Study Design

PsABIOnd (ClinicalTrials.gov identifier: NCT05049798) is a prospective, observational cohort study across 20 countries (Argentina, Australia, Austria, Belgium, Brazil, Canada, Colombia, France, Germany, Greece, Italy, Japan, Mexico, the Netherlands, South Korea, Spain, Sweden, Switzerland, Taiwan and the United Kingdom) that will collect data on adult patients with a confirmed diagnosis of PsA who are starting guselkumab or an IL-17 inhibitor as a first, second, third or fourth line of PsA biologic therapy per standard clinical practice and licence. Study treatments (index drugs) include guselkumab and IL-17 inhibitor therapies. Non-index drugs are all other bDMARDs, including TNF inhibitors, other IL-23 inhibitors and JAK inhibitors. Index drugs and non-index drugs count as separate lines of biological treatment both before and during the study.

All aspects of treatment and clinical management of participants in this observational study will follow routine clinical practice or any local and overarching guidelines, and all treatment decisions will be at the sole discretion of the treating rheumatologist prior to, and independently of, participation in the study. The study plans to enrol up to approximately 1300 participants, including approximately 650 patients who start receiving guselkumab and approximately 650 patients who start receiving an IL-17 inhibitor at study entry. To minimise the chance of unequal distribution between cohorts, enrolment will be reviewed at least every 6 months, and participating rheumatology centres will pause enrolment in the overrepresented cohort while continuing enrolment in the other cohort until distribution is balanced between cohorts.

Study Objectives

The primary objective of this study is to evaluate the treatment persistence with guselkumab and IL-17 inhibitors initiated at enrolment into PsABIOnd (Table 1).

Table 1 Study objectives and measurements

The secondary objectives are to evaluate effectiveness in terms of validated musculoskeletal and composite outcomes of index treatments, to examine potential predictors of response, to describe treatment persistence and treatment patterns for different lines of biological treatment, to collect safety data, to investigate presence and clinical features of concomitant conditions (e.g. psoriasis, uveitis) and comorbidities (e.g. cardiovascular disease), to evaluate the disease and treatment effectiveness from the patient perspective [quality of life (QoL), disease impact, work productivity, etc.], to identify and assess predictors of treatment persistence, and to explore reasons for stopping/switching treatments for PsA (Table 1).

Participant Selection (Main Study)

Adult patients (aged 18 years or older) will be eligible to participate in the study if they have a confirmed diagnosis of PsA determined by a rheumatologist with reference to ClASsification criteria for Psoriatic ARthritis (CASPAR) [18], and start guselkumab or any approved IL-17 inhibitor as a first, second, third or fourth line of bDMARD therapy for PsA as part of their routine clinical care. All participants will be required to provide written informed consent, confirming study participation and allowing for data collection and source verification, before any study-related procedures. Patients will not be eligible to take part in the study if they start guselkumab or an IL-17 inhibitor as fifth or further line of bDMARD, have already received guselkumab or the specific IL-17 inhibitor index treatment, have previously received an investigational drug or used an investigational device within 30 days of study start, are currently enrolled in an interventional study or Janssen-sponsored observational study, or are unwilling or unable to participate in long-term data collection. For the purpose of this study, a switch from a branded originator bDMARD to related biosimilar(s) or vice versa will not be considered a separate treatment line, i.e. will be counted as one prior line of bDMARD therapy.

All participants who provide their written consent for data collection and receive at least one dose of an index drug during the study will be included in the analyses.

Study Visit Schedule

After a treatment decision has been taken by the treating rheumatologist, eligible patients will be enrolled in the study, and baseline data will be recorded.

Participants will be followed for a maximum of 36 months (+3 months) from the first administration of the initial index treatment. The treatment period will begin on the day the participant receives the first administration of index treatment, and all subsequent visits will be calculated according to this date, except when a switch in bDMARD or switch to a JAK inhibitor treatment takes place. Treatment interruptions of less than 3 months (93 days) will be considered a ‘drug holiday’ and will not be considered as stopping treatment. Study visits (data collection time points) will occur in line with the standard of care and are expected to happen every 6 (±3) months, plus an additional visit at 3 months after the participant’s first dose of their initial index treatment with guselkumab or an IL-17 inhibitor (Fig. 1A).

