only 3.3% (n = 7) and 2.9% (n = 3) of patients in the secukinumab and placebo-secukinumab groups, respectively, who were mNY-negative at baseline were scored as mNY-positive at week 104. Overall, 1.7% and 3.4% of patients with no syndesmophytes at baseline in the secukinumab and placebo-secukinumab group, respectively, developed ≥ 1 new syndesmophyte over 2 years. Reduction in SI joint BME observed at week 16 with secukinumab (mean [SD], − 1.23 [2.81] vs − 0.37 [1.90] with placebo) was sustained through week 104 (− 1.73 [3.49]). Spinal inflammation on MRI was low at baseline (mean score, 0.82 and 1.07 in the secukinumab and placebo groups, respectively) and remained low (mean score, 0.56 at week 104). Conclusion Structural damage was low at baseline and most patients showed no radiographic progression in SI joints and spine over 2 years in the secukinumab and placebo-secukinumab groups. Secukinumab reduced SI joint inflammation, which was sustained over 2 years. Trial registration ClinicalTrials.gov, NCT02696031.

AIM:Certolizumab pegol (CZP), an Fc-free, PEGylated tumor necrosis factor inhibitor (TNFi), has shown rapid and sustained reduction in signs and symptoms of rheumatoid arthritis (RA). Elevated rheumatoid factor (RF) level has been associated with RA disease progression and poorer TNFi response. We assessed the efficacy of CZP in patients with early and established RA across baseline RF levels.METHODS:This post-hoc analysis included data from 6 trials: C-OPERA (NCT01451203), pooled RAPID trials (RAPID-1 [NCT00152386], RAPID-2 [NCT00160602], J-RAPID [NCT00791999], RAPID-C [NCT02151851]), and EXXELERATE (NCT01500278). Patients who received CZP or placebo/comparator with methotrexate (MTX) were categorized by baseline RF quartiles. Efficacy was assessed with Disease Activity Score-28 erythrocyte sedimentation rate (DAS28-ESR).RESULTS:Overall, 316, 1537, and 908 patients were included in C-OPERA, pooled RAPID trials, and EXXELERATE, respectively. Patient demographics and baseline disease characteristics were similar between treatment groups and across RF quartiles. DAS28-ESR low disease activity (LDA) and remission (REM) rates were numerically higher in the CZP + MTX group than PBO + MTX group at weeks 12 and 24, across RF quartiles. LDA and REM rates in the CZP + MTX groups were comparable across RF quartiles at weeks 12 and 24. Mean DAS28-ESR decreased from week 0 to week 24 in the CZP + MTX groups, across RF quartiles.CONCLUSION:CZP showed steady efficacy across baseline RF quartiles in patients with early and established RA, over 24 weeks. CZP treatment may be considered in patients with RA irrespective of baseline RF levels and time from diagnosis.

To assess the rapidity of magnetic resonance imaging (MRI) measured synovitis (as measured by synovial thickening using the RAMRIS‐SAFE score) and bone edema in active rheumatoid arthritis (RA) subjects treated with golimumab. Secondary aims: to correlate MRI measures with disabilities of the arm, shoulder, and hand (DASH), physician global (PhysG) and patient global (PatG) assessments.

Objectives. To evaluate the inhibition of progression of structural joint damage through week 48 in patients with moderately to severely active RA receiving upadacitinib as monotherapy or in combination with MTX. Methods. Radiographic progression was assessed in two phase 3 randomized controlled trials. MTX-naive patients were randomized to upadacitinib 15 or 30 mg once daily or MTX monotherapy (SELECT-EARLY, n = 9 45), while MTX inadequate responders (IRs) were randomized to upadacitinib 15 mg once daily or adalimumab 40 mg every other week or placebo added to background MTX (SELECT-COMPARE, n = 1629). The mean changes from baseline in modified total Sharp score (mTSS), joint space narrowing and erosion scores were determined. Data were analysed both by linear extrapolation for missing data imputation and treatment switching and as observed. Results. In patients naIve or with limited exposure to MTX (SELECT-EARLY), mean changes from baseline to week 48 in mTSS were 0.03 for upadacitinib 15 mg, 0.14 for upadacitinib 30 mg and 1.00 for MTX based on linear extrapolation (P < 0.001 for both upadacitinib doses vs MTX). Among patients with an inadequate response to MTX (SELECT-COMPARE), the mean change from baseline in mTSS was significantly reduced in the upadacitinib 15 mg plus MTX group vs placebo plus MTX (0.28 vs 1.73; P < 0.001). The mean change from baseline in the adalimumab plus MTX group was 0.39. Conclusion. Upadacitinib monotherapy or in combination with background MTX was effective in inhibiting the progression of structural joint damage through week 48 in MTX-naive and MTX-IR patients with RA.

