Synergistic Improvements in Synovitis, Enthesitis, and Patient-Reported Outcomes for Patients with Psoriatic Arthritis Treated with Ixekizumab in SPIRIT Trials
verfasst von:
Lars-Erik Kristensen, Dennis McGonagle, Martin Rudwaleit, Hideto Kameda, Peter Adler Würtzen, Marcus Ngantcha, Thorsten Holzkämper, Josef Smolen
Synovitis and enthesitis are key manifestations in psoriatic arthritis (PsA). This descriptive analysis investigated the association between improvement in synovitis and enthesitis, individually and combined, and improvement in patient-reported outcomes (PROs) including health-related quality of life (HRQoL) for patients with PsA from the SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H trials who presented with synovitis and enthesitis at baseline and received ixekizumab (IXE) treatment.
Methods
In this post hoc analysis, data are presented from patients with PsA treated with IXE every 4 weeks from two phase III studies (SPIRIT-P1 and SPIRIT-P2) and one phase IIIb/IV study (SPIRIT-H2H) who had both synovitis and enthesitis at baseline. Associations between improvements in synovitis and improvements in enthesitis were explored using Pearson analyses through week 52. Associations between improvements in both, either, and neither condition with improvements in PROs (36-item Short Form Health Survey Physical Component Score [SF-36 PCS], the European Quality-of-Life 5 Dimensions 5 Levels [EQ-5D-5L] including the EQ-5D Visual Analogue Score [VAS] and the EQ-health index, Patient’s Global Assessment [PtGA], and pain VAS) were assessed descriptively through week 52.
Results
Results demonstrated the synergistic improvements in synovitis and enthesitis, individually or combined, and improvements in PROs including HRQoL, for patients treated with IXE through week 52. An association between improvements in synovitis and enthesitis symptoms was observed through week 52. Patients who achieved resolution of both synovitis and enthesitis reported highest improvements in SF-36 PCS, EQ-5D-5L, pain VAS, and PtGA.
Conclusion
Synergistic improvements in two key PsA domains, namely synovitis and enthesitis, and improvements in PROs including HRQoL, were observed for patients with PsA treated with IXE through week 52. These findings support PsA treatment goal aiming to achieve the lowest possible level of disease activity in all disease domains.
Trial registration numbers
SPIRIT-P1 (NCT01695239), SPIRIT-P2 (NCT02349295), and SPIRIT-H2H (NCT03151551).
Prior Presentation: Data from this manuscript was previously presented virtually as a poster at the American College of Rheumatology – ACR Convergence 2021 (virtual).
Key Summary Points
Psoriatic arthritis (PsA) is a disease affecting multiple domains such as peripheral arthritis, enthesitis, dactylitis, and skin.
Biologic disease-modifying antirheumatic drug (DMARD)-naïve and tumour necrosis factor inhibitor-experienced patients from SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H trials achieved resolution of multiple PsA domains after ixekizumab treatment, as shown for joint swelling and enthesitis.
An association between improvements in synovitis and enthesitis was observed through week 52, and those improvements, in turn, were individually and simultaneously observed alongside improvements in patient-reported outcomes including health-related quality of life.
This work provides evidence that successfully treating two PsA domains, namely synovitis and enthesitis, may be associated with a more pronounced improvement in health-related quality of life, as opposed to treating each domain individually.
Introduction
Psoriatic arthritis (PsA) is a chronic, inflammatory rheumatic disease characterised by multiple musculoskeletal and non-musculoskeletal manifestations, such as peripheral arthritis, enthesitis, axial disease, dactylitis, skin psoriasis, and nail psoriasis [1‐3]. These manifestations hinder patients’ physical activity and quality of life (QoL) [4]. Enthesitis is characterised by the inflammation of entheseal sites including the tendon, ligament, or joint-capsule insertions [5]. Of note, the presence of enthesitis has been associated with worse disease outcomes, pain, and QoL burden [6]. Synovitis, the pathological basis of peripheral arthritis, can occur at the same time, e.g. as secondary synovitis following enthesitis, or separately, in psoriatic arthritis [7, 8]. Synovitis is routinely assessed through the examination of swollen and tender joint counts [9, 10]. Swollen joints have been identified as an appropriate proxy for synovitis evaluation in patients with PsA [11]. Clinical synovitis is reported in most patients with established PsA [12] while enthesitis is reported in about 30% of patients with PsA [6]. Magnetic resonance imaging (MRI) studies have demonstrated a link between synovitis and enthesitis in swollen joints of patients with PsA and in arthritis more generally, i.e. the ”synovio-entheseal complex” [8]. Therefore, synovitis and enthesitis are important manifestations which have to be accounted for in PsA treatment.
