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Systemic sclerosis
Results from the international collaborative systematic literature review informing the 2023 EULAR recommendations for the treatment of systemic sclerosis
  1. Alain Lescoat1,2,
  2. Eugenia Bertoldo3,
  3. Jelena Čolić4,
  4. Tania Santiago5,
  5. Yossra A Suliman6,
  6. Jenny Emmel7,
  7. Philip G Conaghan8,
  8. Yannick Allanore9,
  9. Francesco del Galdo10,11
  1. 1IRSET, Rennes, Bretagne, France
  2. 2Internal Medicine and Clinical Immunology, Rennes University Hospital, Rennes, France
  3. 3Department of Medicine, Rheumatology Unit, Universita degli Studi di Verona, Verona, Italy
  4. 4Rheumatology, University of Belgrade Faculty of Medicine, Beograd, Serbia
  5. 5Rheumatology, University of Coimbra, Coimbra, Portugal
  6. 6Department of Rheumatology and Rehabilitation, Faculty of Medicine, Assiut University Faculty of Medicine, Assiut, Egypt
  7. 7Medical Education, Leeds Teaching Hospitals NHS Trust, Leeds, UK
  8. 8Rheumatology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
  9. 9Department of Rheumatology A, Université Paris Descartes, Faculté de Médecine, Paris, France
  10. 10School of Medicine, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
  11. 11LTHT, NIHR Leeds Biomedical Research Centre, Leeds, UK
  1. Correspondence to Professor Francesco del Galdo; f.delgaldo{at}leeds.ac.uk

Abstract

Background The EULAR recommendations for the treatment of systemic sclerosis (SSc) were updated in 2017, informed by a systematic literature review (SLR) completed in 2014.

Objectives The aim of this new SLR was to provide the most up-to-date literature to underpin contemporary EULAR recommendations for the management of SSc.

Methods 30 searches for 30 interventions (including several outcomes/clinical questions), and 1 dedicated search (with several interventions) for calcinosis were prioritised by the task force. Three types of questions were defined: type I questions, unchanged as compared with the previous recommendations; type II questions exploring interventions already mentioned in the previous recommendations but with new outcomes; type III questions for new interventions.

Results 14 490 abstracts were retrieved from the databases on 31 March 2022 and 2021 abstracts were retrieved on 11 October 2022. 483 new full texts were evaluated and 172 new articles were included for the first search and 9 for the second search. The majority of the questions covered by this SLR explored new interventions (40% of type III questions) or new outcomes (26% of type II questions). New interventions included targeted therapies such as abatacept, Janus kinase inhibitors or nintedanib, and updated questions incorporated the results from key game-changing randomised controlled trials including trials on tocilizumab, mycophenolate or rituximab in SSc-interstitial lung disease.

Conclusions This SLR provides and summarises the highest level of evidence for the new EULAR recommendations for the treatment of SSc, providing an unprecedented comprehensive overview of recent knowledge on SSc treatments and participating in defining the future research agenda.

  • systemic sclerosis
  • scleroderma, systemic
  • therapeutics
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/ard-2024-226429

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • In 2017, the European Scleroderma Trials and Research, under the aegis of the EULAR, proposed a revised set of recommendations for the treatment of systemic sclerosis (SSc).

    • These recommendations were based on a systematic literature review (SLR) that concluded in 2014.

    • An update was necessary to inform future recommendations.

    WHAT THIS STUDY ADDS

    • This SLR provides and summarises the highest level of evidence to address questions prioritised for the new EULAR recommendations for the treatment of SSc.

    • It offers a comprehensive overview of the evidence on SSc treatments and contributes to defining the research agenda for SSc management.

    • The 2023 SLR includes targeted therapies (eg, abatacept, Janus kinase inhibitors and nintedanib) and incorporates results from key, game-changing trials on tocilizumab, mycophenolate and rituximab.