To better inform clinicians about the use of etanercept biosimilar (SB4) in patients with rheumatoid arthritis (RA), COMPANION-B, a prospective real-world observational study, evaluated the effectiveness of the voluntary switch from originator (etanercept, ETN) to SB4 in patients with stable RA (low-disease activity/remission). The study recruited adult patients (18 years or older) with RA (2010 American College of Rheumatology criteria) prescribed ETN as their first or second biologic for at least 6 months across 14 sites in Canada and five in Australia. Patients had stable disease (Disease Activity Score-28 using erythrocyte sedimentation rate [DAS28-ESR] less than 3.2) at enrollment with no evidence of flare within the previous 3 months. Concomitant disease-modifying antirheumatic drugs (DMARDs) were permitted. Patients could elect to continue ETN or voluntarily switch to SB4 in consultation with their doctors. The primary effectiveness measure was the proportion of patients with disease worsening (defined as a DAS28-ESR increase of at least 1.2 from baseline and minimum score of at least 3.2 or a defined modification in RA treatment) during 12 months of follow-up. The secondary effectiveness measure was the proportion of patients with disease worsening at month 6. Serious adverse events (SAEs) and non-serious adverse reactions (NSARs) were recorded. Of 163 patients enrolled, 109 elected to continue on ETN and 54 switched to SB4; 65.8% of patients received non-biologic DMARD(s), 52.6% methotrexate, and 10.5% oral corticosteroid(s). At month 12, the proportion of patients with disease worsening was comparable in the ETN group (22.8% [95% CI 15.0–32.2]) and SB4 group (17.6% [95% CI 8.4–30.9]). Similarly, the proportions of patients with disease worsening were also comparable at month 6 (ETN: 7.9% [95% CI 3.5–15.0]; SB4: 7.8% [95% CI 2.2–18.9]). SAEs were low and similar across both groups (ETN: 8.7%; SB4: 5.7%). NSARs were slightly higher in the SB4 vs. ETN group (13.2% vs. 2.9%). SB4 demonstrated comparable effectiveness to ETN over 12 months in patients with stable RA who voluntarily switched to the biosimilar in a real-world setting.

Abstract Background/Aims For patients with RA who are refractory to biologic disease-modifying antirheumatic drugs (bDMARDs), such as tumor necrosis factor inhibitors (TNFis), optimal disease control is less likely to be achieved with subsequent therapy. In line with recommendations from EULAR and ACR, switching to a treatment with a different mechanism of action is appropriate for these patients. Objectives To describe the efficacy and safety of upadacitinib (UPA) 15 mg once daily in patients with RA and an inadequate response or intolerance to TNFis (TNFi-IR). Methods A post hoc subgroup analysis was conducted in TNFi-IR patients who were treated with UPA 15 mg once daily in three Phase 3 clinical trials: SELECT-BEYOND, -CHOICE, and -COMPARE. For COMPARE, only patients treated with adalimumab and switched to UPA as rescue therapy were included. ≥20/50/70% improvement in ACR criteria, DAS28-CRP, Clinical Disease Activity Index, and Simple Disease Activity Index, as well as change from baseline in HAQ-DI and other patient-reported outcomes (PROs) were reported through 24 weeks. Non-responder imputation was used for all missing categorical outcomes; as observed (COMPARE) or multiple imputation (CHOICE, BEYOND) were used for missing continuous outcomes. Pooled safety results were presented as exposure-adjusted event rates (EAERs) with a cut-off of June 30, 2021. Results 568 TNFi-IR patients