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Ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets interleukin (IL)-17A, is approved for the treatment of patients with PsA, radiographic and non-radiographic axial spondyloarthritis, and paediatric (≥ 6 years old) and adult moderate-to-severe plaque psoriasis. The dose approved for PsA in most geographies is 160 mg IXE at week 0 followed by 80 mg IXE every 4 weeks (Q4W). For patients with concomitant moderate-to-severe psoriasis, after the initial dose of 160 mg the approved dose is 80 mg IXE every 2 weeks (Q2W) from week 2 to week 12, followed by 80 mg IXE Q4W thereafter [13]. The long-term efficacy of IXE treatment has been demonstrated up to 3 years in phase III clinical trials (SPIRIT-P1 and SPIRIT-P2) and up to 52 weeks in a phase IIIb/IV head-to-head study (SPIRIT-H2H) [14‐16]. IXE treatment has previously demonstrated improvements in patient-reported outcomes (PROs) including QoL for patients with PsA [17, 18]. Data from SPIRIT-P1 and SPIRIT-P2 studies have demonstrated the improvement or resolution of enthesitis and dactylitis after 24-week IXE treatment [19]. Additional and longer-term investigation of PROs after PsA treatment might provide further insights into the synergistic effect of improvements in synovitis and improvements in enthesitis on PROs, including health-related QoL (HRQoL) for patients with PsA.
The objective of the current analysis was to explore the association between improvement in synovitis and improvement in enthesitis in patients with PsA treated with IXE through week 52 within the SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H trials who presented with synovitis and enthesitis at baseline. Additionally, the analysis explored an association between improvements in synovitis, enthesitis, and simultaneous improvement in both conditions with improvements in PROs including HRQoL through week 52.
Methods
Participants and Study Design
This post hoc analysis included data from three randomised, phase III and IIIb/IV studies, involving patients with active PsA who were either biologic disease-modifying antirheumatic drug (DMARD)-naïve (SPIRIT-P1 [NCT01695239, phase III] and SPIRIT-H2H [NCT03151551, phase IIIb/IV]); or tumour necrosis factor (TNF) inhibitors-experienced (SPIRIT-P2 [NCT02349295], phase III). The designs, as well as efficacy and safety data from these trials have been previously published [18, 20, 21]. In SPIRIT-P1, patients were randomised 1:1:1:1 to receive IXE Q2W, IXE Q4W, adalimumab Q2W, or placebo. In SPIRIT-P2, patients were randomised 1:1:1 to receive IXE Q2W, IXE Q4W, or placebo. In SPIRIT-H2H, patients were randomised 1:1 to receive IXE or adalimumab in their approved doses. All patients randomised to IXE received a starting dose of 160 mg given as two subcutaneous injections at week 0 followed by 80 mg subcutaneous injections of IXE Q2W or Q4W thereafter.
The studies were compliant with ethical guidelines including the Declaration of Helsinki and other relevant laws and regulations. The three trials were approved by each site’s ethical review committee/institution review board; names of all principal investigators and participating study sites have been previously published [18, 20, 21]. All patients provided written informed consent.
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Synovitis and Enthesitis Assessments
Synovitis was assessed using Swollen Joint Count (SJC) of 66 joints. Enthesitis was assessed at six sites (lateral epicondyle [left and right], medial femoral condyle [left and right], and Achilles tendon insertion [left and right]) using the Leeds Enthesitis Index (LEI). Each site was assigned a score based on the absence (0) or presence (1) of tenderness, yielding an overall score in the range of 0–6, where a higher score indicates greater number of sites affected by enthesitis. The proportion of patients achieving resolution of synovitis or enthesitis was evaluated at week 52. Resolution of synovitis was defined as SJC = 0 and resolution of enthesitis was defined as LEI = 0.
PROs including HRQoL Assessment
HRQoL was assessed using the 36-item Short Form Health Survey (SF-36) Physical Component Summary score (PCS) and the European Quality of Life-5 Dimensions 5 Level (EQ-5D-5L). The SF-36 is a self-reported survey with 36 items and two summary scores, a Physical Component Summary score (PCS) and a Mental Component Summary score (MCS). Each summary score is standardised to a norm-based score with a range of 0–100, where higher scores indicate better QoL. EQ-5D-5L comprises two components: patient self-rating (EQ-VAS) and a descriptive system (EQ-5D health index). The patient self-rating uses a 0–100 mm visual analog score (VAS) scale, where 0 = worst health imaginable and 100 = best health imaginable. The descriptive system encompasses five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). The descriptive system is measured using five levels ranging from no problems to extreme problems and is converted into a summary health index using an equation that substitutes the levels of each dimension into a value. Disease activity was evaluated using the self-reported Patient’s Global Assessment (PtGA) of Disease Activity VAS assessing how patients feel their PsA is on a particular day. Experienced pain was evaluated using the self-reported Pain VAS assessing patient’s current level of pain. Both PtGA and pain VAS are scored on a 0–100 mm scale, where higher scores indicate more disease activity or greater pain intensity. The means change from baseline in SF-36 PCS, EQ-5D-5L, PtGA, and pain VAS were calculated over time for patients who reached or did not reach resolution of synovitis or enthesitis at week 52.
