Introduction
Psoriatic arthritis (PsA) is a chronic inflammatory disease that presents with both musculoskeletal and non-musculoskeletal manifestations [
1,
2]. Musculoskeletal manifestations of PsA include peripheral arthritis, spondylitis, dactylitis, and enthesitis, whereas non-musculoskeletal manifestations include substantial skin and nail disease that can range from mild to severe in intensity. PsA is also associated with inflammatory bowel disease and uveitis. In addition, patients with PsA show impairment in physical, work, and social activities.
The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), the European League Against Rheumatism (EULAR), and the American College of Rheumatology (ACR)/National Psoriasis Foundation share common treatment goals for patients with PsA: to improve health-related quality of life (HRQoL); achieve robust improvement of musculoskeletal manifestations; prevent structural damage; and control non-musculoskeletal manifestations, including skin disease [
2‐
4]. Kavanaugh et al. [
5] confirmed that improvement in both joint and skin manifestations is necessary to optimise improvement in HRQoL. For this reason, a combination of two validated outcome measures (≥ 50% improvement in ACR criteria [ACR50] and 100% improvement in Psoriasis Area Severity Index score [PASI100]) was defined as the primary endpoint in the phase IIIb/IV 52-week head-to-head SPIRIT-H2H trial (NCT03151551) of the interleukin (IL)-17A antagonist ixekizumab and the tumour necrosis factor (TNF) inhibitor adalimumab [
6]. Ixekizumab is a high-affinity monoclonal antibody that selectively targets IL-17A; it is approved in the USA and European Union for the treatment of moderate-to-severe plaque psoriasis (PsO) in adults and children aged ≥ 6 years and PsA and axial spondyloarthritis in adults [
7,
8].
SPIRIT-H2H enrolled patients with active PsA and PsO who were naïve to biologic disease-modifying antirheumatic drugs (bDMARDs) and had experienced an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). The primary and major secondary objectives of the study were achieved at week 24, with ixekizumab being superior to adalimumab for the percentage of patients who simultaneously achieved an ACR50 and PASI100 response, non-inferior for ACR50 response, and superior for PASI100 response [
6]. In addition, the efficacy of both treatments was maintained at 52 weeks, with a significantly higher proportion of patients treated with ixekizumab versus adalimumab simultaneously achieving ACR50 and PASI100 at this time (39 versus 26%,
p < 0.001) [
9]. Ixekizumab also showed greater efficacy than adalimumab for improvement in a number of additional musculoskeletal, non-musculoskeletal, and HRQoL outcomes at week 24 and/or week 52 [
6,
9].
The primary endpoint of SPIRIT-H2H (simultaneous achievement of an ACR50 and PASI100 response) has not been validated. Therefore, to determine whether additional benefits related to various PsA domains were observed in patients simultaneously achieving ACR50 and PASI100 at weeks 24 and 52, this analysis aimed to describe efficacy and HRQoL outcomes in patients achieving versus not achieving the primary endpoint at weeks 24 and 52 in the overall SPIRIT-H2H study population, irrespective of treatment allocation.
Materials and methods
SPIRIT-H2H design
The design of SPIRIT-H2H (NCT03151551) has already been presented [
6] and is therefore described only briefly here. SPIRIT-H2H was a 52-week, multicentre, randomised, open-label, assessor-blinded, parallel-group study evaluating the efficacy and safety of ixekizumab versus adalimumab in adult patients fulfilling Classification for Psoriatic Arthritis criteria for active PsA (tender joint count ≥ 3/68, swollen joint count ≥ 3/66) and with active PsO (body surface area [BSA] involvement of ≥ 3%) who had an inadequate response to ≥ 1 csDMARDs and were naïve to bDMARDs [
6]. Patients were randomised (1:1 and stratified by the presence of moderate-to-severe PsO and concomitant csDMARD use) to the approved dosage regimens of ixekizumab or adalimumab based on the presence/absence of moderate-to-severe PsO [
6]. Moderate-to-severe PsO was defined as PASI ≥ 12 with a static Physician Global Assessment ≥ 3 and BSA involvement of ≥ 10% at baseline. A stable dose of csDMARDs, including methotrexate, could be maintained throughout the study if the patient was receiving such treatment at screening.