were included: 146 from BEYOND, 263 from CHOICE, and 159 from COMPARE. Mean duration since RA diagnosis was longer for BEYOND and CHOICE versus COMPARE; CV risk factors were common among this refractory population. ACR20/50/70 and disease activity outcomes observed in the TNFi-IR population were generally consistent with the overall BEYOND and CHOICE bDMARD-IR populations, and consistent across the three studies in the TNFi-IR subgroups. Improvements in PROs including HAQ-DI, fatigue, pain, and morning stiffness over 24 weeks were observed (data not shown). Pooled safety results reporting 1574.8 PY of exposure in the TNFi-IR subgroup showed similar results to the overall BEYOND and CHOICE bDMARD-IR study populations, with EAERs of 3.1 events/100 PY for herpes zoster and 0.8 events/100 PY for adjudicated major adverse CV events and venous thromboembolism, and malignancy excluding non-melanoma skin cancer. The EAER of any AE leading to death was 1.4 events/100 PY. Conclusion In this post hoc subgroup analysis, TNFi-IR patients treated with UPA 15 mg achieved clinically meaningful efficacy responses over 24 weeks, with safety consistent with the overall bDMARD-IR patient population in the Phase 3 program. Disclosure R. Fleischmann: Consultancies; Consultant for AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Galvani, Gilead, GSK, Janssen, Novartis, Pfizer Inc, and UCB. Grants/research support; Grant/research support from AbbVie, Amgen, Biosplice, Bristol-Myers Squibb, Flexion, Gilead, Horizon, Eli Lilly, Galvani, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, Selecta, Teva, UCB, Viela, and. L. Bessette: Consultancies; AbbVie, Amgen, Bristol-Meyers Squibb, Celgene, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, and Pfizer, Roche, Sanofi-Aventis, Teva, and UCB. Member of speakers’ bureau; AbbVie, Amgen, Bristol-Meyers Squibb, Celgene, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, and Pfizer, Roche, Sanofi-Aventis, Teva, and UCB. Grants/research support; AbbVie, Amgen, Bristol-Meyers Squibb, Celgene, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, and Pfizer, Roche, Sanofi-Aventis, Teva, and UCB. S. Hall: Consultancies; AbbVie, Amgen, Bristol-Meyers Sqibb, Eli Lilly, Gilead, Janssen, Merck, Novartis, and UCB. Grants/research support; AbbVie, Amgen, Bristol-Meyers Sqibb, Eli Lilly, Gilead, Janssen, Merck, Novartis, and UCB. J. Sparks: Consultancies; Consulted for AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer. M. Jain: Consultancies; Amgen, Abbvie, Eli Lilly, Pfizer, and Novartis. Grants/research support; Amgen, Abbvie, Eli Lilly, Pfizer, and Novartis. A. Kakehasi: Consultancies; Amgen, Janssen, UCB, AbbVie, Pfizer, Eli Lilly, Novartis, Sandoz, Fresenius Kabi. Member of speakers’ bureau; Amgen, Janssen, UCB, AbbVie, Pfizer, Eli Lilly, Novartis, Sandoz, Fresenius Kabi. Grants/research support; Amgen, Janssen, UCB, AbbVie, Pfizer, Eli Lilly, Novartis, Sandoz, Fresenius Kabi. Y. Song: Shareholder/stock ownership; full-time employees of AbbVie and may own stock or options. S. Meerwein: Shareholder/stock ownership; full-time employees of AbbVie and may own stock or options. R. DeMasi: Shareholder/stock ownership; full-time employees of AbbVie and may own stock or options. J. Suboticki: Shareholder/stock ownership; full-time employees of AbbVie and may own stock or options. A. Rubbert-Roth: Consultancies; AbbVie, AbbVie Deutschland, Amgen, Bristol-Myers Squibb, Chugai Pharmaceuticals, Eli Lilly, F. Hoffman-La Roche, Gilead Sciences, Janssen Global Services, Novartis, and Sanofi Pasteur.

