SPondyloarthritis: EARly Definition (ASAS-SPEAR): Analysis of Symptom Duration Thresholds Using Pooled Data from Randomized Controlled Trials

Proposal
12126

Title of Proposed Research

Lead Researcher

Sofia Ramiro

Affiliation

Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands. Department of Rheumatology, Zuyderland Medical Center, Heerlen, the Netherlands

Funding Source

Potential Conflicts of Interest

Data Sharing Agreement Date

14 October 2022

Lay Summary

Background: Spondyloarthritis (SpA) is a heterogeneous disease with a vast spectrum of manifestations, ranging from a presentation predominantly with axial manifestations, axial spondyloarthritis (axSpA), to predominantly with peripheral manifestations, peripheral spondyloarthritis (pSpA). The Assessment of SpondyloArthritis international Society (ASAS) identified the need to establish astandardized definition for the term ‘early axSpA' in research setting. The ASAS-SPEAR (SPondyloarthritis EARlydefinition) project aims at proposing a consensus definition of ‘early axSpA' to be employed in research, in orderto avoid the use of arbitrary or heterogeneous definitions.Objective: To evaluate the relationship between symptom duration and clinical response in patients with axSpAtreated with biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic disease-modifyingantirheumatic drugs (tsDMARDs).Study design: A systematic literature review (SLR) with meta-analysis will be performed. The SLR have been conducted in the context of the ASAS-European Alliance of Associations for Rheumatology (EULAR) recommendations for the management of axSpA, which was used to identify eligible studies. This includes the SLR conducted for the ongoing, 2022 update of the recommendations. Inclusion criteria for the studies, following the PICO (Participants, Intervention, Comparator and Outcomes) framework.Participants: Participants will be adult patients (age >18 years) with axSpA categorized in early vs established disease based on symptom duration and with definitions using different cut-offs. Interventions will be treatment with bDMARDs, or tsDMARDs; comparator will be placebo.Main Outcome Measure(s): Outcomes will include disease activity, functional limitation, and overall functioning and health, and they will be analysed at the timing of the primary endpoint. The primary endpoint of this SLR/meta-analysis will be Assessment in SpondyloArthritis international Society 40% (ASAS40) response at 6 months in treated patients compared with placebo for patients with early vsestablished disease.Statistical Analysis: The analysis will have 2 steps: 1) analysis at the individual study level; 2) meta-analysis of all included studies. Making use of the aggregated data from each trial, pooled analyses will be performed. Conclusion: It is relevant to know whether patients who are treated earlier or later in the course of their disease (with a definition based on symptom duration) have different outcomes or response to treatment. Analyses to assess treatment outcomes according to the different thresholds of symptom duration in patients included in randomized controlled trials aim to inform the final decision on the ‘early axSpA' definition.

Study Data Provided

[{ "PostingID": 21042, "Title": "NOVARTIS-CAIN457H2315", "Description": "Study of Efficacy and Safety of Secukinumab in Patients With Non-radiographic Axial Spondyloarthritis (PREVENT)" },{ "PostingID": 21043, "Title": "NOVARTIS-CAIN457H3301", "Description": "SKIPPAIN - Speed of Onset of SecuKinumab-Induced Relief From Pain in Patients With AxIal SpoNdyloarthritis (SKIPPAIN)" }]

Statistical Analysis Plan

The analysis will have 2 steps: 1) analysis at the individual study level; 2) meta-analysis of all included studies.From the individual included RCTs, aggregated data will be computed based on the above-mentioned outcomes atthe timing of the primary endpoint as well as baseline characteristics of the included patients (age, gender,symptom duration) in each treatment arm. Missing data will be imputed using the non-responder imputation (NRI)method for categorical outcomes.Concerning outcomes, for categorical variables relative risk (RR) (ratio of the incidence in the early group and theincidence in the established group) will be calculated for the groups of active treatment and placebo (3).Additionally, relative risk ratios (RRR) will be calculated, representing the treatment effect [active vs placebo]between the two groups [early vs established]), together with the 95% confidence interval (95% CI) (4,5). Numberneeded to treat (NNT) (number of patients we need to treat in order to achieve one additional patient reaching theoutcome) will be assessed (6). For the continuous variables, differences in differences (DID), which represent thedifference between treatment effect in early and established disease, will be calculated (7).Making use of the aggregated data from each trial, pooled analyses will be performed (8). Pooled RR and RRR, aswell as DiD will be estimated using fixed (I2 <50%) or random (I2 ?50%) effects depending on the heterogeneity ofthe studies.Sensitivity analyses: we plan to assess the primary and secondary endpoints in defined subgroups, if the obtaineddata allows it:i) Stratified by SpA phenotype, i.e. separately for r-axSpA and nr-axSpAii) Stratified by the presence of any syndesmophyteiii) Stratified by drug class, i.e. separately for patients treated with TNF inhibitors, IL-17 and JAK inhibitorsiv) Stratified by bDMARD experience, i.e. separately for patients with inadequate response to non-steroidal anti-inflammatory drugs (NSAID-IR) and patients with inadequate response to bDMARDs (bDMARD-IR)R-Cran V.3.5.1 software and the package ‘meta' will be used for the statistical analysis.

Publication Citation

Benavent D, Navarro-Compán V, Capelusnik D, Ramiro S. Does symptom duration impact on treatment response in axial spondyloarthritis? A meta-analysis of randomized controlled trials. Rheumatology (Oxford). 2025 Nov 1;64(11):5872-5882.
DOI: https://doi.org/10.1093/rheumatology/keaf382