Statistical Analysis
This descriptive exploratory analysis only included patients with both synovitis (defined as SJC score > 0) and enthesitis (defined as LEI > 0) at baseline treated with IXE Q4W. Pearson correlation statistics were employed to assess the association between improvements in synovitis and improvements in enthesitis at various timepoints from baseline up to week 52. The association between resolution of synovitis and enthesitis and improvements in PROs including HRQoL was assessed descriptively. This analysis evaluated the improvements in PROs including HRQoL versus resolution of both, either, or neither PsA domains, namely synovitis and enthesitis, using the mean change from baseline with standard deviation (SD) and the associated confidence interval at week 24 and week 52. The improvement among patients with both or either resolution was compared to patients with neither resolution using a generalised linear model for each of the outcomes reported. Missing data were imputed using a modified baseline observation carried forward method. The significance level of the tests was set to 0.05, so any p value < 0.05 was considered significant. No multiplicity testing adjustment was planned for this analysis.
Results
Baseline Demographics and Patient Characteristics
This analysis included patients from SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H who were treated with IXE Q4W and presented with both synovitis and enthesitis at baseline. This population comprises 64% (68/107), 56% (68/122), and 56% (159/283) of patients enrolled in SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H, respectively. At baseline, some numerical differences are observed in the proportion of included male participants within each study, representing 38.2% (26/68) from SPIRIT-P1, 45.6% (31/68) from SPIRIT-P2, and 56.6% (90/159) from SPIRIT-H2H. Otherwise, patient demographics and disease characteristics were similar across the three trials (Table 1). For patients included from SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H, the following characteristics were reported at baseline: mean (± SD) TJC was 22.2 ± 13.3, 25.0 ± 14.4, and 21.3 ± 12.8; mean (± SD) SJC was 11.4 ± 7.1, 13.6 ± 12.0, and 11.1 ± 8.3; mean (± SD) LEI was 2.9 ± 1.5, 2.9 ± 1.4, and 2.5 ± 1.4; mean (± SD) PtGA was 61.9 ± 17.4, 67.6 ± 21.1, and 62.9 ± 20.2; mean (± SD) pain VAS was 60.8 ± 17.1, 64.9 ± 22.3, and 61.3 ± 21.8; mean (± SD) SF-36 PCS was 31.2 ± 10.1, 31.3 ± 9.4, and 37.0 ± 7.8; mean (± SD) EQ-5D 5L was 0.6 ± 0.2, 0.6 ± 0.2, and 0.5 ± 0.2, and mean (± SD) EQ-5D 5L VAS was 52.5 ± 19.3, 51.5 ± 22.8, and 53.2 ± 20.7, respectively.