Background Patients (pts) with axial spondyloarthritis (axSpA) often experience delayed diagnosis, which can lead to treatment delay 1 . However, earlier diagnosis and treatment of axSpA pts can lead to a greater clinical response 2 . Secukinumab (SEC) 150 mg has demonstrated sustained improvement in signs and symptoms over 2 years in non-radiographic (nr)-axSpA pts 3 . Objectives To assess the efficacy of SEC in pts with nr-axSpA [tumour necrosis factor (TNF) naïve] by subgroups of younger versus (vs) older pts and early vs late symptom duration of back pain. Methods PREVENT ( NCT02696031 ) is a phase 3, randomised study in pts with nr-axSpA and detailed study design is reported previously4. In this post hoc analysis, efficacy outcomes including Assessment of SpondyloArthritis international Society 40 (ASAS40), ASAS partial remission (ASAS PR), Ankylosing Spondylitis Disease Activity Score-C-reactive protein (ASDAS-CRP) inactive disease (ID) and low disease activity (LDA), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and the proportion of pts meeting the minimal clinically important difference criteria for total back pain (improvement of ≥50%) were assessed in the TNF naïve population. Age categories included 4 approximately equally distributed age groups (18 to 33, 34 to 42, 43 to 51 and ≥52 years). The categories for time since onset of back pain as a surrogate of disease symptoms and sign, was based on patients’ distribution and the hypothesis that patients with shorter disease duration will present better results (≤2, >2 to 5, >5 to 10 and >10 years). Missing responses were imputed as non-response up to Week (Wk) 16 and reported as observed at Wks 52 and 104. Data is presented here for categories 18-33 vs ≥52 years and patients with symptom duration ≤2 vs >10 years. Results At Wk 104, greater improvements in ASAS40 scores were reported in younger (18-33 years) vs older age categories (>52 years) treated with SEC and also in patients with shorter disease duration (≤2 years) when compared to long term disease (Figure 1 and Table 1). Table 1. Efficacy responses with SEC up to Week 104 based on age and symptom duration Age 18-33 years Age >52 years ≤2 years of back pain >10 years of back pain SEC 150 mg LD (N=61) SEC 150 mg NL (N=59) PBO (N=61) SEC 150 mg LD (N=25) SEC 150 mg NL (N=33) PBO (N=28) SEC 150mg LD (N=51) SEC 150 mg NL (N=33) PBO (N=47) SEC 150 mg LD (N=50) SEC 150 mg NL (N=46) PBO (N=49) ASDAS-CRP ID and LDA 50.8* 55.9* 34.4* 36.0* 39.4* 21.4* 51.0* 48.5* 40.4* 44.0* 30.4* 26.5* 77.4 # 81.1 # 72.2 # 45.8 # 46.7 # 33.3 # 77.3 # 60.0 # 77.3 # 53.3 # 48.7 # 37.2 # 71.7 † 70.2 † 77.6 † 50.0 † 57.1 † 60.9 † 74.4 † 69.2 † 82.1 † 55.3 † 53.3 † 53.8 † BASDAI 50 45.9* 47.5* 27.9* 28.0* 36.4* 17.9* 45.1* 51.5* 29.8* 34.0* 23.9* 20.4* 77.8 # 71.7 # 72.2 # 37.5 # 53.3 # 37.0 # 75.6 # 60.0 # 75.0 # 46.7 # 46.2 # 43.2 # 73.5 † 72.3 † 77.6 † 47.6 † 60.9 † 52.2 † 78.0 † 65.4 † 76.9 † 53.8 † 53.1 † 51.3 † ASAS PR 29.5* 32.2* 8.2* 12.0* 12.1* 7.1* 27.5* 24.2* 8.5* 18.0* 10.9* 12.2* 41.5 # 50.9 # 38.9 # 12.5 # 20.0 # 22.2 # 45.5 # 40.0 # 38.6 # 22.2 # 23.1 # 20.5 # 46.9 † 44.7 † 59.2 † 23.8 † 31.8 † 21.7 † 56.1 † 34.6 † 46.2 † 25.6 † 25.8 † 23.1 † Total back pain 50.8* 50.8* 27.9* 24.0* 30.3* 32.1* 51.0* 48.5* 36.2* 32.0* 23.9* 32.7* 74.1 # 75.5 # 72.2 # 58.3 # 46.7 # 44.4 # 73.3 # 63.3 # 72.7 # 53.3 # 48.7 # 47.7 # 71.4 † 68.1 † 79.6 † 61.9 † 52.2 † 52.2 † 75.6 † 69.2 † 74.4 † 61.5 † 50.0 † 59.0 † Data is presented as % of responders. Symbols are used to denote the Weeks. *Week 16; # Week 52; † Week 104 . All patients received open-label SEC 150 mg treatment after Week 52 up to Week 104 . ASDAS-CRP ID and LDA (ASDAS-CRP <2.1); Total back pain improvement ≥50% . LD, loading dose; NL, without loading; PBO, placebo Conclusion Efficacy responses were numerically higher with SEC in patients with nr-axSpA with shorter symptom duration and in younger age. These data suggest that earlier treatment improves patient outcomes in nr-axSpA. References [1]Lapane KL, et al. BMC Fam Pract . 