The ASAS-OMERACT core domain set for axial spondyloarthritis

1 Title: The ASAS-OMERACT Core Domain Set for Axial Spondyloarthritis Authors: Navarro-Compán V. Rheumatology Service, Hospital Universitario la Paz-IdiPaz, Madrid, Spain, ORCID: 0000-0002-4527-852X Boel A. Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands, Orchid ID: 0000-0003-2016-1744 Boonen A. Department of Internal Medicine, Division of Rheumatology, Maastricht University Medical Center, the Netherlands and Care and Public Health Research Institute (CAPHRI), Maastricht University, the Netherlands. ORCID: 0000-0003-0682-9533 Mease P. Division of Rheumatology, Swedish Medical Center/Providence St. Joseph Health and University of Washington, Seattle, WA, USA. ORCID: 0000-0002-6620-0457 Landewé R. Department of rheumatology & clinical immunology, Amsterdam University Medical Center | loc. amC, Amsterdam & Zuyderland MC |loc. Heerlen, The Netherlands. ORCID: 0000-0002-0577-6620 Kiltz U. Rheumazentrum Ruhrgebiet Herne, Ruhr-University Bochum, Germany. ORCID: 0000-0001-5668-4497 Dougados M. Université de Paris Department of Rheumatology - Hôpital Cochin. Assistance Publique - Hôpitaux de Paris INSERM (U1153): Clinical epidemiology and biostatistics, PRES Sorbonne Paris-Cité. Paris, France. Baraliakos X. Rheumazentrum Ruhrgebiet Herne, Ruhr-University Bochum, Germany, ORCID: 0000-0002-9475-9362 Bautista-Molano W. Rheumatology Department, University Hospital Fundación Santa Fe de Bogotá and School of Medicine Universidad El Bosque. Bogotá, Colombia ORCID: 0000- 0003-0684-9542 Carlier H, Global Clinical Development Immunology, S.A. Eli Lilly Benelux N.V., Brussels, Belgium Chiowchanwisawakit P, Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand. ORCID: 0000-0002-4253-9229 Dagfinrud H. Dept of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway. de Peyrecave N. UBC Pharma, Brussels, Belgium. El-Zorkany B. Rheumatology department, Cairo University. ORCID: 0000-0003-2704-9712 Fallon L. Inflammation and Immunology – Global Medical Affairs, Pfizer Inc, Kirkland, Quebec, Canada. Gaffney K. Rheumatology Department, Norfolk & Norwich University Hospitals NHS Foundation Trust, Norwich, UH. ORCID: 0000-0002-7863-9176 Garrido-Cumbrera M. Health & Territory Research (HTR), Universidad de Sevilla, Seville, Spain. Spanish Federation of Spondyloartrhtis Associations (CEADE), Madrid, Spain. ORCID: 0000-0001-9727-1189 Gensler LS. Division of Rheumatology, Department of Medicine, University of Calfornia, San Francisco, San Francisco, CA, USA. ORCID: 0000-0001-6314-5336 Haroon N, University of Toronto, Departement of Medicine, University Health Network, Schroder Artritis Institute, Toronto. ORCID: 0000-0003-3210-477 Jongkees M. Patient Research Partner, Amsterdam, The Netherlands. Kwan YH, Program in Health Systems and Services Research, Duke-NUS Medical School, Department of Pharmacy, National University of Singapore, Department of Rheumatology and Immunology, Singapore General Hospital, ORCID ID: 0000-0001-7802-9696 Machado PM; Centre for Rheumatology & Department of Neuromuscular Diseases, University College London, London, United Kingdom; National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, University College London 2 Hospitals NHS Foundation Trust, London, UK; Department of Rheumatology, Northwick Park Hospital, London North West University Healthcare NHS Trust, London, UK. ORCID: 0000- 0002-8411-7972 Maksymowych WP. Department of Medicine, University of Alberta, Edmonton, Canada. ORCID: 0000-0002-1291-1755 Poddubnyy D. Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité – Universitätsmedizin Berlin, Berlin, Germany, ORCID: 0000-0002-4537-6015 Protopopov M. Department of Gastroenterology, Infectiology and Rheumatology, Campus Benjamin Franklin, Charité – Universitätsmedizin Berlin, Germany. ORCID ID: 0000-0003- 4840-5069 Ramiro S. Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands; Department of Rheumatology, Zuyderland Medical Center, Heerlen, the Netherlands, ORCID ID: 0000-0002-8899-9087 Shea B. Ottawa Hospital Research Institute, School of Epidemiology and Public Health, University of Ottawa, Ontario. Canada Song IH, AbbVie, Immunology Clinical Development, 1 North Waukegan Road Building AP31-2, North Chicago, IL 60064, USA. van Weely S, Department of Orthopaedics, Rehabilitation and Physical Therapy, Leiden University Medical Center, Leiden, the Netherlands. ORCID: 0000-0001-8560-4687 van der Heijde D, Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands, ORCID: 0000-0002-5781-158X Corresponding author: Victoria Navarro-Compán, Rheumatology service, Hospital Universitario la Paz-IdiPaz, Madrid, Spain. Paseo de la Castellana, 261, Madrid, 28046, Spain. [email protected]. Conflicts of interest: V. Navarro-Compán has received research grants/honoraria from AbbVie, Janssen, Lilly, Novartis, Pfizer, and UCB. A. Boel has no competing interests to declare. A. Boonen receibe research grants from Abbvie ad Novartis and honoraria for boards or lectures form Abbvie, Galapagos and Lilly. R. Landewé: Honoraria from AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Eli-Lilly, Novartis, Pfizer, UCB Pharma. Director of Rheumatology Consultancy BV. U. Kiltz has received grant and research support and consultancy fees from AbbVie, Amgen, Biogen, Chugai, Eli Lilly, Fresenius, Gilead, GSK, Janssen, MSD, Novartis, Pfizer, Roche and UCB. M. Dougados: Consulting feesPfizer, AbbVie, Amgen, BMS, Boehringer Ingelheim, Celgene, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, UCB Pharma. W. Bautista-Molano has received research speaker´s fees from Janssen, Lilly, Novartis, Pfizer, and Biopas. X. Baraliakos: Consulting fees AbbVie, Amgen, BMS, Celgene, Galapagos, Gilead, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, UCB. P. Chiowchanwisawakit: research grants/honoraria from Novartis, Pfizer, Zuellig Pharma, Janssen. N. de Peyrecave: Employee of UCB Pharma. 3 B. Elzorkany received consultancy, research grants, and speaker's fees from: AbbVie, Amgen, BMS, Eva, Hekma, Janssen, Lilly, MSD, New Bridge, Novartis, Pfizer, Roche, Sanofi‐Aventis, and Servier. L. Fallon: Employee and shareholder of Pfizer Inc. K. Gaffney: Research Grants from AbbVie, Lilly, Novartis, Pfizer, UCB. Consulting Fees: AbbVie, Celltrion, Celgene, Gilead, Lilly, MSD, Novartis, Pfizer, UCB: Director Spondyloarthritis Academy (SPATE UK). LS. Gensler has received research grants/honoraria from AbbVie, Eli Lilly, Gilead, GSK, Janssen, Novartis, Pfizer, and UCB. N. Haroon: consultant for Amgen, Abbvie, Eli Lilly, Janssen, Merck, Novartis, Pfizer and UCB. PM. Machado has received consulting/speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript. WP. Maksymowych: Consulting fees Abbvie, BMS, Boehringer, Celgene, Lilly, Janssen, Novartis, Pfizer, UCB; Research and/or Educational Grants Abbvie, Novartis, Pfizer; Chief Medical Officer CARE Arthritis Limited S. Ramiro has received research grants from Galapagos, MSD, Novartis, Pfizer and consulting fees from AbbVie, Eli Lilly, MSD, Novartis, UCB and Sanofi. D. Poddubnyy: Research support from: AbbVie, Lilly, MSD, Novartis, and Pfizer Consulting fees from: AbbVie, Biocad, Gilead, GlaxoSmithKline, Eli Lilly, MSD, Novartis, Pfizer, Samsung Bioepis, and UCB. Speaker fees from: AbbVie, Bristol-Myers Squibb, Lilly, MSD, Novartis, Pfizer, and UCB. I-H. Song, employee of AbbVie, Immunology Clinical Development, USA. D. van der Heijde: Consulting fees AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Galapagos, Gilead, Glaxo-Smith- Kline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma. Director of Imaging Rheumatology bv. Keywords: core outcome set, outcome, domain, axial spondyloarthritis, ankylosing spondylitis. Funding: The Assessment of Spondyloarthritis international Society (ASAS) funded Anne Boel and Victoria Navarro-Compán to work on the project to update the core outcome set. Acknowledgements: We would like to thank Shawna Grosskleg for her contribution to the project. We would like to thank all patients from the Spondylitis Association of America, Canadian Spondylitis Association and National Axial Spondyloarthritis Society for their participation in the Delphi survey. We would also like to thank all ASAS members and the participants of the OMERACT workshop for their participation in the project. PMM is supported by the National Institute for Health Research (NIHR), University College London Hospitals (UCLH), Biomedical Research Centre (BRC). Disclaimer: The views expressed here are those of the authors and do not necessarily represent the views of the (UK) National Health Service (NHS), the National Institute for Health Research (NIHR), or the (UK) Department of Health. Author contribution: VN-C and DvdH wrote the first draft of the manuscript. All authors participated actively in the project. All authors critically reviewed the manuscript for important intellectual contribution and approved the final version. 4 ABSTRACT Background: The current core outcome set for ankylosing spondylitis (AS) has had only minor adaptations since its development 20 years ago. Considering the significant advances in this field during the preceding decades, an update of this core set is necessary. Objective: To update the ASAS-OMERACT core outcome set for AS into the ASASOMERACT core outcome set for axial spondyloarthritis (axSpA). Methods: Following OMERACT and COMET guidelines, an international working group representing key stakeholders (patients, rheumatologists, health professionals, pharmaceutical industry and drug regulatory agency representatives) defined the core domain set for axSpA. The development process consisted of: i) Identifying candidate domains using a systematic literature review and qualitative studies; ii) Selection of the most relevant domains for different stakeholders through a 3-round Delphi survey involving axSpA patients and axSpA experts; iii) Consensus and voting by ASAS; iv) Endorsement by OMERACT. Two settings are considered based on the type of therapy investigated in the trial: symptom modifying therapies and disease modifying therapies. Results: The updated core outcome set for axSpA includes 7 mandatory domains for all trials (disease activity, pain, morning stiffness, fatigue, physical function, overall functioning and health, and adverse events including death). There are 3 additional domains (extramusculoskeletal manifestations, peripheral manifestations and structural damage) that are mandatory for disease modifying therapies and important but optional for symptom modifying therapies. Finally, 3 other domains (spinal mobility, sleep, and work and employment) are defined as important but optional domains for all trials. Conclusion: The ASAS-OMERACT core domain set for AS has been updated into the ASASOMERACT core domain set for axSpA. The next step is the selection of instruments for each domain. 