Psoriatic arthritis

Efficacy of Apremilast on Whole-Body Inflammation Indices in Patients With PsA :Assessments by Whole-Body MRI in the Ph4 MOSAIC Study

Efficacy of Apremilast on Whole-Body Inflammation Indices in Patients With Psoriatic Arthritis: Assessments by Whole-Body Magnetic Resonance Imaging in the Phase 4 MOSAIC Study

Background:

Psoriatic arthritis (PsA) is characterized by various patterns of inflammatory arthritis, enthesitis, dactylitis, and spondylitis. Apremilast is an oral immunomodulating phosphodiesterase-4 inhibitor that is indicated for treatment of PsA. Whole-body magnetic resonance imaging (WB-MRI) allows assessment of joints and entheses of the entire body in one examination when using the Outcome Measures in Rheumatology Clinical Trial (OMERACT) MRI whole-body scoring system for inflammation in peripheral joints and entheses (MRI-WIPE), which has not previously been applied in a clinical trial. Here we evaluate the efficacy of apremilast 30 mg BID (APR) on peripheral inflammation indices as measured by WB-MRI.

Objectives:

To evaluate how APR affects inflammation in peripheral joints and entheses of patients with PsA as assessed by WB-MRI.

Methods:

The phase 4 MOSAIC study was a multicenter, single-arm, open-label study evaluating APR (either as monotherapy or in combination with stable methotrexate) in patients with active PsA (diagnosis ≥3 months but ≤5 years, meeting the CASPAR criteria for PsA) for treatment up to 48 weeks. WB-MRI was performed at baseline, Week 24, and Week 48. Images were read and adjudicated by 2 experienced readers who were blinded to time of acquisition and clinical information. From WB-MRI, changes in the total peripheral inflammation index (83 joints and 33 entheses) were calculated using the OMERACT MRI-WIPE scoring system, as were changes in separate enthesitis and joint inflammation WB-MRI indices (WIPE-enthesitis and WIPE-joint inflammation). Changes in the heel enthesitis inflammation index (HEMRIS),

the hip joint inflammation MRI index (HIMRISS), and the knee joint inflammation MRI index (KIMRISS) were explored.

Results:

Overall, 122 patients were enrolled and treated with APR; 55% were women, mean age was 47 years, and patients had a mean duration of PsA of 1.9 years. The least squares mean (95% CI) change from baseline in total WIPE score based on total peripheral inflammation index (including both joint and enthesitis inflammation) as assessed by WB-MRI was -3.49 (- 5.46, -1.52) at Week 24 and -4.06 (-6.39, -1.72) at Week 48, indicating significant improvement in peripheral inflammation (Figure). Significant improvements were also observed in the WIPE-joint inflammation scores at both Week 24 and 48, and in the WIPE- enthesitis scores at Week 48 (Figure). Both the heel enthesitis inflammation index (HEMRIS) and the hip joint inflammation MRI index (HIMRISS) showed little change, while the knee joint inflammation MRI index (KIMRISS) showed numerical, but not significant, improvement (Figure). No new safety signals were identified.

Conclusion:

Patients with PsA treated with APR experienced a significant reduction in total peripheral inflammation, including significant improvement in peripheral joint inflammation and enthesitis, as assessed by WB-MRI. Results highlight the efficacy of APR on inflammatory manifestations of PsA as well as the benefit of using WB-MRI as a measure of inflammatory disease activity.

Apremilast Reduces Inflammation in Patients With Psoriatic Arthritis.

Apremilast Reduces Inflammation as Measured by MRI of the Hand in Patients With Psoriatic Arthritis: Primary Results from the Phase 4 MOSAIC Study

Background:

Psoriatic arthritis (PsA) is characterized by inflammatory arthritis, enthesitis, dactylitis, and spondylitis. Apremilast is an oral immunomodulating phosphodiesterase-4 inhibitor approved for the treatment of PsA. The impact of apremilast on objective measures of inflammation and structural progression of PsA has not yet been characterized. Here, we evaluate the efficacy of apremilast 30 mg BID (APR) on inflammation measured by dedicated MRI of the hand.

Objectives:

To evaluate the efficacy of APR on inflammation and imaging outcomes and the safety profile of APR in this setting.

Methods:

MOSAIC (NCT03783026) was a phase 4, multicenter, single-arm, open-label study in patients (pts) with active PsA (≥3 months but ≤5 years since diagnosis, meeting CASPAR criteria for PsA) evaluating APR as monotherapy or in combination with stable methotrexate. Pts were treated with APR for 48 weeks and had MRI of the hand (contrast-enhanced) performed at baseline (BL), Week 24, and Week 48. All images were read and adjudicated by 2 experienced readers blinded to clinical information and time of acquisition. The primary endpoint was change from BL in the composite score of hand bone marrow edema (BME), synovitis, and tenosynovitis in fingers 2–5, as assessed by the PsA MRI Score (PsAMRIS) at Week 24. Total inflammation score, comprised of BME, synovitis, tenosynovitis, and periarticular inflammation in fingers, was also assessed. Structural progression was assessed by the total hand damage score (determined by bone erosion and bone proliferation in fingers 2–5). Subgroup analyses based on BL disease activity as measured

by Clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) were performed for key endpoints.

