Background
Psoriatic arthritis (PsA) is a chronic inflammatory disorder, associated with musculoskeletal manifestations (peripheral arthritis, spondylitis, enthesitis, and dactylitis) and extra-musculoskeletal manifestations (skin and nail disease) [
1,
2], which has significant impact on health-related quality of life (HRQoL) and disability [
3]. Of these, enthesitis is a clinical, periarticular manifestation seen both at early and late phases of the disease [
4‐
6] which can differentiate PsA from rheumatoid arthritis [
2,
7]. Enthesitis is defined as inflammation of tendon, ligament, or joint capsule insertion sites to bone and may be important in PsA development [
2,
8]. Entheses are anatomically, functionally, and physiologically associated with synovia and form the “synovio-entheseal complex” which are comprised of soft and hard tissue. The enthesis organ dissipates stress, which may be a potential triggering mechanism of enthesitis and, ultimately, PsA [
5,
9,
10]. About 30–50% of patients with PsA suffer from enthesitis based on standard clinical examination, which may, however, underestimate or misinterpret such symptoms [
8], since imaging studies have revealed the prevalence rate to be as high as 70% [
11].
Type 3 innate lymphoid cells and γ훿T cells are present at entheseal sites which on activation stimulate the production of interleukin (IL)-17 [
4,
12]. The IL-17 pathway augments the influx and activation of neutrophils which are the effector cells of entheseal inflammation, and stimulates the release of proteases and reactive oxygen species that lead to pain response during entheseal inflammation [
4,
8].
Enthesitis is frequently associated with increased pain, fatigue, physical disability, structural damage, and reduced work productivity compared to patients without enthesitis [
13,
14]. According to the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), enthesitis reflects higher disease burden and represents one of the six clinical core domains requiring diagnosis, assessment, and treatment in PsA [
1,
15]. The recently updated American College of Rheumatology/National Psoriasis Foundation guideline has recommended treatment with IL-17 or IL-12/23 inhibitor in PsA patients with predominant enthesitis who have severe psoriasis or contraindications to first-line treatment with tumor necrosis factor inhibitors (TNFi) [
16].
Secukinumab, a fully human, monoclonal IgG1κ antibody that directly inhibits IL-17A, has been shown to provide significant and sustained improvement in the different facets of active PsA [
17‐
20]. In the FUTURE 2 and FUTURE 3 studies, secukinumab demonstrated early and sustained clinical efficacy in PsA patients up to 4 years [
18‐
21]. Secukinumab 300 and 150 mg provided rapid and sustained resolution of enthesitis in ~ 70% of patients with enthesitis at baseline through 4 years in FUTURE 2 [
18,
19,
21] and in ~ 50% patients through 1 year in FUTURE 3 [
20].
Herein, we present a comprehensive post hoc analysis using pooled data from the FUTURE 2 and FUTURE 3 studies over 2 years, to further evaluate the effect of secukinumab on (a) enthesitis count (EC; defined by the Leeds Enthesitis Index [LEI]), (b) time to resolution of enthesitis, (c) shift in baseline EC (1, 2, or 3–6) to resolution, and (d) the occurrence of enthesitis in patients with no enthesitis at baseline. We also evaluated if clinical outcomes were similarly improved with secukinumab irrespective of the presence of enthesitis at baseline.
Discussion
The current knowledge on the treatment of enthesitis is limited. Most randomized, controlled trials in PsA focus on polyarticular disease, which accounts only for a subgroup of PsA. To date, no randomized, controlled study has been specifically designed to evaluate the treatment of enthesitis. Notably, most clinical trials in which enthesitis indices were applied to assess enthesitis outcomes among patients displaying this symptom at baseline were not adequately powered to assess enthesitis [
25‐
28].
The objectives of this pooled analysis from the FUTURE 2 and FUTURE 3 studies were to describe the demographics and clinical characteristics of the patients who had both polyarticular disease as per inclusion criteria and baseline enthesitis, and to assess the efficacy of secukinumab on resolution of enthesitis in patients with PsA over 2 years. The present analysis showed that the 65% of PsA patients who were diagnosed with enthesitis at baseline had more severe disease activity and reduced physical function compared with patients without enthesitis. This is consistent with data from the Corrona registry in PsA showing a higher disease activity, a poorer functional status, a worse quality of life, and greater patient-reported pain and fatigue in patients with enthesitis compared to those without enthesitis [
13]. Enthesitis, therefore, is an important clinical domain of PsA that serves as an indicator of disease severity and high disease burden.