Table 1
Patient baseline demographics and disease characteristics presented with synovitis (SJC > 0) and enthesitis (LEI > 0) at baseline in SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H
Baseline characteristics
SPIRIT-P1
SPIRIT-P2
SPIRIT-H2H
Number of patients, n/N (%)
68/107 (64%)
68/122 (56%)
159/283 (56%)
Age (years)
50.1 ± 9.7
51.4 ± 14.3
45.9 ± 11.5
Male, n (%)
26 (38.2)
31 (45.6)
90 (56.6)
TJC (68-joints)
22.2 ± 13.3
25.0 ± 14.4
21.3 ± 12.8
SJC (66-joints)
11.4 ± 7.1
13.6 ± 12.0
11.1 ± 8.3
LEI > 0
2.9 ± 1.5
2.9 ± 1.4
2.5 ± 1.4
PtGA (0–100 mm)
61.9 ± 17.4
67.6 ± 21.2
62.9 ± 20.2
Patient pain VAS (0–100 mm)
60.8 ± 17.1
64.9 ± 22.3
61.3 ± 21.8
SF-36 PCS
31.2 ± 10.1
31.3 ± 9.4
37.0 ± 7.8
EQ-5D 5L
0.6 ± 0.2
0.6 ± 0.2
0.5 ± 0.2
EQ-5D 5L VAS
52.5 ± 19.3
51.5 ± 22.8
53.2 ± 20.7
Data are mean ± standard deviation unless otherwise stated
TJC tender joint count, SJC swollen joint count, LEI Leeds Enthesitis Index, PtGA Patient’s Global Assessment of Disease Activity, VAS visual analogue scale, SF-36 Medical Outcomes Study 36-item Short Form Health Survey, PCS Physical Component Score, EQ-5D 5L European Quality of Life-5 Dimensions 5 Level
Synergistic Improvements of Synovitis and Enthesitis Through Week 52
Across these three trials, IXE treatment resulted in improvement in both synovitis and enthesitis up to week 52, demonstrated by the decreasing values in Fig. 1. For patients from SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H, mean change from baseline (± SD) at week 52 in SJC was − 8.8 ± 7.5, − 9.6 ± 12.6, and − 9.4 ± 8.2 and mean change from baseline (± SD) in LEI was − 1.9 ± 1.7, − 1.8 ± 1.9, and − 1.8 ± 1.5, respectively (Supplemental Table 1). Among the 295 patients included in this analysis, 128 (43.4%) patients achieved resolution in both synovitis and enthesitis, and 93 (31.5%) patients achieved resolution of either synovitis or enthesitis (Table 2). In those achieving resolution of enthesitis after 52 weeks, the residual SJC was down − 10.97 from baseline, and in those achieving resolution of synovitis at week 52, the residual LEI was down − 1.25 from baseline. At week 52, the Pearson coefficient between improvements in synovitis and enthesitis was 0.33, 0.35, and 0.25 for patients from SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H respectively. Overall, a positive correlation between improvement in simultaneous synovitis and enthesitis from baseline through week 52 was observed (Table 3).
Fig. 1
Mean change from baseline in synovitis and enthesitis from baseline through week 52 in SPIRIT-P1 (a), SPIRIT-P2 (b), and SPIRIT-H2H (c). CFB change from baseline, SJC swollen joint count, LEI Leeds Enthesitis Index
Table 2
Synovitis and enthesitis resolution at week 52 in SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H
Synovitis and enthesitis resolution
SPIRIT-P1
SPIRIT-P2
SPIRIT-H2H
Total number of patients, n
68
68
159
Resolution: both, n (%)
23 (33.8%)
23 (33.8%)
82 (51.6%)
Resolution: either, n (%)
25 (36.8%)
19 (27.9%)
49 (30.8%)
Resolution: synovitis only, n (%)
6 (8.8%)
8 (11.8%)
25 (15.7%)
Resolution: enthesitis only, n (%)
19 (27.9%)
11 (16.2%)
24 (15.1%)
Resolution: neither, n (%)
20 (29.4%)
26 (38.2%)
28 (17.6%)
SJC CFB (66-joints, week 52)
− 8.8 ± 7.5
− 9.6 ± 12.6
− 9.4 ± 8.2
LEI CFB (week 52)
− 1.9 ± 1.7
− 1.8 ± 1.9
− 1.8 ± 1.5
Data are mean ± standard deviation unless otherwise stated.
SJC swollen joint count, LEI Leeds Enthesitis Index, CFB change from baseline
Table 3
Mean change from baseline of PROs for patients who achieved resolution of synovitis and enthesitis at week 24 and week 52