Results:

A total of 122 pts enrolled and received APR. Mean age was 47 years, 55% were women, and mean duration of PsA was 1.9 years. The Full Analysis Set (FAS) included 98 pts evaluable for the primary endpoint (having BL and Week 24 data); 4 had major protocol deviations and 94 were evaluable as part of the per protocol (PP) population. The least- squares (LS) mean (95% CI) change from BL in the composite inflammation score of BME, synovitis, and tenosynovitis as assessed by PsAMRIS (FAS) was -2.32 (-4.73, 0.09) at Week 24 and -2.91 (-5.45, -0.37) at Week 48 (Figure). In the PP population, the LS mean (95% CI) change from BL in the composite score at Weeks 24 and 48 indicated a significant reduction of disease activity (Figure). Significant improvements from BL were seen in total inflammation scores (BME + synovitis + tenosynovitis + periarticular inflammation) in the FAS (Figure). The structural outcome indicated by the total hand damage score, including bone erosion, showed no significant change from BL to Week 48 (Figure). Pts also experienced significant improvements from BL in cDAPSA at Weeks 24 and 48 (Figure).

Subgroup analyses based on disease activity at BL showed significant improvements from BL in inflammation in pts with moderate disease activity (ModDA; cDAPSA score >13 to ≤27) and no significant change from BL in total damage (Figure). Though it was insignificant, pts with high disease activity (HDA; cDAPSA score >27) did have improvement from BL in inflammation indices (Figure).

Common treatment-emergent adverse events were diarrhea (33.6%), nausea (12.3%), headache (10.7%), nasopharyngitis (7.4%), and dyspepsia (6.6%). No new safety signals were identified.

Conclusion:

Pts with PsA treated with APR had improvements in both clinical indices and objective MRI indices of inflammation assessed by PsAMRIS in the target hand at Week 24 and Week 48, confirming an effect of APR on clinical and inflammatory manifestations of PsA. Pts with ModDA seemed to have greater improvement from BL in MRI inflammation scores than pts with HDA. No significant structural progression was observed. These results offer important insights on the effect of apremilast in PsA and highlight the value of using MRI and PsAMRIS as measures of inflammatory disease activity and change following treatment.

A Phase IV, Multicenter, Single-Arm, Open-Label Study to Evaluate the Impact of Apremilast on Hand and Whole-Body MRI Outcomes in Patients with Psoriatic Arthritis (MOSAIC): Rationale, Design, and Methods.

Copyright © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ
Annals of the Rheumatic Diseases. 2019 June;78(2)_suppl. doi: 10.1136/annrheumdis-2019-eular.1368

Abstract

BACKGROUND:
Phase III clinical trials have shown apremilast (APR) reduced PsA signs/symptoms and improved physical function,but no study has addressed its impact on structural disease progression. MRI is a highly sensitive, validated tool to assess inflammatory and structural changes, as it can detect soft tissue inflammation, bone marrow edema (BME) lesions, bone erosion and proliferation in peripheral joints and axial skeleton. Whole-body (WB)-MRI, a relatively novel technique in musculoskeletal studies, allows assessment of all peripheral/axial joints and entheses in 1 examination. Recent, consensus-based and semi-quantitative scoring methods were developed and validated. This study is the first to systematically use new state-of-the-art MRI scoring methodologies to assess PsA inflammatory and structural changes in a global clinical trial.

OBJECTIVES:
To assess APR efficacy on inflammatory indices and imaging outcome measures associated with PsA structural progression by conventional static MRI and dynamic contrast-enhanced (DCE)-MRI of the most affected hand and WB-MRI.

METHODS:
The study aims to enroll 120 biologic-naïve adults with PsA for ≥3 mos to ≤5 yrs and prior treatment with ≤2 conventional DMARDs. Subjects must have ≥3 swollen and ≥3 tender joints, hand involvement (≥1 swollen joint or ≥1 dactylitis) and ≥1 active enthesitis site. After 4-wk screening, all eligible patients will receive APR 30 mg twice daily (titrated during the first 5 days) as monotherapy or in combination with methotrexate for 48 wks, with a 4-wk observational follow-up. Conventional MRI and optional DCE-MRI of the most affected hand and WB-MRI of the entire body will be performed at Wks 0, 24 and 48. The primary endpoint is change from BL to Wk 24 in OMERACT PsA MRI (PsAMRIS) composite score of BME + synovitis + tenosynovitis. Other imaging endpoints include change from BL to Wk 48 in PsAMRIS composite score (BME + synovitis + tenosynovitis) and change from BL to Wks 24 and 48 in PsAMRIS composite score (BME + synovitis), PsAMRIS composite inflammation score (BME + synovitis + tenosynovitis + periarticular inflammation), PsAMRIS total damage score (erosion + bone proliferation), WB-MRI indices (including peripheral joint inflammation index and peripheral enthesis inflammation index), hip and knee inflammation MRI scores (HIMRISS, KIMRISS), OMERACT heel enthesitis MRI indices, axial inflammation indices (SPARCC, CanDen), DEMRIQ-Volume and DEMRIQ-Inflammation and other DCE-MRI–derived parameters. Clinical parameters will include SJC/TJC, cDAPSA, SPARCC Enthesitis Index, Leeds Enthesitis Index, Leeds Dactylitis Index, PASDAS, PtGA, PhGA, Patient’s Assessment of Pain, HAQ-DI, and BASDAI and impact of disease (PsAID12). Safety and tolerability also will be assessed.

RESULTS:
The study protocol was approved by an independent ethics committee and is now enrolling in the USA. Selected countries in Europe and Russia will also participate. MRI, clinical and patient-reported outcomes will be analyzed.

CONCLUSION:
This study will provide important evidence of APR’s impact on inflammatory/structural changes by assessing all PsA musculoskeletal domains (peripheral arthritis, enthesitis, dactylitis and axial disease). Furthermore, it will yield information on use of conventional MRI–, WB-MRI– and DCE-MRI–driven outcome measures in PsA clinical trials.