5 INTRODUCTION The management of axial spondyloarthritis (axSpA) has come a long way in the last two decades(1, 2). The development of new therapeutic options, especially pharmaceutical drugs, covering the entire spectrum of the disease has been a major advance (3, 4). This progress should go hand-in-hand with updating outcome measures, so that all studies consistently assess the most relevant domains and instruments for axSpA. Clinical trials seek to evaluate whether an intervention is effective and safe. This is determined by comparing the effects of a specific intervention on selected outcomes versus a control to identify the possible beneficial or harmful effects of the intervention. Therefore, the careful selection of appropriate outcomes is crucial when designing clinical trials and other clinical studies. To avoid selective reporting of outcomes and to facilitate comparison of results across trials, it is important to use standardised outcomes(5). Moreover, it is important to use outcomes that are relevant to all stakeholders. Such issues can be addressed with the development and application of an agreed standardised set of outcomes for all clinical trials, which is defined as the core outcome set for a specific health condition, population and setting(6). The core outcome set represents the minimum that should be measured and reported in all clinical trials. Nevertheless, this does not imply that the outcomes in a particular study should be restricted to those in the core outcome set(7). Rather, there is an expectation that the core outcomes will be collected and reported to allow the results of trials and other studies to be compared, contrasted and combined as appropriate. Therefore, the use of a core outcome set may reduce heterogeneity of outcomes between studies in axSpA, will lead to research that is more likely to have measured relevant outcomes, and is of potential value to use in clinical audit and meta-analyses. Also, it enhances the value of evidence synthesis by reducing the risk of outcome reporting bias and ensuring that all trials contribute relevant information(5, 6). Although the core outcome sets are essential, not many have been developed according to the highest standard and/or have been implemented adequately. The most notable work relating to outcome standardisation has been conducted by the Outcomes Measures in Rheumatology (OMERACT) collaboration, which is an independent initiative of international health professionals interested in outcome measures in rheumatology, having its first meeting and definition of a core outcome set in 1992(8). This successful initiative was followed by a more global group also addressing other fields outside of Rheumatology, set up as the Core Outcome Measures in Effectiveness Trials (COMET) Initiative in 2010. The aim of COMET is to promote the development of core sets and bring together researchers interested in the development and application of core outcome sets(9). The Assessment of SpondyloArthritis international Society (ASAS) is an international group of experts in the field of spondyloarthritis (SpA), with the ultimate goal to improve the overall health and outcome of patients with SpA(10, 11). Outcome assessment has always been the focus of ASAS, similar to OMERACT, and both organisations have collaborated closely. In fact, the development of the ASAS-OMERACT core set for outcome measures in ankylosing spondylitis (AS) was the first activity undertaken by ASAS after its launch in 1995. The first preliminary ASAS core set for AS was published in 1997(12). This was followed by a publication in 1999 on the selection of the instruments for each outcome in the core set(13). And finally, the core set was endorsed by OMERACT in 1999(14, 15). In 2007 minor changes in relation to a few selected instruments were implemented by a consensus process by ASAS(16). As shown by a recent systematic literature review, the ASAS-OMERACT core set for AS was well implemented after its original publication two decades ago(17). However, since then, there have been major advances in the field of SpA as well as in the methodology to develop core sets, which may have an impact on the agreed outcomes two decades ago. Main 6 accomplishments in the field of axSpA outcomes include the use of magnetic resonance