Fig. 1

Study schedule for A participants in the main study and B participants in the eDaily by PsABIOnd substudy. aAfter baseline assessment, main study visit time points include: month 3 (±3 months), month 6 (± 3 months), then every 6 months (±3 months) and at the ‘end of treatment’ (+1 month) or ‘start of treatment’ visit (if 2 months have passed since the ‘end of treatment’ visit). bSee Table 2 (main study) and Table 3 (substudy) for a detailed list of assessments and measures. cThe baseline period will require a minimum of 9 days of actigraphy data collection (ideally 14 days). dAlso collected in PsABIOnd main study. ePRO electronic patient-reported outcome, FiRST Fibromyalgia Rapid Screening Tool, HAQ-DI Health Assessment Questionnaire-Disability Index, PsA psoriatic arthritis, PsAID-12 Psoriatic Arthritis Impact of Disease-12, VAS Visual Analogue Scale

Data Collection

Data sources will include validated ePROs and physician-completed assessments (Fig. 1A and Table 2). All physician-completed assessments will be performed using validated assessment tools as per standard of care of patients with PsA by rheumatologists [EULAR and GRAPPA–Outcome Measures in Rheumatology (OMERACT) recommendations]. Site initiation and monitoring activities will aim to ensure standardisation of assessments across participating study sites and countries.

Table 2 Data collection schedule (main study)

The data collected will be used to calculate composite endpoints, including the clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) [19], minimal disease activity (MDA) [20] and very low disease activity (VLDA). If C-reactive protein (CRP) is available, DAPSA and Ankylosing Spondylitis Disease Activity Score–CRP (ASDAS–CRP) will also be calculated. The assessments by the rheumatologist (or trained assessor) will include dactylitis digit count, Leeds Enthesitis Index score, psoriasis body surface area (BSA) and nail involvement (i.e. number of affected nails on hands and feet) (Table 2).

To document treatment persistence, the start and stop date (first and last administration dates) of guselkumab and index IL-17 inhibitor treatments will be recorded for each participant. The stop date will be defined as the date that the last dose of treatment was administered plus one dosing interval (the time between the last treatment and the next scheduled treatment), except when a switch in bDMARD treatment occurs. If a patient switches treatment, treatment persistence will be considered as the time until the next bDMARD treatment is started, if not longer than one treatment dispensing interval between the end of the previous treatment and the start of the new treatment, or until withdrawal or death, whichever occurs first. Treatment adherence for all biological treatments for PsA will be documented through recording treatment continuity at each visit and information on missed doses since last visit.

ePROs will include the Fibromyalgia Rapid Screening Tool (FiRST), EuroQoL 5 Dimension 5-Level (EQ-5D-5L), Health Assessment Questionnaire-Disability Index (HAQ-DI), Psoriatic Arthritis Impact of Disease-12 (PsAID-12), Patient Global Disease Activity Psoriatic Arthritis Visual Analogue Scale (PtGA PsA VAS), Pain Visual Analogue Scale (VAS), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Work Productivity and Activity Impairment Questionnaire:PsA (WPAI:PsA), 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9), Dermatology Life Quality Index (DLQI) and Patient Acceptable Symptom State (PASS) (Table 2).

Safety data will be collected through reporting adverse events (AEs) and events of special interest at each follow-up visit, from the first use of guselkumab or an IL-17 inhibitor within the study until the participant completes or leaves the study.

Data Analysis

All participants who provide their written consent for data collection and receive guselkumab or an IL-17 inhibitor in this study will be included in the statistical analyses.

Baseline participant and disease characteristics will be summarised using descriptive statistics. Clinical response and effectiveness parameters and observed values as well as changes from baseline will be summarised descriptively at each time point. For continuous/ordinal variables, the number of observations, mean, standard deviation, median, minimum and maximum will be described. For categorical variables, the number, percent, and 95% confidence interval (CI) per category will be summarised. For baseline characteristics and effectiveness endpoints, the summary of continuous/ordinal variables will include the 95% CI of the mean, the summary of categorical variables will include the 95% CI of the proportion.

Because the choice of treatment is at the discretion of the participant’s rheumatologist, and not the result of randomisation, any comparison between treatment cohorts will be exploratory in nature. For these comparisons, propensity score (PS) analysis will be used to adjust for relevant observed baseline covariate imbalances. PS stratification (quintiles) and in addition inverse probability of treatment weighting will be used as sensitivity analysis. PS-adjusted comparisons between treatment cohorts will include persistence of initial treatment, achievement of MDA, VLDA, cDAPSA low disease activity (including remission), cDAPSA remission, BSA improvement, and change from baseline in PsAID-12 total and subdomain scores. Persistence time will be compared using PS-adjusted Cox regression analysis. Binomial effectiveness endpoints will be compared using PS-adjusted logistic regression analysis. Continuous effectiveness endpoints will be compared using PS-adjusted multiple linear regression analysis. Results will be presented as adjusted and unadjusted odds ratios, hazard ratios, or regression coefficients, including 95% CI.