After the week-24 database lock and initial analysis run, nine patients with active PsO and BSA ≥ 3% were found to have been assessed as PASI = 0 at baseline, a medical inconsistency that was resolved using medical judgement. These patients were considered PASI100 responders if PASI = 0 and BSA = 0 at postbaseline visits.
SPIRIT-H2H was conducted in accordance with the ethical principles of the Declaration of Helsinki; all patients provided written informed consent and the study protocol was approved by the ethical review board (17/LO/0794) prior to the start of study-related procedures.
Current analyses
The current post hoc analyses report efficacy and HRQoL endpoints in four independent analysis groups based on achievement of study endpoints, including a simultaneous ACR50 and PASI100 response (the primary endpoint), using the overall SPIRIT-H2H intention-to-treat (ITT) population, irrespective of treatment group. The four response groups were combined responder (CR24; patients who achieved simultaneous ACR50 and PASI100 response), joint responder (JR24; patients who achieved ACR50 but not PASI100 response), skin responder (SR24; patients who achieved PASI100 but not ACR50 response), and non-responder (NR24; patients who did not achieve ACR50 or PASI100 response after 24 weeks of treatment). Patients were also reallocated into the four groups based on responses after 52 weeks of treatment (CR52, JR52, SR52, and NR52, respectively). Patients who withdrew before week 24 or 52 were allocated to the groups who did not achieve an ACR50 or PASI100 response, based on non-responder imputation principles.
Analysis endpoints
Musculoskeletal endpoints were the proportions of patients at weeks 24 and 52 who achieved a simultaneous ACR50 and PASI100 response; an ACR50, ACR20, and ACR70 response; Disease Activity in Psoriatic Arthritis (DAPSA) ≤ 4 (remission); DAPSA ≤ 14 (low disease activity or remission); minimal disease activity (MDA; 5/7 criteria) and 7/7 MDA criteria (very low disease activity [VLDA]); resolution of enthesitis (Spondyloarthritis Research Consortium of Canada [SPARCC] Enthesitis Index = 0 or Leeds Enthesitis Index [LEI] = 0) among patients with enthesitis at baseline (SPARCC Enthesitis Index > 0 or LEI > 0); resolution of dactylitis (Leeds Dactylitis Index-Basic [LDI-B] = 0) among patients with dactylitis at baseline (LDI-B > 0); and no impairment of physical function (Health Assessment Questionnaire-Disability Index [HAQ-DI] ≤ 0.5). Additionally, change from baseline was evaluated for SPARCC and LEI among patients with enthesitis at baseline, LDI-B among patients with dactylitis at baseline, HAQ-DI, and 36-Item Short Form Survey (SF-36) physical component score (PCS) and SF-36 mental component score (MCS).
Non-musculoskeletal endpoints were the proportions of patients at weeks 24 and 52 who achieved a PASI75, PASI90, and PASI100 response; resolution of fingernail psoriasis (Nail Psoriasis Severity Index [NAPSI] fingernails = 0) among patients with fingernail involvement at baseline (NAPSI > 0); and a Dermatology Life Quality Index score of 0 or 1 (DLQI 0,1).
Analysis methods
Baseline characteristics of each response group were summarised and compared descriptively (mean and standard deviation for categorical outcomes, and absolute and relative frequencies for categorical outcomes) for the week-24 and week-52 groups.