Timepoint
Synovitis and enthesitis resolution
SF-36 PCS
EQ VAS
EQ-5D health index
Pain VAS
PtGA
SPIRIT-P1
Week 24
Both
12.6 ± 9.9
(8.1;17.1) n = 21
15.7 ± 18.0
(7.5;23.9) n = 21
0.20 ± 0.19
(0.11;0.29) n = 21
− 44.9 ± 24.5
(− 56.1;− 33.7) n = 21
− 47.1 ± 24.5
(− 58.2;− 35.9) n = 21
Either
7.6 ± 10.7
(3.2;12.1) n = 25
15.0 ± 26.1
(4.2;25.7) n = 25
0.10 ± 0.17
(0.03;0.18) n = 25
− 30.8 ± 22.6
(− 40.2;− 21.5) n = 25
− 38.2 ± 21.5
(− 47.1;− 29.3) n = 25
Neither
6.1 ± 8.4
(1.9;10.3) n = 18
8.8 ± 19.9
(− 1.0;18.7) n = 18
0.11 ± 0.16
(0.03;0.19) n = 18
− 25.5 ± 25.5
(− 37.8;− 13.2) n = 19
− 22.2 ± 26.0
(− 34.7;− 9.7) n = 19
Week 52
Both
13.1 ± 9.8
(8.6;17.6) n = 21
19.1 ± 19.5
(10.2;28.0) n = 21
0.24 ± 0.16
(0.16;0.31) n = 21
− 48.4 ± 19.0
(− 57.0;− 39.7) n = 21
− 48.6 ± − 23.1
(− 59.1;− 38.0) n = 21
Either
9.3 ± 9.9
(5.3;13.4) n = 25
15.7 ± 26.9
(4.6;26.8) n = 25
0.09 ± 0.15
(0.03;0.15) n = 25
− 28.3 ± 27.7
(− 39.7;− 16.8) n = 25
− 35.4 ± 28.5
(− 47.2;− 23.6) n = 25
Neither
7.7 ± 10.1
(2.7;12.7) n = 18
10.9 ± 26.9
(− 2.5;24.3) n = 18
0.11 ± 0.20
(0.02;0.21) n = 18
− 22.1 ± 28.0
(− 35.6;− 8.6) n = 19
− 17.1 ± 23.9
(− 28.6;− 5.6) n = 19
SPIRIT-P2
Week 24
Both
5.1 ± 11.5
(0.0;10.2) n = 22
14.5 ± 20.8
(5.3;23.7) n = 22
0.15 ± 0.27
(0.03;0.27) n = 22
− 28.1 ± 31.7
(− 42.2;− 14.1) n = 22
− 31.6 ± 28.9
(− 44.4;− 18.7) n = 22
Either
4.4 ± 7.1
(1.0;7.8) n = 19
10.9 ± 35.4
(− 6.2;28.0) n = 19
0.12 ± 0.15
(0.04;0.19) n = 19
− 20.1 ± 23.7
(− 31.5;− 8.6) n = 19
− 28.3 ± 24.8
(− 40.2;− 16.3) n = 19
Neither
1.9 ± 8.9
(− 1.7;5.5) n = 26
10.1 ± 25.4
(− 0.1;20.4) n = 26
0.07 ± 0.20
(− 0.01;0.15) n = 26
− 15.3 ± 20.6
(− 23.6;− 7.0) n = 26
− 17.4 ± 24.1
(− 27.1;− 7.6) n = 26
Week 52
Both
9.7 ± 10.7
(5.0;14.5) n = 22
18.3 ± 15.5
(11.4;25.1) n = 22
0.23 ± 0.24
(0.12;0.34) n = 22
− 40.2 ± 25.2
(− 51.4;− 29.0) n = 22
− 43.9 ± 25.8
(− 55.3;− 32.4) n = 22
Either
8.0 ± 6.6
(4.8;11.2) n = 19
20.7 ± 26.3
(8.1;33.4) n = 19
0.15 ± 0.17
(0.07;0.23) n = 19
− 28.5 ± 26.0
(− 41.1;− 15.9) n = 19
− 33.0 ± 30.6
(− 47.8;− 18.2) n = 19
Neither
1.6 ± 8.7
(− 2.6;5.8) n = 19
5.7 ± 25.9
(− 6.8;18.2) n = 19
0.05 ± 0.22
(− 0.06;0.15) n = 19
− 12.0 ± 22.4
(− 22.7;− 1.2) n = 19
− 14.3 ± 29.8
(− 28.7;− 0.1) n = 19
SPIRIT-H2H
Week 24
Both
11.2 ± 8.6
(9.3;13.1) n = 81
23.3 ± 23.2
(18.1;28.4) n = 81
0.25 ± 0.25
(0.20;0.31) n = 81
− 35.2 ± 29.0
(− 41.6;− 28.8) n = 81
− 40.3 ± 24.4
(− 45.7;− 34.9) n = 81
Either
6.7 ± 9.7
(3.9;9.5) n = 48
13.0 ± 26.2
(5.4;20.6) n = 48
0.13 ± 0.21
(0.07;0.19) n = 48
− 21.7 ± 29.9
(− 30.4;− 13.0) n = 48
− 23.2 ± 30.7
(− 32.1;− 14.3) n = 48
Neither
1.5 ± 7.5
(− 1.4;4.4) n = 28
8.0 ± 23.1
(− 0.9;17.0) n = 28
0.10 ± 0.25
(0.01;0.20) n = 28
− 17.6 ± 25.2
(− 27.3;− 7.8) n = 28
− 18.2 ± 23.9
(− 27.5;− 8.9) n = 28
Week 52
Both
11.3 ± 8.4
(9.4;13.2) n = 81
25.2 ± 24.1
(19.8;30.5) n = 81
0.27 ± 0.26
(0.21;0.32) n = 81
− 39.5 ± 32.3
(− 46.6;− 32.3) n = 81
− 42.8 ± 26.9
(− 48.8;− 36.8) n = 81
Either
6.3 ± 7.9
(4.0;8.6) n = 48
12.2 ± 26.7
(4.5;20.0) n = 48
0.12 ± 0.20
(0.06;0.17) n = 48
− 26.0 ± 24.6
(− 33.2;− 18.8) n = 48
− 26.2 ± 25.1
(− 33.5;− 18.9) n = 48
Neither
3.9 ± 7.2
(1.1;6.7) n = 28
12.4 ± 24.8
(2.8;22.0) n = 28
0.10 ± 0.22
(0.02;0.19) n = 28
− 20.1 ± 25.7
(− 30.1;− 10.1) n = 28
− 22.2 ± 28.1
(− 33.1;− 11.2) n = 28
Data are presented as mean ± standard deviation with 95% confidence intervals
SF-36 36-Item Short Form Health Survey, PCS Physical Component Score, EQ-5D-5L European Quality of Life-5 Dimensions 5 Level, VAS visual analogue scale (mm), PtGA Patient Global Assessment of Disease
×
Synergistic Improvements in Synovitis or Enthesitis with Improvements in PROs Including HRQoL Through Week 52