Safety analyses will be descriptive and will include the exposure adjusted incidence and type of AEs, serious AEs, possibly related AEs and related AEs leading to study or treatment discontinuation.

The sample size is not based on an assumed effect size of effectiveness endpoints, rather on providing clinically acceptable 95% CI. The study plans to enrol up to approximately 650 participants receiving guselkumab and approximately 650 participants receiving an IL-17 inhibitor. Therefore, using a conservative response of 50%, a sample size of 650 would give a 95% CI of (46.1%; 53.9%), which would still be considered of clinical interest (sufficiently narrow).

The effectiveness analyses will be performed on the Effectiveness Set, which consists of all enrolled patients without major protocol deviation, with at least one administration of guselkumab or an IL-17 inhibitor during the study who have a visit with any data assessment at baseline and any post-baseline visits. In general, the imputation rules will apply mainly for missing dates.

eDaily by PsABIOnd—an eHealth Substudy

The objective of the eDaily substudy is to explore the associations between actigraphy and ePRO data from the substudy and ePROs from the main study, and between the ePROs and electronic diary (eDiary) for pain, fatigue, mood, skin, morning stiffness and severity used in the substudy and the actigraphy collected measures.

Approximately 150 participants from selected study sites in a number of European countries will be offered entry into the eDaily substudy, which will document the impact of guselkumab or IL-17 inhibitor treatment on patient wellbeing and symptoms using smartphone-based ePRO collection, and continuous activity and sleep measurement using a wearable actigraphy device (Fig. 1B). The enrolment of participants into the substudy will be periodically reviewed to aim for numerically balanced treatment cohorts. The substudy will collect baseline data for 9–14 days before the first administration of the index treatment, followed by a 24-week (+4 weeks) observation period on treatment.

Participants will be included in the substudy if they satisfy all inclusion criteria for the main study, and in addition, if they have agreed to install the smartphone app on their personal smartphone and to complete the substudy assessment and are willing to wear the provided actigraphy device for the duration of their participation in the substudy.

Data for this substudy will be collected using a smartphone-based patient app (eDaily) and a wearable actigraphy device. The medical-grade ActiGraph CentrePoint Insight Watch (CPIW) developed by the ActiGraph corporation will be used according to manufacturer’s instructions [21]. The CPIW will continuously capture and record high-resolution tri-axial acceleration data at 32 Hz; data will be transferred from the device to the provider’s secure cloud storage in real time over the entire substudy period. Participants will have access to their own data (sleep and physical activity) from the device with a 24–48-h delay for the duration of the study. The eDaily app will capture self-reported joint pain and general pain, mood, fatigue, skin, morning stiffness and presence of PsA flares on a daily basis (eDiary). In addition, participants will be asked to complete ePRO questionnaires in the app on a weekly and monthly basis. A detailed overview of the frequency and timing of data collection in the eDaily substudy is presented in Table 3.

Table 3 Data collection schedule (eDaily substudy)

Data collected in eDaily will be analysed using descriptive statistics. For all continuous variables, descriptive statistics will include the number of participants, mean, standard deviation, median, minimum, maximum and 95% CI where applicable. All categorical variables will be summarised using frequencies, percentages and 95% CI, where applicable. Correlations, scatter plots and regressions will be used to investigate the relationship between (1) the ePRO data collected in the main study, (2) the ePRO data collected by means of the smartphone-based app and (3) various actigraphy measures (daily activity, sleep duration, etc.). Standard actigraphy endpoints are included in Table 4.

Table 4 Actigraphy endpoints (eDaily substudy)Patient Involvement

PsABIOnd was developed in collaboration with a group of representatives of an international patient advocacy group (PAG). During two workshops (advisory boards) held in 2020 and 2021, lead study investigators sought input from PAG representatives on the study design, data collection methods and frequency, acceptability, and patient experience with questionnaires, wearables and mobile devices. PAG representatives reviewed the questionnaires, the time consumption and the wearable actigraphy device. In addition, eDaily by PsABIOnd was developed in collaboration with a group of patients receiving treatment for psoriatic arthritis prescribed by a rheumatologist or dermatologist during advisory boards held in 2021. During the semi-structured interviews, the participants were presented with the solution prototype, lead study investigators sought input from representatives on the app design, data collection methods and frequency, acceptability, and patient experience with questionnaires, wearables and mobile devices. Patients reviewed the questionnaires, the time consumption and the wearable actigraphy device.