Categorical endpoints were examined at week 24 according to response group at week 24. The proportions of patients achieving responses to categorical endpoints were analyzed using logistic regression with non-responder imputation in the ITT population and included treatment, concomitant csDMARD use at baseline, and moderate-to-severe PsO involvement as factors. Differences between CR24 (who simultaneously achieved an ACR50 and PASI100 response at week 24) and each of the other three response groups at week 24 (JR24, SR24, and NR24) were also evaluated using Fisher’s exact test. Similar analyses were performed at week 52 for CR52 (who simultaneously achieved an ACR50 and PASI100 response at week 52) compared with each of the other three response groups at week 52 (JR52, SR52, and NR52).
Adjusted change from baseline in endpoints of interest in each response group was evaluated using an analysis of covariance model that included treatment, moderate-to-severe PsO at baseline, and baseline value as factors. Missing data were imputed using a modified baseline observation carried forward approach. Differences in least squares mean change were evaluated using t-tests.
Analyses were performed using SAS Enterprise Guide 7.15. Sankey diagrams were created to visualise the trajectory of response at week 52.
Discussion
To optimise the benefits of treatment and improve the HRQoL of patients with PsA, all symptoms need to be considered [
5]. Indeed, GRAPPA and EULAR recommendations indicate that the goal of treatment for patients with PsA is achievement of the lowest possible level of disease activity in all affected domains of the disease [
2,
4]. Therefore, a number of unidimensional and multidimensional tools and treatment targets have been developed and validated to assess the musculoskeletal (articular and extra-articular) or non-musculoskeletal manifestations of PsA and the impact of disease on HRQoL. It would be useful if some of these measures, which encompass a variety of symptoms, could be combined to reflect treatment responses across a range of PsA manifestations.
The primary endpoint of the SPIRIT-H2H trial was a combination of both validated joint and skin measures [
6]. ACR50 is a relatively stringent endpoint for musculoskeletal disease, and PASI100 is a very stringent endpoint for skin disease. The current analysis found that the simultaneous achievement of an ACR50 and PASI100 response, regardless of active treatment, reflected high response rates for additional musculoskeletal and non-musculoskeletal endpoints evaluated in SPIRIT-H2H and commonly used to assess treatments for PsA. In particular, patients in CR24 or CR52, who achieved simultaneous ACR50 and PASI100 at week 24 or 52, respectively, also achieved consistently high response rates for ACR70, MDA, VLDA, and DAPSA remission, and resolution of enthesitis, dactylitis, nail psoriasis, and impairment of physical function (HAQ-DI ≤ 0.5), thereby providing value to both patients and treating clinicians. Compared with the other corresponding response groups, including JR24 and JR52 (ACR50 response only), patients in CR24 or CR52 consistently achieved the highest response rates for specific musculoskeletal endpoints, non-musculoskeletal endpoints, and composite endpoints, and in many instances, the differences were statistically significant. These results indicate optimal control of PsA domains in the majority of patients who simultaneously achieved an ACR50 and PASI100 response, particularly at week 52. With regard to ACR 50 response at week 24, more male than female patients appeared to achieve this response. However, further analyses are warranted to determine a possible gender difference on disease presentation or severity, or on response to treatment, as has been reported previously [
10‐
12].
Although HAQ-DI and SF-36 HRQoL endpoints improved to a greater extent in patients in JR24 or JR52 than in those in SR24 or SR52, respectively, the improvements were generally highest in CR24 and CR52, respectively, confirming the value of the combined endpoint. These SF-36 findings are possibly explained by improvements in joint function having a large impact on the PCS component of the SF-36, although improvement in the MCS was also greatest in patients with an ACR50 response, with or without a PASI100 response (CR24, JR24, CR52, and JR52). In contrast and as expected [
13], the highest response rates for DLQI 0,1 were reported in patients who achieved a PASI100 response, irrespective of an ACR50 response (CR24, SR24, CR52, and SR52). However, as for the musculoskeletal endpoints, a DLQI 0,1 response was most likely to be observed in patients in CR24 or CR52.