    • Additionally, this SLR manuscript presents the most updated and highest level of evidence on interventions and outcomes not ultimately included in the final version of the recommendations but still potentially useful for clinicians.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • This SLR provided the new EULAR SSc treatment recommendations task force with the available evidence published since 2014, informing the development of updated treatment guidelines.

    Introduction

    Systemic sclerosis (SSc) is a rare and heterogeneous systemic autoimmune disease characterised by a triad of pathogenic factors that includes (i) vasculopathy, (ii) inflammation and autoimmunity and (iii) fibrosis characterised by collagen deposit in the skin and internal organs such as lungs or myocardium.1 Three main subsets of SSc are described based on the extent of skin fibrosis2 3: diffuse cutaneous SSc (dcSSc) with distal and proximal skin involvement, limited cutaneous SSc (lcSSc) characterised by distal skin fibrosis and SSc sine scleroderma, defined by the absence of skin fibrosis despite SSc-related features. To date, SSc is the rheumatic disease with the highest individual mortality rate.1 The main causes of death are SSc-interstitial lung disease (SSc-ILD) and SSc-related heart involvement.4 Considering the complexity of the disease and the need for early intervention to limit the onset and/or progression of life-threatening manifestations,5 there is an important need for treatment recommendations.6 7

    The European Scleroderma Trials and Research (EUSTAR) under the aegis of EULAR proposed a first set of recommendations in 2009 that were updated by a new publication in 2017 based on a dual combination of expert opinion and evidence from the literature.6 7 The 2017 recommendations were based on a systematic literature review (SLR) that ended up in 2014.6 Since then, there has been an unprecedented wave of phase II and phase III randomised controlled trials (RCTs) that have led to significant progress in the understanding and management of SSc.8 Based on these RCTs, new drugs have been approved by regulatory agencies including nintedanib, a tyrosine kinase inhibitor with antifibrotic properties approved in the treatment of SSc-ILD in the USA, Europe and Japan9; tocilizumab, a humanised monoclonal antibody targeting the IL-6 receptor and approved in the USA for the treatment of SSc-ILD10 11 and rituximab, a chimeric monoclonal antibody targeting CD20 and approved in Japan.12–14 All these new approvals since the 2017 EULAR recommendations for the treatment of SSc stress the need for an update of these recommendations. Most of these RCTs focused on SSc-related skin involvement and ILD, with a majority of trials designed for dcSSc, but comprehensive updated guidelines for the management of other key SSc-related manifestations in all patients with SSc, including lcSSc and sine scleroderma, are still needed.15 Such updated recommendations are meant to involve statements regarding key major manifestations, included rare although severe SSc-related complications such as scleroderma renal crisis (SRC).16

    To that end, an SLR is needed to summarise the main available date, inform the discussions and to help define the level of evidence and strength of recommendations. Considering the high number of SSc-related clinical manifestations, and the high number of related outcomes, an SLR providing the most up-to-date content of the literature for the recommendations of SSc is a challenge, making this disease specific among all rheumatic diseases and other sets of EULAR recommendations. The objective of the proposed SLR was to provide a critical review of the updated evidence on SSc treatment to address the questions prioritised by an international task force. The results from this SLR informed the next steps that defined the 2023 EULAR recommendations for the treatment of SSc. The current manuscript provides the methodology, detailed protocol and key results of this SLR.

    Methods

    Protocol

    This SLR was based on an updated version of protocols used for the 2009 and 2017 SSc recommendations as published previously.6 7 Task force members for this SLR included a methodologist (PGC), a librarian (JE), five reviewers for abstract screening, data extraction and summaries of available evidence (AL, TS, JČ, EB; AL also supervised all others) and the two leaders of the recommendations task force (FdG and YAS). The SLR protocol was not declared prior to the beginning of the search considering that (a) this SLR was time-sensitive to be able to deliver the recommendations on time and to remain updated, (b) the SLR protocols from the prior recommendations were already published and approved, (c) this was an update of the previous SLR and not a new SLR started from scratch. This report follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline for the report of SLR.