2021;22(1):251 [2]Poddubnyy D, Sieper J. Curr Rheumatol Rep . 2020;22(9):47 [3]Poddubnyy D, et al. Ann Rheum Dis . 2021;80 (suppl1):707 [4]Deodhar A et al. Arthritis Rheumatol . 2021;73(1):110-120 Disclosure of Interests Atul Deodhar Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Glaxo Smith & Kline, Janssen, Novartis, Pfizer, UCB, Grant/research support from: AbbVie, Eli Lilly, Glaxo Smith & Kline, Novartis, Pfizer, UCB, Denis Poddubnyy Speakers bureau: AbbVie, BMS, Lilly, MSD, Novartis, Pfizer, UCB, Roche, Consultant of: AbbVie, BMS, Eli Lilly, MSD, Novartis, Pfizer, UCB, Roche, Grant/research support from: AbbVie, MSD, Novartis, Pfizer, Ricardo Blanco Speakers bureau: AbbVie, Pfizer, Roche, Bristol-Myers, Janssen, UCB pharma, MSD and Lilly, Consultant of: AbbVie, Pfizer, Roche, Bristol-Myers, Janssen, UCB pharma and MSD, Grant/research support from: AbbVie, MSD, and Roche, Stephen Hall Speakers bureau: Novartis, Merck, Janssen, Pfizer, Eli Lilly, and UCB, Consultant of: Novartis, Merck, Janssen, Pfizer, Eli Lilly, and UCB, Grant/research support from: AbbVie, UCB, Janssen, and Merck, Marina Magrey Consultant of: Eli Lily, Novartis, Grant/research support from: AbbVie, UCB and Amgen, Erhard Quebe-Fehling Shareholder of: Shareholder of Novartis, Employee of: Novartis, Renato Calheiros Shareholder of: Shareholder of Novartis, Employee of: Novartis, Patricia Pertel Shareholder of: Shareholder of Novartis, Employee of: Novartis, Helena Marzo-Ortega Speakers bureau: AbbVie, Biogen, Celgene, Janssen, Lilly, Novartis, Pfizer, Takeda and UCB, Consultant of: AbbVie, Celgene, Janssen, Moonlake, Lilly, Novartis, Pfizer and UCB, Grant/research support from: Janssen, Novartis and UCB

BackgroundSustained clinical remission (REM) is the primary treatment goal for patients with rheumatoid arthritis (RA), with low disease activity (LDA) being an appropriate target for treatment-refractory patients.1,2ObjectivesTo evaluate the sustainability of response to the JAK inhibitor, upadacitinib (UPA) 15 mg once daily (QD), among patients with prior inadequate response or intolerance to biologic DMARDs.MethodsData come from the 12-week, phase 3 randomized, placebo (PBO)-controlled SELECT-BEYOND trial of UPA 15 mg or 30 mg QD in patients with moderate to severe RA on stable background conventional synthetic (cs) DMARDs. Initiation, change, or discontinuation of background RA medications, including ≤2 csDMARDs, was allowed starting at Week 24. Patients completing the 12-week trial were able to enter a long-term extension of up to 5 yrs with all PBO patients switching to UPA.3 This post hoc analysis evaluated REM (CDAI ≤2.8; SDAI ≤3.3), LDA (CDAI≤10; SDAI≤11), and DAS28(CRP) <2.6/≤3.2 at first occurrence of response before Week 60, as well as at 3, 6, and 12 months following initial response in patients randomized to UPA 15 mg. For those patients who achieved REM/LDA, Kaplan-Meier was used to define the time from when the response was first achieved to the earliest date at which the response was lost at two consecutive visits or discontinuation of study drug. The predictive ability of time to REM/LDA was evaluated using Harrell’s concordance (c)-index (range: 0 to 1, where 0.5 indicates a model that is no better at predicting an outcome than random chance). The date of the last follow up was 16 April 2018, when all patients had reached the Week 60 visit. Non-responder imputation was used for missing data. Only data from the approved 15 mg dosage