imaging (MRI), the development of the Ankylosing Spondylitis Disease Activity Score (ASDAS)(18), validated enthesitis scores(19), and the ASAS Health Index(20, 21). With regards to the methodology to develop core sets, there is no gold standard yet but during the last years OMERACT and COMET have intensively worked to provide specific guidance about how this should be done, e.g. OMERACT handbook and Filter 2.0, COMET handbook and Core Outcome Set-STAndards for Development (COS-STAD) (5, 7, 22, 23). Moreover, there have been developments with respect to the definition of the disease. The presence of definite sacroiliitis on radiographs is mandatory to define AS. With the availability of MRI became evident that there are also forms without radiographic sacroiliitis. This socalled non-radiographic axSpA (nr-axSpA) together with AS, also known as radiographic axSpA (r-axSpA) defines the entire spectrum of the disease, called axSpA(1, 24). The new classification thus also requires an update of the ASAS-OMERACT core outcome set for axSpA. The ASAS group decided to update the original version into the ASAS-OMERACT core outcome set for axSpA and started working on this process in 2018 according to the currently accepted methodology. The first step of this project is the selection of what to measure (core domain set). Thereafter, it needs to be defined how to measure each of the chosen domains – selecting instruments or tools (core measurement set). Both, what to measure and how to measure will form the final core outcome set. Here we present the results of the first step. METHODS For this project, OMERACT and COMET guidelines were followed (5, 22, 25-27), but taking into account that the goal this process was an update of an existing core set and not a completely new one. The main phases of the development process for a core set are summarised in Figure 1. Define the scope First of all, the steering committee of the project defined the scope of the core set, which was established as follows: Health condition: axSpA, with or without peripheral rheumatological manifestations (arthritis, enthesitis and dactylitis) and with or without extra-musculoskeletal manifestations (uveitis, inflammatory bowel disease and psoriasis). Pure peripheral SpA was excluded. Population: Patients 18 years or older with axSpA, covering the whole spectrum of the disease including nr-axSpA and r-axSpA, early disease and established disease. The lower limit of the age range (18 years) was based on ethical considerations arguments, as this is the common limit required to include patients in interventional studies. Types of intervention: Pharmacological and non-pharmacological interventions, excluding surgery. According to the type of intervention, two main scenarios are considered: i) Symptom modifying antirheumatic therapies (SMART). This type of therapy improves the symptoms and clinical features of inflammatory manifestations and include non-pharmacological treatment (e.g. physical exercise) and symptom modifying antirheumatic drugs (SMARD) such as non-steroidal anti-inflammatory drugs (NSAIDs). ii) Disease modifying antirheumatic drugs (DMARDs). This type of intervention changes the course of the disease by a) improving and sustaining functioning and overall health and b) preventing or significantly decreasing structural damage (e.g. cytokine inhibitors). Settings: Two main settings are described: i) Research: clinical trials and longitudinal observational studies (including registries); and ii) Clinical practice. Nevertheless, due to the 7 known differences in the development process between the different settings, ASAS decided to work first on a core set for the research setting and later develop a core set for the clinical practice setting. Register in the COMET database The COMET Initiative database is a repository of studies relevant to the development of core outcome sets. At the beginning of the project, the steering committee checked in this database that no other group was working on the update of this core set. Once this was confirmed, the project was registered in the COMET database on 19th of March 2018. Further details are available at COMET website.(28) A detailed protocol of the project was written by two of the co-chairs (VN-C and DvdH) and reviewed by all members of the steering committee. OMERACT and COMET guidelines were considered for this purpose. Working group First, a steering committee was formed. This consisted of the four co-chairs of the project (DvdH, VN-C, AB and PM), two additional ASAS members with expertise in OMERACT and COMET methodology (RL, MD), one patient representative (UK) and one fellow (AB). The steering committee invited the members of the axSpA working group based on their background, geographical region, knowledge, experience with trials and the stakeholder group to which they belong. Potential conflicts of interest of the invited members were listed and discussed by the steering committee. The working group was formed at the beginning of 2018 involving a total of 28 participants (including the steering committee), representing those stakeholders who will use the core set in research, including rheumatologists and methodologists (17), healthcare professionals (2), patient research partners (3), representatives from pharmaceutical companies (4) and drug regulatory agencies (1), and a research-fellow (1).