Compliance with Ethics Guidelines

This study will be performed in accordance with the Declaration of Helsinki of 1964 and its later amendments. Prior to any data collection or study procedures, the study sponsor, participating rheumatology investigators and study sites will obtain the necessary approvals from their national/local Independent Ethics Committee/Institutional Review Board (IEC/IRB). A list of IECs for those countries in the main study that received ethical approval by 1 September 2022 is included in the Supplementary Material (Supplementary Table 1); a list of IECs for those countries participating in the eDaily substudy is included in the Supplementary Material (Supplementary Table 2). Signed informed consent will be obtained from all patients before enrolment. Participants will be told of the observational nature of the study and that the sponsor only intends to collect information and follow the course of biological treatments of PsA as prescribed in the clinical practice setting. Only patients who are fully able to understand the nature of the study and provide their consent voluntarily will be enrolled. Patients will be informed that their participation in the observational study does not involve any invasive or therapeutic procedures outside of clinical practice, which will continue in accordance with local and overarching guidelines.

Study results will be disseminated at international and regional scientific conferences and via scientific publications in peer review journals. Any scientific presentations or publications will be developed in accordance with Good Publication Practice and International Committee of Medical Journal Editors guidelines. Results will also be posted via the ClinicalTrials.gov website (https://clinicaltrials.gov/ct2/show/NCT05049798).

Current protocol version: Protocol Amendment 2 (CNTO1959PSA4001), 29 April 2022; eDaily by PsABIOnd substudy Protocol Amendment 1 (CNTO1959PSA4001), 8 June 2022.

Strengths and Limitations

One of the key strengths of the PsABIOnd study is its global nature, with the participation of 20 countries across 5 continents. This is unusual for an observational study, which tend to be based on regional data. As a non-interventional study, its limitations include the lack of randomisation, potential effect of bias and missing data. Observational studies have the potential to play a larger role in validating drugs as long as potential biases and confounders are properly addressed. Because the treatments will not be assigned centrally, different treatment cohorts may have imbalances in patient and disease characteristics. Local variability in treatment patterns and local regulatory rules for using index therapies in different global regions may also limit the interpretation of some results. Nevertheless, PsABIOnd will provide important knowledge on the therapeutic effect of guselkumab and IL-17 inhibitors in routine clinical practice. Patients will not be pre-selected and will receive the index therapies regardless of the study, resulting in a more accurate reflection of the real-world patient population than that which can be achieved with RCTs. PsABIOnd will include a large cohort of participants (up to 1300) and will collect data over 36 months, providing valuable information on the long-term safety of these treatments in routine clinical practice. Potentially, specific patterns or subgroups of patients with a preferential response to a given intervention could be detected.

Due to the recent increase in the number of available treatments for patients with PsA, it is becoming more difficult for rheumatologists to make informed treatment decisions for individual patients in their clinical practice. There is a lack of consensus across international guidelines, which can partially be explained by the lack of large prospective head-to-head studies comparing different biological therapies. PsABIOnd will indirectly compare guselkumab with IL-17 inhibitors, treatments that target a regulator and an effector on the IL-23/IL-17 pathway in PsA, during routine clinical practice. Data derived from PsABIOnd will contribute to the knowledge of possible non-overlapping roles these cytokines may have across different disease domains. Similar patient cohorts have previously been enrolled in PsABio [22], a recent real-world study of ustekinumab and TNF inhibitors, applying the same main outcome assessments, meaning that there will be the opportunity to indirectly compare patient outcomes in PsABIOnd with the historical cohorts of PsABio in the future. Given the large amount of information that will be collected both at baseline and during follow-up visits, there is the potential to rank predictors of response to these therapies using new technologies such as machine learning.

Finally, emerging digital health technologies have the potential to collect data outside healthcare settings, capture changes in symptoms on a frequent basis, and thus help generate detailed information on chronic relapsing–remitting diseases such as PsA. eDaily by PsABIOnd—an eHealth substudy, will collect data continuously and/or with high frequency and will generate a between-visits clinical picture of disease and treatment impact on patients with PsA. Examples of additional important clinical information could include the speed of onset of treatment effect, short-term fluctuation in symptoms versus long-term flare-ups. The study is designed as an observational study, so any observations made in eDaily will not be taken into account to modify the routine care of patients taking part in PsABIOnd. However, these results are expected to make an important contribution to the understanding of PsA and may influence patient care in the future.