    Question selection and categorisation

    The questions and intervention of interest were selected through an online survey followed by an online consensus meeting. Only questions with 80% of agreement during the consensus meeting were included in the SLR. This approach is further detailed in the recommendation article. Unless specified, questions were focused on a specific intervention, and several subitems were defined if several outcomes per intervention were to be explored. Sixty-seven clinical questions addressing 30 different interventions were explored (table 1). Each question was considered separately with 30 SLRs for the 30 interventions (including several outcomes), and 1 dedicated SLR (with several interventions) for calcinosis (31 searches in total). Calcinosis was explored through a dedicated SLR, considering that (a) this outcome was mentioned as a priority by patient representative during the first consensus meeting and (b) a systematic search for all available interventions for calcinosis was needed to fully cover this outcome, which appeared to be neglected so far.

    View this table:
    Table 1

    List of the 31 searches/questions and related outcomes prioritised by the task force, and number of publications* related to these searches

    Three categories of questions were defined prior the beginning of the SLR:

    • Type I questions: questions that were unchanged as compared with the previous set of recommendations, that is, same interventions and same outcome(s) of interest.

    • Type II questions: questions exploring the efficacy/effectiveness of an intervention already mentioned in the previous set of recommendations but with new outcome(s) added for this update of the recommendations.

    • Type III questions: new interventions not mentioned in the previous set of recommendations.

    Searching strategy

    • Databases: Embase, PubMed and Cochrane Systematic Reviews.

    • Search terms:

      • For type I and II questions: search terms from the previous set of recommendations were kept unchanged.

      • For type III questions: new search terms were designed with the help of a dedicated librarian after discussion with the SLR task force.

      • Search terms for all questions can be requested from the corresponding author.

    • Population of interest:

    • Publication dates and time period:

      • Two rounds of SLR were performed to ensure the most up-to-date level of evidence, using the same approach for both rounds. Between the two rounds, reviewers also performed regular manual searches before the consensus meeting (October 2022) to ensure a real-time update of the level of evidence before the consensus meeting.

    Supplemental material

    →First round:

    • for type I and type II questions: new articles published from 1 October 2014 to 31 March 2022.

    • For type III questions: from inception of the databases to 31 March 2022.

    → Second round:

    • for types I, II and III questions, all new articles published from 1 April 2022 to 30 November 2022, with same or higher level of evidence were included.

    Eligibility criteria

    Online supplemental table 2 provides the inclusion and exclusion criteria.

    Level of evidence and grade of recommendation

    Level of evidence and grade of recommendation were based on the Centre for Evidence-Based Medicine (CEBM) classification (OCEBM levels of evidence, University of Oxford: https://www.cebm.ox.ac.uk/resources/levels-of-evidence/ocebm-levels-of-evidence).

    Abstract screening for full-text review

    Abstract screening was performed using Rayyan software. In case of any doubt, abstracts were discussed among the team and were included rather than excluded for full-text evaluation to ensure comprehensiveness.

    Full-text evaluation

    For all abstracts selected, full-text evaluation was performed to refined inclusion and exclusion criteria adapted to each question and to define the highest level of evidence required for final inclusion in the data extraction step (table 1).

    For each question type, the selection strategy was further refined as follows based on full-text evaluation:

    • For type I questions: selection of studies only with a same or higher level of evidence.

    • For type II questions: selection of studies only with a same or higher level of evidence, article selected from the previous set of recommendation were kept for data extraction to include new outcomes that had not been explored in the previous set of recommendations.

    • For type III questions: selection of studies with the highest level of evidence since inception of the databases.

    Data extraction

    Data extraction template was defined prior to the beginning of the SLR based on the existing protocols from the previous sets of recommendations.6

    10% of all articles from each reviewer (ie, from 6 to 12 articles per reviewer) were assessed by a second reviewer to ensure consistency and reliability of data extraction. In case of discrepancy, data extraction from the considered study was discussed with senior task leader to reach consensus.

    • For type I questions: data extraction from the previous set of recommendations was kept unchanged, new articles were added to the data extraction file and level of evidence was updated accordingly.