Across the SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H trials, improvements in mean SF-36 PCS, EQ VAS, EQ-5D health index, Pain VAS, and PtGA were observed for patients treated with IXE from baseline through week 52, regardless of resolution of synovitis or enthesitis (Fig. 2). Moreover, most pronounced statistical significance is observed for patients who achieved resolution of both conditions through week 52.
Fig. 2
Improvement from baseline in SF-36 PCS (a), EQ VAS (b), EQ-5D-5L health index score (c), Pain VAS (d), and PtGA (e) through week 52 in SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H. Both: includes patients who achieved resolution of both synovitis and enthesitis at week 52. Either: includes patients who achieved resolution of either synovitis and enthesitis at week 52. Neither: includes patients who did not achieve resolution of synovitis or enthesitis at week 52. SF-36 36-Item Short Form Health Survey, PCS Physical Component Score, CFB Change from Baseline, EQ-5D-5L European Quality of Life-5 Dimensions 5 Level, VAS visual analogue scale (mm), PtGA Patient Global Assessment of Disease. Minimal clinically important difference for SF-36 PCS (a), EQ-5D health index (c), Pain VAS (d), and PtGA (d) are outlined with a hashed line [31]. The improvement among patients with both or either resolution was compared to patients with neither resolution at each timepoint using a generalised linear model for each outcomes. Statistical significance is presented for the following timepoints only: week 12, 16, 24, 32, and 52. *p < 0.05, #p < 0.01, +p < 0.001
×
SF-36 PCS
At week 52, the greatest mean improvement from baseline in SF-36 PCS in the three trials was observed in patients who achieved resolution of both synovitis and enthesitis, followed by those who achieved resolution of either synovitis or enthesitis (Fig. 2a). Improvements in SF-36 PCS for patients who achieved resolution of both manifestations corresponded to a mean change from baseline (± SD) of 13.1 ± 9.8, 9.7 ± 10.7, and 11.3 ± 8.4 at week 52 for patients from SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H, respectively (Table 3).
EQ VAS
In SPIRIT-P1 and SPIRIT-H2H, patients achieving resolution of both manifestations reported the greatest improvement in EQ VAS at week 52, corresponding to a mean change from baseline (± SD) of 19.1 ± 19.5 and 25.2 ± 24.1, respectively. Patients achieving resolution of either manifestation achieved the greatest mean improvement from baseline in EQ VAS in SPIRIT-P2, closely followed by those achieving resolution of both at week 52 (Fig. 2b). For all other timepoints reported for SPIRIT-P2, patients achieving resolution of both manifestations reported higher EQ VAS improvements.
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EQ-5D Health Index
Across the three trials, the greatest mean improvement from baseline in the EQ-5D health index was observed in patients who achieved resolution of both synovitis and enthesitis at week 52 (Fig. 2c). Improvements in EQ-5D health index corresponded to a mean change from baseline (± SD) of 0.2 ± 0.2, 0.15 ± 0.3, and 0.25 ± 0.3 in SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H at week 24, respectively, and 0.24 ± 0.2, 0.23 ± 0.2, and 0.27 ± 0.3 in SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H at week 52, respectively (Table 3). Of note, in SPIRIT-P1 and SPIRIT-H2H, patients achieving resolution of either or neither manifestation showed similar improvement trends and mean values in EQ-5D health index (Fig. 2c).