(29) OMERACT workshop application In December 2018 the steering committee submitted an application for having an axSpA workshop to vote on the core domains at the OMERACT 2020 meeting, initially scheduled for April in Colorado. This application was accepted in February 2019. Nevertheless, due the COVID-19 pandemic the face-to-face meeting was postponed and eventually replaced by a virtual workshop in November 2020. Identify all candidate and relevant domains for stakeholders Figure 2 shows a summary of the different phases of the process to identify the possible domain candidates and to select the final set of core domains by means of reducing the extensive list to a concise set. This part has been published in detail in a separate manuscript(30) (Boel et al, submitted). Briefly, a list of the candidate domains was identified using three different sources and later two groups of stakeholders (patients and experts) selected the domains that should be considered for inclusion in the core set via two identical but separate Delphi surveys, which were launched between November 2nd and December 30th 2018. Working group consensus The working group met twice during the update process. The first meeting took place in January 2019 in Amsterdam and the second virtually in November 2019. The views from all key stakeholder groups were considered. The purpose of these meetings was to provide all stakeholders the opportunity to discuss the results of the Delphi survey and to agree on a proposal for a final core set according to the new format of the OMERACT onion(25). As shown in figure 3, this follows a structure in which the domains are placed in concentric spheres by decreasing importance classifying the outcomes in three categories: i) mandatory, ii) optional but important and iii) for research agenda. ASAS consensus 8 After discussion with the working group, the results of the Delphi survey were presented and discussed with all ASAS members in a plenary session during the ASAS annual workshop 2019 in Amsterdam. By consensus, the following decisions were made: - If a domain was included in the original core set, there should be a strong reason for excluding the domain in the updated core set. - If a domain had been selected for the SMART scenario, this should be selected for the DMARD scenario too. This thinking is in line with registration of drugs: drugs can show disease modification in addition to relieving of signs and symptoms. No registered treatment for axSpA has been shown to only impact structural damage progression, and even in such a trial, signs and symptoms should be assessed to know if an effect on these is lacking. Finally, the agreed domains by the working group in the virtual meeting were presented to all the ASAS members in a plenary session during the annual ASAS workshop, in January 2020 in Houston. After discussion, each full ASAS member voted anonymously using a digital voting system (engagenow.live) on agreement with the final proposed set of domains by answering the following question “Do you agree with the proposed onion of domain core set”? The predefined requirement to accept the proposed outcomes was that at least 50% of the members voted positively. OMERACT endorsement Finally, the ASAS proposal of the core domain set was presented at a specific OMERACT 2020 virtual meeting, which took place on November 13th. In total, 125 participants recruited by ASAS and OMERACT attended the meeting in two different time zone sessions to ensure that participants around the world could partake. Pre-reading material was sent to all participants, which included a whiteboard video (accessible at https://omeract.org/workinggroups/axial-spa), one-pager with the definitions for each of the selected domains (shown in table 1) and a lay summary. Each meeting lasted for 90 minutes and included a plenary session, 5-7 breakout sessions (with a facilitator, a content expert, a reporter, at least one patient research partner and 5 representatives from other stakeholders) and a final voting session. All participants were asked to vote anonymously on two questions using the Zoom polling feature for meetings: i) can you accept the proposed set as mandatory domains for all trials? and ii) can you accept the proposed additional domains as mandatory for disease modifying drug trials? The results were summarised in two groups: patient research partners and other stakeholders. The predefined requirement to endorse the core set was that at least 70% of the participants in each group accepted the proposal. RESULTS Relevant Domains for stakeholders As mentioned, the results for the selected domains to be considered for inclusion in the final core outcome set have been published in detail