    • For type II questions: results from the new outcomes were collected from articles including in the previous set of recommendations, data extraction was kept unchanged for outcomes already retrieved in the previous set of recommendations. New articles were added to the data extraction file, results from previous and new outcomes were collected, the level of evidence was updated accordingly.

    • For type III questions: data from articles according to the defined template were retrieve and level of evidence was defined based on the available studies.

    Level of evidence for each question was discussed within the team and with a methodologist to collectively define the final level of evidence, informing the strength of the upcoming recommendation statements.

    Quality appraisal

    The articles fulfilling the inclusion criteria for data extraction with the highest level of evidence for each search underwent quality appraisal using the JADAD scale.6 A scale such as the Cochrane ‘Risk of Bias’ tool could have been preferred but as this was an update of the previous set of recommendations, we used the same scale as used previously.6 For each study, quality appraisal from 0 to 5 was collected in the data extraction table, together with the extracted data for each outcome of interest.

    Continued update of the level of evidence and second round of SLR

    SLR task leaders and experts ensured that new studies fulfilling the inclusion criteria and with the adapted level of evidence published since 31 March 2022 were included and discussed during subsequent face-to-face meetings throughout the process to maintain an updated level of evidence on all questions. A new systematic search for all questions was performed in all three databases in December 2022, and all abstracts published from 31 March 2022 to 1 December 2022 were included, and screened following the same approach as for the first round of SLR.

    Results

    Questions included in the SLR

    The list of 31 questions is provided in table 1 and online supplemental table 3. As compared with the previous set of recommendations, some interventions were suppressed as they were not selected during the consensus exercise: azathioprine, fluoxetine, non-steroid anti-inflammatory drugs, statins, tumour necrosis factor-α inhibitors, lymph drainage.

    On the contrary, 11 new interventions were explored, including 4 new targeted therapies: selexipag, abatacept, Janus kinase (JAK) inhibitors and nintedanib. Regarding newly explored outcomes, emphasis was made on survival, musculoskeletal manifestations (MSK) and heart involvement, as compared with the previous set of recommendations.

    Included studies

    Figure 1 and online supplemental figure 1 provide the overall flowcharts for first and second searches. 172 and 9 articles were included for data extraction based on first and second search, respectively. These 181 (172+9) selected articles published since 2014 included 76 RCTs (41.9%) and 24 SLR or meta-analyses (13,3%) (online supplemental table 3). 171 articles from the previous set of recommendations were included and updated in case of missing outcomes. These 171 articles from the previous recommendations included 35 RCTs (20.5%) and 22 SLR or meta-analyses (12.9%). In total, 352 articles were included and extracted to define the level of evidence and support the discussions on the final statements for this updated set of recommendations.

    Figure 1
    Figure 1

    Flowchart for the first search. Computed search (31 March 2022) and hand search (11 October 2022).

    Regarding the level of evidence, all following outcomes reached a level 1 (1a, 1b or 1c) of evidence: skin fibrosis, survival, ILD, patient-reported outcomes (PRO), Raynaud’s phenomenon (RP), digital ulcers (DU), pulmonary arterial hypertension (PAH), heart involvement, MSK, quality of life (QoL) and hand function. Despite available RCTs (level of evidence 1b), some outcomes such as heart involvement or MSK were not the primary outcome measures in these trials, and were only secondary/exploratory outcomes from negative RCTs (ie, unmet primary objective) leading to a strength of recommendations of at best B (ie, extrapolation of results from level 1 studies). The highest level of evidence was 2a for small intestinal bacterial overgrowth, 2b for gastrointestinal (GI) (including gastro-oesophageal reflux disease), 2b for SRC, 3b for erectile dysfunction, 4 for calcinosis-related outcomes, with various levels of evidence depending on the interventions (table 1).