Pain VAS
Similarly, patients achieving resolution of both synovitis and enthesitis experienced less pain at week 52 compared to those who achieved resolution of only one or neither manifestation (Fig. 2d). Pain reduction at week 52 corresponds to a mean change from baseline (± SD) of − 48.4 ± 19.0, − 40.2 ± 25.2, and − 39.5 ± 32.3 for patients who achieved resolution of both manifestations from SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H, respectively. Patients who did not achieve resolution of either manifestation experienced the lowest mean improvement in pain VAS at week 52, with little separation between this group and patients who achieved resolution of either condition within the three trials.
PtGA
Finally, the most pronounced mean improvement in PtGA was observed in patients who achieved resolution of both synovitis and enthesitis, followed by patients who achieved resolution of either synovitis or enthesitis (Fig. 2e). Patients who achieved resolution of both manifestations reported a mean improvement (± SD) in PtGA of − 47.1 ± 24.5, − 31.6 ± 28.9, and − 40.3 ± 24.4 in SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H at week 24, respectively, and − 48.6 ± 23.1, − 43.9 ± 25.8, and − 42.8 ± 27.0 in SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H at week 52, respectively.
Overall, the most pronounced improvements in PROs, including HRQoL, were observed in patients who achieved resolution of both enthesitis and synovitis. Despite minor variations, mean change from baseline in SF-36 PCS, EQ VAS, ED-5D health index, Pain VAS, and PtGA exhibited monotonic trends from baseline to week 52. Together, these analyses of patients treated with IXE through week 52 demonstrate the synergistic improvement or resolution of synovitis or enthesitis and improvements in PROs including HRQoL in SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H trials.
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Discussion
This study demonstrated the synergistic improvements in synovitis and improvements in enthesitis alongside improvements in PROs including HRQoL with IXE treatment across SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H trials. Patients who achieved resolution of both synovitis and enthesitis at week 52 experienced greater improvements in PROs including HRQoL. These findings further support the importance of addressing multiple domains in PsA treatment decisions, as recommended by current guidelines, e.g. EULAR [2].
Patients with PsA suffering from multiple manifestations such as dactylitis or enthesitis are more likely to report greater pain, fatigue, and higher levels of work or activity impairment [22]. This analysis demonstrated the synergistic improvements in synovitis and enthesitis and improvements in PROs including HRQoL, highlighting the beneficial effect of IL-17 inhibitors on joint swelling and enthesitis. Moreover, in theory one may not expect the resolution of apparent synovitis and enthesitis in patients with a fibromyalgia or osteoarthritis (OA) component for the following reasons. Firstly, the presence of pain and tenderness in OA joints and potential osteophytic bone thickening or soft tissue swelling could collectively be evaluated as part of the PsA synovitis spectrum [23, 24]. Secondly, significant fibromyalgia and tenderness may be conflated with enthesitis as clinical swelling is usually absent in subjects with active enthesitis [25]. Therefore, one might conclude that in this case, “true” resolution of PsA-related enthesitis and associated synovitis has occurred [7].
It has been previously demonstrated that 24-week IXE treatment achieved enthesitis resolution for 39% of biologic DMARD-naïve and TNFi-experienced patients from SPIRIT-P1 and SPIRIT-P2 studies [19]. In the present analysis, with the inclusion of additional biologic DMARD-naïve patients from SPIRIT-H2H trial, 52-week IXE treatment achieved synovitis and enthesitis resolution for 43.4% of patients. Additionally, resolution of either synovitis or enthesitis was achieved for 31.5% of patients from SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H trials after 52-week IXE treatment. Together, these findings demonstrate a high level of resolution of two PsA domains after IXE treatment which may lead to enhanced HRQoL for patients with PsA.
Previous studies have demonstrated an association between improvements in PROs including HRQoL and resolution of one or more PsA manifestations. Specifically, findings from the ACHILLES study with secukinumab, despite not meeting its primary endpoint, suggested a link between clinical improvements in global assessment of disease and SF-36 and improvements in heel enthesitis [26]. In the DISCOVER-2 trial on guselkumab, improvements in PROs including HRQoL were reported after treatment of multiple PsA domains [27]. This analysis demonstrated that at baseline, multiple clinical features and PROs are associated with HRQoL measures. Specifically, high levels of TJC were associated with worse levels of EQ-5D-5L index scores and high levels of SJC were associated with worse EQ-VAS scores. Additionally, the 24-week IXE treatment has previously demonstrated improvements in skin and nail symptoms as well as pronounced improvements in PROs including HRQoL [28]. Moreover, patients in the current study who achieved resolution of both synovitis and enthesitis experienced the most pronounced improvement in PROs including HRQoL. These findings confirm that all PsA domains should be assessed at baseline and support therapeutic strategies targeting multiple PsA domains. The current PsA treatment recommendations by GRAPPA and the European League Against Rheumatism (EULAR) emphasize the importance of addressing all PsA manifestations [29, 30]. Together, these findings align with PsA recommendations advising the consideration of all PsA domains in PsA treatment course.