Clinically, enthesitis is invariably perceived as tenderness at entheses with entheseal swelling being uncommon. Different indices have been developed to help assess and measure enthesitis. The most commonly used indices for the assessment of enthesitis include the Spondyloarthritis Research Consortium of Canada (SPARCC), Maastricht ankylosing spondylitis enthesitis score (MASES), and LEI [
24], which are clinically validated, reliable, and sensitive to change. The LEI and SPARCC are more specific for enthesitis in PsA, examining 6 and 16 sites of enthesitis, respectively. The LEI is easy to perform, and when compared with MASES, SPARCC, and Berlin indices, LEI correlates most consistently with the clinical parameters of disease activity in patients with PsA [
24,
29]. Furthermore, LEI is capable of distinguishing between patients with and without active PsA [
23]. In the present analysis, we used the clinical resolution of enthesitis (EC = 0) which is a very stringent outcome in contrast with the LEI change from baseline used in most PsA clinical trials with TNFi [
27,
28,
30]. TNFi were shown to improve peripheral enthesitis as assessed by clinical indices of enthesitis in PsA [
25‐
27,
30]. However, little is known on the median time to resolve enthesitis, and the magnitude of response by enthesitis severity, by time since diagnosis, or after switch to other TNF inhibitors [
27,
28,
30] as well as development of enthesitis over time in patients with no enthesitis at baseline.
In the overall population, patients with enthesitis at baseline treated with secukinumab showed higher rates of full resolution of enthesitis compared with placebo at week 16, which further improved at week 104. The magnitude of response was higher in patients treated with secukinumab 300 than 150 mg. Similarly, secukinumab showed early and sustained resolution of enthesitis in TNFi-naïve and TNFi-IR patients through 2 years, with higher response in TNFi-naïve than TNFi-IR patients. Resolution of enthesitis data from this pooled analysis are in line with previously reported enthesitis data from the FUTURE 5 trial where an early and sustained resolution was observed up to 2 years (week 24, 61.4% [
P < 0.0001] and 54.6% [
P < 0.001] with secukinumab 300 and 150 mg, respectively, vs 34.4% with placebo; week 104, 78% and 80.3% with secukinumab 300 and 150 mg, respectively) [
31,
32].
These post hoc analyses illustrate for the first time in the literature the kinetics of enthesitis response to a biologic treatment as assessed by time to resolution of enthesitis, complemented with a shift analysis from baseline to weeks 24, 52, or 104, and heat map analysis. Secukinumab provided faster resolution of enthesitis compared with placebo in the overall population, as well as in both TNFi-naïve and TNFi-IR patients, with faster response in TNFi-naïve than TNFi-IR patients. These data are encouraging because enthesitis is known to be very painful and limiting, and can last for prolonged periods if not treated appropriately. Although full resolution took longer time in the more refractory TNFi-IR patients, the median time for achieving complete resolution was within the first 3 months. Secukinumab 300 mg showed faster resolution compared with 150 mg in the overall population and TNFi-naïve patients.
The shift analysis of enthesitis from baseline to week 24 by degree of severity of EC at baseline showed higher rate of full resolution in patients with mild to moderate enthesitis (EC = 1 or 2) with secukinumab 150 and 300 mg than placebo at week 24, with increased resolution at weeks 52 and 104. In contrast, no difference in full resolution of enthesitis was observed at week 24 between placebo and secukinumab 150 or 300 mg in patients with EC of 3–6 and proportions of patients from this group who had full resolution at weeks 52 and 104 were lower than in patients with less severe enthesitis. This highlights that achievement of full resolution in patients with more severe disease takes longer time and is more difficult to achieve. Heat map analysis helped visualizing EC resolution at individual level and extends the findings of the shift analysis by visually showing that from week 24 to 104, most patients treated with secukinumab sustain resolution of enthesitis.
The majority of patients without baseline enthesitis (89%) did not develop enthesitis over 2 years of treatment with secukinumab 300 or 150 mg. This supports the hypothesis that IL-17A inhibition may prevent the development of new enthesitis sites as well as providing sustained resolution of enthesitis in patients with baseline enthesitis.
TNFi studies have indicated that PsA patients with enthesitis are a difficult-to-treat population with a lower odds of achieving minimal disease activity (MDA) compared to patients without enthesitis [
33]. Indeed, the absence of enthesitis is a predictor of MDA in patients treated with TNFi [
34]. In contrast, secukinumab-treated patients with PsA showed higher ACR and PASI responses, reduced disease activity, and improved physical function and HRQoL versus placebo, regardless of enthesitis status at baseline. A greater magnitude of improvement in signs and symptoms, physical function, and quality of life was observed in patients with enthesitis at baseline treated with secukinumab 300 mg than with 150 mg. Importantly, the response rates in patients with and without enthesitis at baseline indicate that secukinumab 300 mg showed similar efficacy on different composite endpoints in both populations. This is in line with a pooled efficacy analysis from FUTURE 2–5 using machine learning which showed a greater response with secukinumab 300 mg over 150 mg in patients with baseline enthesitis [
35]. These improvements reported across all endpoints were sustained or further increased over 104 weeks of secukinumab treatment, which were consistent with the FUTURE 1 and 5 studies [
17,
31,
32].