    This updated SLR included a substantial number of RCTs with JADAD score of 5 (ie, high-quality RCTs) as compared with the previous set of recommendations (14 RCTs, figure 2). The outcome with the highest number of RCTs was skin, used as primary outcome in four high-quality RCTs published since 2014,10–12 17 18 all dedicated to dcSSc, followed by ILD (three high-quality RCTs) and PAH (two high-quality RCTs).9 14 19–22 ILD and PAH trials included patients with SSc (lcSSc and dcSSc) and patients with connective tissue disease (CTD)-ILD and CTD-associated PAH or idiopathic PAH. Although DU was the primary end point in two trials published in 2016 (both negative on their primary objective), no new trials were published since 2016.23 24 On the contrary, the majority of high-quality RCTs exploring the impact of active therapy on skin were published in the past 3 years (2020–2023) and they were also negative for their primary outcome measure (modified Rodnan skin score (mRSS)) excepted the Study of the Efficacy and Safety of Rituximab in Participants With Systemic Sclerosis (DESIRES) trial assessing the efficacy of rituximab on mRSS.10–12 17 18

    Figure 2
    Figure 2

    High-quality randomised controlled trials (JADAD=5) included in this systematic literature review, published since the previous set of recommendations and sorted by publication date and primary outcome. CYC, cyclophosphamide; DU, digital ulcers; HSCT, haematopoietic stem cell transplantation; ILD, interstitial lung disease; MMF, mycophenolate mofetil; PAH, pulmonary arterial hypertension; RP, Raynaud’s phenomenon; SSc, systemic sclerosis; TOFA, tofacitinib.

    Conclusions from data extraction

    For all interventions, the SLR team provided a brief final conclusion including the main results from the studies with the highest level of evidence for each outcome, and a proposal on the strength of the recommendations. All conclusions were provided by the reviewer in charge of the considered intervention and then revised by another reviewer (AL). In case of discrepancies on the level of evidence/grade of recommendations, the final decision was collectively made with all task force leaders, including the methodologist (PGC). All 31 summaries are provided in tables 2–4 for types I, II and III questions, respectively. The list of the 90 main references used to write these summaries are included as online supplemental materials. These brief conclusions were not used as statements for the recommendations per se but were used as discussion starting points during the consensus meetings. Each time it was needed, the data extraction tables of the studies were presented during the consensus exercise to further support the discussion and explore details that were not covered by the summaries. Final statements for the recommendations were based on the outcomes of interest. Interventions were included for each outcome as deemed appropriate by the task force members, including international experts and patient representatives. The summaries from tables 2–4 include the most updated and highest level of evidence for all 30 interventions (and calcinosis), with associated references, including for interventions and/or outcomes that were not ultimately retained in the final version of the recommendations.

    View this table:
    Table 2

    Main conclusions for type I questions based on the highest available level of evidence used as starting points for the discussions during the consensus exercise

    View this table:
    Table 3

    Main conclusions for type II questions based on the highest available level of evidence used as starting points for the discussions during the consensus exercise

    View this table:
    Table 4

    Main conclusions for type I questions based on the highest available level of evidence used as starting points for the discussions during the consensus exercise

    Discussion

    The main objective of this SLR was to inform the task force on the highest level of evidence available for the 31 searches prioritised in this new update of the EULAR/EUSTAR recommendations for the treatment of SSc. The main results of the SLR (tables 2–4) were used as discussion starting points for the consensus meeting that defined the final statement for each outcome/organ involvement of interest in the updated recommendations. This approach ensured that these recommendations were based on updated results from the literature, incorporated expert opinion—especially when the level of evidence was low—and included the perspectives of patient representatives.