separately (Boel A et al, submitted). After the three Delphi-rounds, a total of 7 domains (pain, physical function, stiffness, disease activity, mobility, overall functioning and health, and peripheral manifestations) were selected to be considered for inclusion in the SMART setting. For the DMARD setting, 6 domains (physical function, disease activity, mobility, structural damage, extra-musculoskeletal manifestations, peripheral manifestations) were selected. All domains selected by experts were also selected by patients. Patients selected all offered domains except ‘emotional function’, including fatigue, work and employment and sleep for both settings in addition to the selected domains. Working group proposal After the virtual meeting in November 2019, the working group agreed on a proposal for the core domains, distributed across the OMERACT onion (Figure 3), which took into account the 9 two decisions previously taken (i.e., only delete a previous domain for strong reasons and all mandatory domains for the SMART setting should also be mandatory for the DMARD setting). This proposal included 7 mandatory domains for all trials independently of the therapy investigated. These mandatory domains were: disease activity, pain, morning stiffness, fatigue, physical function, overall functioning and health, and adverse events including death. In addition, 3 extra domains (extra-musculoskeletal manifestations, peripheral manifestations, and structural damage) were included as mandatory for DMARDs, leaving them as optional but important for SMART. As a clarification, structural damage was included as a mandatory domain for at least one trial during the development program of a specific DMARD but not in every trial on that DMARD. Finally, 3 other domains (spinal mobility, sleep, and work and employment) were included as important but optional for all trials. No domain was included in the research agenda layer. ASAS voting In total, 92% of ASAS members participating in the annual workshop voted to accept this proposal. Furthermore, three other aspects related to the domains included in the final onion were voted on. Most members agreed that the most appropriate term when referring to inflammatory bowel disease, uveitis and psoriasis in patients with axSpA is ‘extramusculoskeletal manifestations (EMMs)’. In addition, the assessment of this domain should include the three mentioned manifestations. The domain “peripheral manifestations” should include arthritis, enthesitis and dactylitis. The working group proposal for the onion was slightly adjusted to include these points. OMERACT endorsement The ASAS proposal for the core domains is depicted in Figure 3 and the definition for each of the domains is provided in Table 1. The proposal was broadly accepted. Combining the results of the two sessions, 100% patient research partners and 99% representatives of other stakeholders voted to accept the 7 mandatory domains set for all trials. Furthermore, 95% patient research partners and 99% representatives of other stakeholders accepted to include the three additional mandatory domains for DMARDs. Finally, some minor edits proposed by OMERACT participants were implemented in the final version of the onion. DISCUSSION The definition of the core domain set responds to one of the relevant unmet needs in the field of axSpA(31). The original core set was developed more than 20 years ago and was well implemented(12, 17). However, after more than two decades this core set became outdated and required revision to address all the advances achieved recently in the field of axSpA and to address the current recommended methodology for development of a core outcome set(32). This manuscript presents the result of a crucial collaborative initiative between ASAS and OMERACT to update the ASAS-OMERACT core outcome set for AS into the ASASOMERACT core outcome set for axSpA. Compared to the original core set, the updated core set for axSpA represents a substantial advance both in content and in the methodology employed. The most recent guidelines for development of a core set were followed as closely as possible. In this sense, the OMERACT and COMET handbooks have been the basis for updating the core set to the highest possible quality(5, 22). The procedure associated with these guidelines is extensive and meticulous. An important aspect of this procedure is the working group and stakeholders participating in the selection of the domains. The updated core set involved all key stakeholders. Furthermore, the number and heterogeneity of participants also increased. While the original core set involved approximately 40 participants the update of the core set involved 376 participants in total, with 16 17. Bautista-Molano W, Navarro-Compán V, Landewé RB, Boers M, Kirkham JJ, van der Heijde D. How well are the ASAS/OMERACT Core Outcome Sets for Ankylosing Spondylitis implemented in randomized clinical trials? A systematic literature review. Clin Rheumatol. 2014;33(9):1313-22. 18. 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