The GRAPPA recommendations issued in 2016 mentioned non-steroidal anti-inflammatory drugs and physiotherapy as initial treatment and TNFi as the first-line biologics for enthesitis in PsA patients [
1]. Limited enthesitis data with secukinumab were available when the GRAPPA recommendations were issued. Data from TNFi studies are difficult to compare with the present pooled analysis as they used either LEI change from baseline or different scoring systems such as MASES and SPARCC [
27,
36]. A head-to-head trial comparing secukinumab and adalimumab, which includes the assessment of enthesitis as a key secondary endpoint, will be reported in the future (NCT02745080). In another head-to-head trial of an IL-17 inhibitor (ixekizumab) versus adalimumab (SPIRIT-P1), ixekizumab showed higher resolution of enthesitis (as measured by LEI) than adalimumab at week 24 (ixekizumab 80 mg once every 4 weeks, 43%, and ixekizumab 80 mg once every 2 weeks, 39%, vs adalimumab, 33%) [
37]. The recently published pooled data from the SPIRIT-P1 and SPIRIT-P2 studies with ixekizumab showed significant resolution of enthesitis at week 24 versus placebo (ixekizumab 80 mg once every 4 weeks, 39%, and ixekizumab 80 mg once every 2 weeks, 35%, vs placebo, 21%) [
38]. Data from the FUTURE studies [
19,
20,
32] along with this pooled analysis provide comprehensive evidence supporting the efficacy of secukinumab on enthesitis in PsA patients.
The potential limitations of the current analysis include its post hoc nature. Clinical enthesitis was not an inclusion criteria in the FUTURE studies. EC by use of the LEI (with only six sites) entails a probability of missing peripheral enthesitis at other sites. Scoring of enthesitis in the medial femoral condyle may be difficult because of joint swelling. Clinical indices such as LEI may not be specific, especially when there is overlap with fibromyalgia, mechanical injury, or tendinitis. Power Doppler Ultrasound was not performed at baseline to confirm the clinical assessment of enthesitis, and X-ray did not evaluate the impact on structural damage at baseline and up to 2 years. Another limitation is that the observed data analyses do not account for dropouts or missing data. There was no placebo group beyond weeks 16/24, and given the post hoc nature of this study, only numerical but no statistical comparisons were done between treatment groups. No additional analysis was done to assess the frequency of each enthesitis site at baseline and if any of them was more sensitive to treatment. The impact of secukinumab on resolution of enthesitis using imaging will be assessed in two multicenter, randomized, placebo-controlled trials which are currently ongoing: (1) the ULTIMATE study (NCT02662985) will use ultrasound to demonstrate the time course of response to secukinumab of enthesitis in biologic naïve PsA patients; (2) the ACHILLES study (NCT02771210) will use magnetic resonance imaging to evaluate the efficacy of secukinumab on resolving Achilles tendon enthesitis in patients with active PsA and axial spondyloarthritis despite current or previous NSAID, DMARD, or TNFi exposure.
Competing interests
LC Coates: Grant/research support from AbbVie, Pfizer, Novartis, Lilly, Celgene and Janssen; Consultant for AbbVie, Amgen, Biogen, Boehringer Ingelheim, Celgene, Gilead, Galapagos, Pfizer, UCB, Novartis, Lilly and Janssen
JK Wallman: Consultant for: AbbVie, Celgene, Lilly, Novartis, UCB
D McGonagle: Grant/research support from: Novartis, Janssen, Pfizer, AbbVie, Lilly; Speakers bureau: Novartis, Janssen, Pfizer, AbbVie, Lilly, UCB
G Schett: Grant/research support from: BMS, Celgene, GSK, Lilly, Novartis; Consultant for: AbbVie, BMS, Celgene, Janssen, Lilly, Novartis, UCB; Speakers bureau: AbbVie, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer
IB McInnes: Grant/research support from: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, UCB; Consultant for: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, UCB; Speakers bureau: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, UCB
PJ Mease: Grant/research support from AbbVie, Amgen, BMS, Celgene, Crescendo Bioscience, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer and UCB; Consultant for AbbVie, Amgen, BMS, Celgene, Crescendo Bioscience, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer and UCB; Speakers bureau for AbbVie, Amgen, BMS, Celgene, Crescendo Bioscience, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer and UCB
L Rasouliyan: Consultant for: Novartis through employment at RTI, Employee of: RTI Health Solutions
E Quebe-Fehling: Shareholder and employee of Novartis
DL Asquith: Shareholder and employee of Novartis
AER Fasth: Employee of Novartis
L Pricop: Shareholder and employee of Novartis
C Gaillez: Shareholder and employee of Novartis and Shareholder of BMS
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