are reported here.ResultsIn patients with active RA despite prior treatment with at least one bDMARD, 34% and 79% of those receiving UPA 15 mg + background csDMARD(s) achieved CDAI REM or LDA through Week 60, respectively. Sustained CDAI REM was attained by 30%, 26%, and 16% of patients randomized to UPA at 3, 6, and 12 months post initial response, while CDAI LDA was achieved by 68%, 61%, and 50% of patients during the same time points (Figure 1). Time to initial clinical response weakly predicted sustained REM but did not predict sustained LDA, with a c-index (95% CI) of 0.62 (0.49, 0.74) and 0.52 (0.44, 0.61), respectively. Through the last follow-up visit at Week 60, 39/61% of patients on UPA remained in CDAI REM/LDA (Figure 2). Of those who lost CDAI REM, 58% remained in CDAI LDA, and 22% recaptured REM by the cut-off date; 18% of patients who lost CDAI LDA recaptured response. Similar results were observed for REM and LDA based on SDAI and for DAS28(CRP) <2.6/≤3.2.ConclusionAmong patients with inadequate response or intolerance to bDMARDs, over three-quarters on UPA 15 mg achieved CDAI LDA, a relevant therapeutic target for these treatment-refractory patients, and nearly two-thirds of those maintained this response through 60 weeks. Additionally, about one-third of UPA-treated patients attained CDAI REM and maintained that response over 60 weeks.References[1]Smolen et al. Ann Rheum Dis 2020;79:685–99.[2]Singh et al. Arthritis Rheumatol 2016;68:1–26.[3]Genovese, et al. Lancet 2018;391:2513–24.AcknowledgementsAbbVie funded these studies and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. No honoraria or payments were made for authorship. Medical writing support was provided by Matthew Eckwahl, PhD, of AbbVie.Disclosure of InterestsRonald van Vollenhoven Consultant of: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Eli Lilly, GSK, Janssen, Medac, MSD, Novartis, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, Arthrogen, Bristol-Myers Squibb, Eli Lilly, GSK, Pfizer, and UCB, Stephen Hall Consultant of: AbbVie, BMS, Lilly, Janssen, Pfizer, UCB, and Novartis., Grant/research support from: AbbVie, BMS, Lilly, Janssen, Pfizer, UCB, and Novartis., Alvin F. Wells Consultant of: AbbVie, Sebastian Meerwein Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Yanna Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Jessica Suboticki Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Roy M. Fleischmann Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, GSK, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, and UCB, Grant/research support from: AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, Janssen, Novartis, Pfizer Inc, Regeneron, Roche, Sanofi-Aventis and UCB

Background Upadacitinib (UPA) has demonstrated efficacy in patients with moderate-to-severe rheumatoid arthritis (RA) across various patient populations. 1–4 Objectives This post hoc analysis aimed to evaluate the consistency in time to achieving meaningful clinical response with UPA 15 mg + conventional synthetic (cs) DMARDs in biologic (b) DMARD-inadequate responder (IR) versus csDMARD-IR patients with RA as well as with UPA 15 mg monotherapy versus UPA 15 mg + csDMARDs in csDMARD-IR patients. Methods Patients originally randomized to UPA 15 mg once daily from four Phase 3 trials were included in this analysis: SELECT-BEYOND 1 and SELECT-CHOICE 2 (UPA 15 mg + csDMARDs in bDMARD-IR patients), SELECT-NEXT 3 (UPA 15 mg + csDMARDs in csDMARD-IR patients), and SELECT-MONOTHERAPY 4 (UPA 15 mg monotherapy in methotrexate-IR patients). Time to response was estimated using the Kaplan–Meier method for clinical outcomes over 24 weeks (26 weeks in SELECT-MONOTHERAPY). Clinical outcomes included achievement of 28-joint Disease Activity