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The presented data bear some limitations that need to be pointed out. The present study is a post hoc analysis of the SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H trials. These three trials employed different study designs and inclusion criteria. The presence of synovitis or enthesitis was not an inclusion criterion in any of these studies. Additionally, patient assessment and medical imaging were not performed at baseline to confirm the presence of synovitis or enthesitis. As a result, the study is descriptive and exploratory, and findings are based on small sample size with large variability. It would be of benefit to confirm these findings with a larger sample size. Finally, in this analysis, the definition of synovitis did not include joint tenderness and assessment of disease activity did not take into consideration Disease Activity in Psoriatic Arthritis (DAPSA).
Conclusion
The findings presented indicate synergistic improvements in synovitis and enthesitis for patients presenting with both conditions at baseline and treated with IXE through week 52 in the SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H trials. Patients who achieved resolution of both synovitis and enthesitis reported simultaneous improvements in PROs including HRQoL.
Acknowledgements
Medical Writing, Editorial, and Other Assistance
Writing and editorial assistance in the preparation of this article were provided by Dr. Catherine Sirafim, an employee of Eli Lilly and Company.
Authorship
All the named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article and have given their final approval for this article.
Declarations
Conflict of Interest
Lars-Erik Kristensen received grants or contracts from Pfizer, AbbVie, Amgen, Galapagos, UCB, Celgene, BMS, MSD, Novartis, Eli Lilly, and Janssen Pharmaceuticals, consulting fees from Pfizer, AbbVie, Amgen, Galapagos, UCB, Celgene, BMS, MSD, Novartis, Eli Lilly, and Janssen Pharmaceuticals, and honoraria from Pfizer, AbbVie, Amgen, Galapagos, UCB, Celgene, BMS, MSD, Novartis, Eli Lilly, and Janssen Pharmaceuticals. Dennis McGonagle received grant funding, support for attending meetings or travel, and support for attending advisory board from Eli Lilly and Company. Martin Rudwaleit received consulting fees from Eli Lilly and Company, Novartis, and UCB, honoraria from AbbVie, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Novartis, and UCB, and support for attending meetings or travel from Janssen, Novartis, Galapagos, AbbVie, and UCB. Hideto Kameda received grants or contracts from Asahi Kasei, Taisho, Mitsubishi-Tanabe, Eisai, Chugai, Pfizer, and AbbVie, consulting fees from Sanofi, Novartis, and AbbVie, honoraria from AbbVie, Asahi Kasei, Bristol Myers, Boehringer Ingelheim, Chugai, Eisai, Mitsubichi-Tanabe, Janssen, Eli Lilly and Company, Novartis, Pfizer, and UCB, support for participation in data safety monitoring board or advisory board from AbbVie, Astellas, Amgen, Eli Lilly and Company, Sanofi, and UCB, and holds a leadership or fiduciary role in the Japan Spondyloarthritis Society. Josef Smolen received grants or contracts from AbbVie, AstraZeneca, Eli Lilly and Company, Novartis, Galapagos, and Roche, consulting fees from AbbVie, Amgen, Ananda, Astro, BMS, Celltrion, Chugai, Eli Lilly and Company, Gilead, Immunovant, MSD, Novartis, Pfizer, Roche, R-Pharma, Samsung, Sanofi, and UCB, and support for attending meetings or travel from Eli Lilly and Company. Thorsten Holzkaemper, Marcu Ngantcha and Peter Adler are employees and shareholders at Eli Lilly and Company. Joanna Burke was a contract statistician for Eli Lilly and Company via Agile who contributed to the manuscript during development. Joanna Burke was not affiliated to Eli Lilly and Company after the completion of this manuscript.
Ethical Approval
The studies were compliant with ethical guidelines including the Declaration of Helsinki and other relevant laws and regulations. The three trials were approved by each site’s ethical review committee/institution review board; names of all principal investigators and participating study sites have been previously published [18, 20, 21]. All patients provided written informed consent.
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Synergistic Improvements in Synovitis, Enthesitis, and Patient-Reported Outcomes for Patients with Psoriatic Arthritis Treated with Ixekizumab in SPIRIT Trials
verfasst von
Lars-Erik Kristensen Dennis McGonagle Martin Rudwaleit Hideto Kameda Peter Adler Würtzen Marcus Ngantcha Thorsten Holzkämper Josef Smolen
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