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      Early and sustained efficacy with apremilast monotherapy in biological-naïve patients with psoriatic arthritis: a phase IIIB, randomised controlled trial (ACTIVE)

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          Abstract

          Objective

          Evaluate apremilast efficacy across various psoriatic arthritis (PsA) manifestations beginning at week 2 in biological-naïve patients with PsA.

          Methods

          Patients were randomised (1:1) to apremilast 30 mg twice daily or placebo. At week 16, patients whose swollen and tender joint counts had not improved by ≥10% were eligible for early escape. At week 24, all patients received apremilast through week 52.

          Results

          Among 219 randomised patients (apremilast: n=110; placebo: n=109), a significantly greater American College of Rheumatology 20 response at week 16 (primary outcome) was observed with apremilast versus placebo (38.2% (42/110) vs 20.2% (22/109); P=0.004); response rates at week 2 (first assessment) were 16.4% (18/110) versus 6.4% (7/109) (P=0.025). Improvements in other efficacy outcomes, including 28-joint count Disease Activity Score (DAS-28) using C reactive protein (CRP), swollen joint count, Health Assessment Questionnaire-Disability Index (HAQ-DI), enthesitis and morning stiffness severity, were observed with apremilast at week 2. At week 16, apremilast significantly reduced PsA disease activity versus placebo, with changes in DAS-28 (CRP) (P<0.0001), HAQ-DI (P=0.023) and Gladman Enthesitis Index (P=0.001). Improvements were maintained with continued treatment through week 52. Over 52 weeks, apremilast’s safety profile was consistent with prior phase 3 studies in psoriasis and PsA. During weeks 0–24, the incidence of protocol-defined diarrhoea was 11.0% (apremilast) and 8.3% (placebo); serious adverse event rates were 2.8% (apremilast) and 4.6% (placebo).

          Conclusions

          In biological-naïve patients with PsA, onset of effect with apremilast was observed at week 2 and continued through week 52. The safety profile was consistent with previous reports.

          Trial registration number

          NCT01925768; Results.

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          Most cited references12

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          Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 Treatment Recommendations for Psoriatic Arthritis.

          To update the 2009 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations for the spectrum of manifestations affecting patients with psoriatic arthritis (PsA).
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            Measuring clinical enthesitis in psoriatic arthritis: assessment of existing measures and development of an instrument specific to psoriatic arthritis.

            To assess currently available tools for measurement of enthesitis and to develop a new instrument specifically for use in psoriatic arthritis (PsA). Twenty-eight patients with PsA underwent clinical assessment over a period of 6 months after change of disease-modifying therapy, usually to methotrexate. Measures of enthesitis included the Mander Enthesitis Index (MEI), the Maastricht Ankylosing Spondylitis Enthesitis Score, the Major index, and the Gladman index. Data from these assessments were used to develop a new enthesitis index, the Leeds Enthesitis Index (LEI). An iterative process of data reduction enabled derivation of the LEI index, which consisted of 6 sites: right and left Achilles insertions, medial femoral condyles, and lateral epicondyles of the humerus. All measures showed significant change from baseline but only the LEI and Gladman indices showed a large effect size. All indices demonstrated a floor effect (a score of 0 when the MEI is >0) but this was minimal for the LEI index. All indices correlated strongly with each other and other measures of disease activity. The LEI is a new enthesitis index designed for use in PsA. It shows good test characteristics that suggest it will be a robust and reliable assessment tool. We suggest that it be adopted for use in any randomized controlled trials and longitudinal observation cohorts involving patients with PsA.
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              Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor

              Objectives Apremilast, an oral phosphodiesterase 4 inhibitor, regulates inflammatory mediators. Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1 (PALACE 1) compared apremilast with placebo in patients with active psoriatic arthritis despite prior traditional disease-modifying antirheumatic drug (DMARD) and/or biologic therapy. Methods In the 24-week, placebo-controlled phase of PALACE 1, patients (N=504) were randomised (1:1:1) to placebo, apremilast 20 mg twice a day (BID) or apremilast 30 mg BID. At week 16, patients without ≥20% reduction in swollen and tender joint counts were required to be re-randomised equally to either apremilast dose if initially randomised to placebo or remained on their initial apremilast dose. Patients on background concurrent DMARDs continued stable doses (methotrexate, leflunomide and/or sulfasalazine). Primary outcome was the proportion of patients achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20) at week 16. Results At week 16, significantly more apremilast 20 mg BID (31%) and 30 mg BID (40%) patients achieved ACR20 versus placebo (19%) (p<0.001). Significant improvements in key secondary measures (physical function, psoriasis) were evident with both apremilast doses versus placebo. Across outcome measures, the 30-mg group generally had higher and more consistent response rates, although statistical comparison was not conducted. The most common adverse events were gastrointestinal and generally occurred early, were self-limiting and infrequently led to discontinuation. No imbalance in major adverse cardiac events, serious or opportunistic infections, malignancies or laboratory abnormalities was observed. Conclusions Apremilast was effective in the treatment of psoriatic arthritis, improving signs and symptoms and physical function. Apremilast demonstrated an acceptable safety profile and was generally well tolerated. Clinical trial registration number NCT01172938.
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                Author and article information

                Journal
                Ann Rheum Dis
                Ann. Rheum. Dis
                annrheumdis
                ard
                Annals of the Rheumatic Diseases
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0003-4967
                1468-2060
                May 2018
                17 January 2018
                : 77
                : 5
                : 690-698
                Affiliations
                [1 ] departmentDepartment of Medicine , University of Queensland , Brisbane, Queensland, Australia
                [2 ] Memorial University of Newfoundland , St. John’s, Newfoundland and Labrador, Canada
                [3 ] departmentDepartment of Internal Medicine, Division of Rheumatology , University of Utah School of Medicine , Salt Lake City, Utah, USA
                [4 ] Celgene Corporation , Summit, New Jersey, USA
                [5 ] Hospital Clínico Universitario , Santiago, Spain
                [6 ] West Tennessee Research Institute , Jackson, Tennessee, USA
                Author notes
                [Correspondence to ] Professor Peter Nash, Department of Medicine, University of Queensland, Brisbane, QLD 4072, Australia; drpnash@ 123456tpg.com.au
                Article
                annrheumdis-2017-211568
                10.1136/annrheumdis-2017-211568
                5909747
                29343507
                57db8598-747a-43fb-b4f1-9fbc92b2b4c7
                © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                History
                : 30 March 2017
                : 13 December 2017
                : 18 December 2017
                Funding
                Funded by: Celgene Corporation;
                Categories
                Clinical and Epidemiological Research
                1506
                2311
                Extended report
                Custom metadata
                unlocked

                Immunology
                spondyloarthritis,das28,disease activity,treatment,psoriatic arthritis
                Immunology
                spondyloarthritis, das28, disease activity, treatment, psoriatic arthritis

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