Score with C-reactive protein (DAS28[CRP]) ≤3.2; low disease activity (LDA) defined as Clinical Disease Activity Index (CDAI) ≤10 and Simple Disease Activity Index (SDAI) ≤11; and 50% improvement in American College of Rheumatology (ACR) core components and morning stiffness (MS) duration/severity. Data presented were as observed. Results Overall, 905 patients were included (SELECT-BEYOND: n=164; SELECT-CHOICE: n=303; SELECT-NEXT: n=221; SELECT-MONOTHERAPY: n=217). csDMARD-IR patients had a mean disease duration of 7.3 (SELECT-NEXT) or 7.5 years (SELECT-MONOTHERAPY); bDMARD-IR patients had a mean disease duration of 12.4 years, with a more refractory population (≥3 prior bDMARDs) in SELECT-BEYOND (23%) than SELECT-CHOICE (10%). In general, the median time to DAS28(CRP) ≤3.2, CDAI LDA, 50% improvement in ACR core components, and 50% improvement in MS duration/severity were consistent across the studies in bDMARD-IR and csDMARD-IR patients. For SELECT-BEYOND, SELECT-CHOICE, SELECT-NEXT, and SELECT-MONOTHERAPY, the median (95% CI) time to achieve DAS28(CRP) ≤3.2 was 12 (12, 16), 12 (8, 12), 12 (8, 12), and 14 (8, 14) weeks, respectively (Figure 1), and the median time to achieve CDAI LDA was 20 (12, 24), 16 (12, 16), 16 (12, 16), and 20 (14, 20) weeks, respectively (Figure 2). A longer median (95% CI) time to achieve SDAI LDA was observed with UPA monotherapy (20 [14, 20] weeks) versus UPA + csDMARDs (12 [12, 16] weeks) in csDMARD-IR patients. Among bDMARD-IR patients, the median (95% CI) time to 50% improvement in pain was longer in SELECT-BEYOND versus SELECT-CHOICE (16 [12, 20] versus 8 [8, 12] weeks). Conclusion In diverse patient populations with RA, patients treated with UPA 15 mg, as monotherapy or with csDMARDs, generally demonstrated consistent time to achieving DAS28(CRP) ≤3.2, CDAI LDA, and 50% improvement in clinical outcomes. References [1]Genovese MC, et al. Lancet 2018;391:2513–24. [2]Rubbert-Roth A, et al. N Engl J Med 2020;383:1511–21. [3]Burmester GR, et al. Lancet 2018;391:2503–12. [4]Smolen JS, et al. Lancet 2019;393:2303–11. Acknowledgements AbbVie funded this study; contributed to its design; participated in data collection, analysis, and interpretation of the data. No honoraria or payments were made for authorship. Medical writing support was provided by Amy Wilson, MSc, of 2 the Nth (Cheshire, UK), and was funded by AbbVie. Disclosure of Interests Andrea Rubbert-Roth Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Chugai, Eli Lilly, Gilead, Janssen, Novartis, Roche, and Sanofi, Bernard Combe Speakers bureau: AbbVie, Bristol-Myers Squibb, Celltrion, Eli Lilly, Gilead/Galapagos, Janssen, Merck, Novartis, Pfizer, Roche/Chugai, and Sanofi, Consultant of: AbbVie, Bristol-Myers Squibb, Celltrion, Eli Lilly, Gilead/Galapagos, Janssen, Merck, Novartis, Pfizer, Roche/Chugai, and Sanofi, Zoltán Szekanecz Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Gedeon Richter, MSD, Pfizer, Roche, Sanofi, and UCB, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Gedeon Richter, MSD, Pfizer, Roche, Sanofi, and UCB, Stephen Hall Speakers bureau: Eli Lilly, Janssen, Merck, Novartis, Pfizer, and UCB; and research grants from AbbVie, Janssen, Merck, and UCB, Consultant of: Eli Lilly, Janssen, Merck, Novartis, Pfizer, and UCB; and research grants from AbbVie, Janssen, Merck, and UCB, Boulos Haraoui Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, and UCB, Suzan Attar: None declared, Anna-Karin H Ekwall Consultant of: AbbVie and Pfizer, Yanna Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Tim Shaw Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Orsolya Nagy Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Ricardo Xavier Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, and UCB