We found that more than half of patients in SR24 or SR52 and about one-third of patients in NR24 or NR52 also achieved an ACR20 response at weeks 24 and 52, respectively. However, response rates for other musculoskeletal and composite endpoints at these times in these response groups were generally low.
EULAR recommends that consideration should be given to each musculoskeletal and non-musculoskeletal manifestation when managing patients with PsA, and that treatment decisions be made accordingly [
2]. GRAPPA and the Outcome Measures in Rheumatology (OMERACT) association recommend that the core PsA domains to be assessed in patients with PsA are joint inflammation and damage, enthesitis, dactylitis, skin and nail disease, spondylitis, function, and HRQoL [
13]. The combined endpoint evaluated in SPIRIT-H2H considered two of these domains: joint and skin activity. However, the current analysis shows that patients in CR24 or CR52 also had high response rates for endpoints relating to enthesitis, dactylitis and nail psoriasis resolution, functioning, and HRQoL, all core domains identified by GRAPPA-OMERACT, as well as the composite endpoints MDA, VLDA, and DAPSA remission.
Patients in CR52, JR52, or SR52 achieved response rates for other endpoints at week 52 that were generally similar to or higher than those achieved at week 24, indicating that the combined endpoint does not lose its association with other PsA endpoints over time. Results also indicate that continued treatment, even when a response is not achieved after 24 weeks of treatment, can be beneficial for many patients.
The current analysis was limited in that it was post hoc. In addition, as only small proportions of patients had dactylitis at baseline, LDI-B response rates should be interpreted with caution. As radiographic progression was not assessed in the SPIRIT-H2H trial, it was not possible to determine potential correlations between simultaneous achievement of ACR50 and PASI100 and inhibition of structural damage.
In conclusion, this post hoc analysis of data from the SPIRIT-H2H study showed that the primary endpoint of simultaneous achievement of an ACR50 and PASI100 response at week 24, irrespective of active treatment arm, signalled additional benefits at week 24 across a wide range of efficacy endpoints, including HRQoL, that are important for patients with PsA. Similar findings were seen in week-52 analyses. Patients meeting this primary endpoint are more likely to achieve a disease state of remission, which is the stated aim of PsA treatment according to GRAPPA and EULAR recommendations.
Declarations
Conflict of interest
Frank Behrens has received research grants from Celgene, Chugai, Janssen, Pfizer, and Roche and consultation/speaker fees from AbbVie; Boehringer Ingelheim; Celgene; Chugai; Eli Lilly and Company; Genzyme; Gilead Sciences, Inc.; Janssen; Merck; Novartis; Pfizer; Roche; Sanofi; and UCB. Soyi Liu Leage and Celine El Baou are employees of Eli Lilly and Company. Christophe Sapin, Inmaculada De La Torre, and Gabriella Meszaros are shareholders and employees of Eli Lilly and Company. Georg Schett has served on speakers bureaus for AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Novartis, Roche, and UCB. Bernard Combe has received grant/research support from Novartis, Pfizer, and Roche-Chugai; served as a consultant for AbbVie; Eli Lilly and Company; Gilead Sciences, Inc.; Janssen; Pfizer; Roche-Chugai; and Sanofi; and served on speakers bureaus for Bristol Myers Squibb; Eli Lilly and Company; Gilead Sciences, Inc.; Merck Sharp & Dohme; Pfizer; and Roche-Chugai. Filip van den Bosch has received grant/research support from AbbVie, Merck, and UCB; served as a consultant for AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Sanofi, and UCB Pharma; and served on speakers bureaus for AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, Janssen, Merck, Novartis, Pfizer, Sanofi, and UCB Pharma. Laure Gossec has received grant/research support from Amgen, Eli Lilly and Company, Galapagos, Janssen, Pfizer, Sandoz, and Sanofi and consulting fees from AbbVie, Amgen, Bristol Myers Squibb, Biogen, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer, Samsung Bioepis, Sanofi-Aventis, and UCB.
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