    This SLR was stratified by research questions prioritised during an online Delphi exercise, and 30 interventions were explored. A specific search was also conducted for calcinosis, considering the potential range of interventions for this specific outcome, which was identified among the priorities by patient partners from the task force. Seven interventions from the previous recommendations were suppressed through the Delphi exercise and 11 new interventions were explored, including targeted therapies.6 A total of 352 articles were analysed and used to inform the consensus meeting. This high number of articles reflects the challenge represented by SSc as compared with other rheumatic diseases, considering the numerous SSc-related clinical manifestations and organ damage, the lack of RCTs for rare although severe manifestations (such as SRC) and the small sample size of some RCTs. For interventions already explored in the previous recommendation but with new outcomes to analyse, all new studies published since October 2014 were included, with data extraction of outcomes included from the previous set of recommendations,6 and new outcomes selected for this new set of recommendations. For such new outcomes, in studies published prior to October 2014, data extraction was only performed on full texts included in the previous set of recommendations. This means that studies only focusing on new outcomes and published before October 2014 were not included and this could be considered as a limitation. Due to the high number of SSc-relates outcomes, the subsequent high number of articles, and the time period covered (almost 10 years), completing this SLR on time while ensuring the most updated evidence available was also challenging, and two searches were conducted for all questions to ensure that no new articles would have been missed during the process (table 1). Considering this time-sensitive issue, only 10% of all articles from each reviewer benefited from a double data extraction. This could be considered a limitation of our approach; however, given the number of retrieved articles, this 10% threshold included 6–12 articles per reviewer, which was deemed sufficient to identify discrepancies in data extraction that would need to be discussed. No major discrepancies were identified based on this double extraction of 10% of the articles. Moreover, AL reviewed all the summaries and ensured that all data included in the 31 summaries were properly extracted. YA and FdG also reviewed the content and the articles reported in these summaries prior to the consensus meeting and for the preparation of the final manuscript of the recommendations.

    Since this SLR was based on the 31 research questions prioritised by the task force, some SSc-related RCTs were not included, such as the trial on rituximab on SSc-PAH or riociguat on skin involvement,25 26 since these outcomes had not been selected through the Delphi exercise for these interventions. This SLR highlights the high number of high-quality RCT published in SSc since the last update, with >14 new RCTs covering important manifestations of the disease such as skin involvement, ILD, vasculopathy or overall survival as primary end points. Although these RCTs reported on their primary end points, secondary and exploratory end points should not be neglected, as some recent approvals by regulatory agencies were based on secondary outcomes despite negative results on the primary objective.8 This is the case for tocilizumab for the treatment of SSc-ILD, since the impact on mRSS in focuSSced and FaSScinate was negative in these trials, but with positive results on SSc-ILD-related outcomes.10 11 18

    This SLR highlights the recent interest in fibrotic manifestations of the disease, including skin fibrosis. Due to this recent emphasis on fibrotic manifestations, these skin-driven RCTs focused on patients with early dcSSc, making lcSSc a neglected subset considering its high prevalence and its impact on QoL.15 27 RCTs focusing on key domains of the disease, such as GI, calcinosis or SRC are still missing resulting in lower levels of evidence for these important manifestations of the disease. Efforts are needed to improve the development of adapted outcome measures for these manifestations and for lcSSc to foster the design of RCTs focusing on these populations.27 This is an important issue since some of these domains are nonetheless considered bothersome from the patients’ perspective.28 The results from this SLR reflected the primary interests of researchers rather than those of patients, although the patient perspective is of growing interest in the management of rare diseases with multiple organ involvement such as SSc. Thus including the patient perspectives during the discussion that defined the final statements of the recommendations was a major point to consider, stressing that recommendations could not be only guided by the SLR. Expert opinion was also needed to deliver a clear message to physicians for the management of important domains or subpopulations that still lack available RCTs. To that end, observational studies for a complex and rare disease like SSc are of upmost importance to support expert opinions. International longitudinal cohorts, such as the EUSTAR database, offer a unique opportunity to guide expert opinion, especially for rare but severe manifestations.4 29–32

    This SLR has some limitations. SLR protocol was not specifically published before starting the literature search and SLR was not referenced, but it was an update, with time-sensitive issues, and protocols from the previous set of recommendations were already published, without major deviation from these protocols.6 7 Abstract screening was performed by only one reviewer, but this was explained by the high number of abstracts to be screened (12 717 for the first search and 2021 for the second search). We may have failed in identifying some studies published before October 2014 with interventions of interest already included in the previous set of recommendations but with new outcomes selected for this update. Live discussion with experts in the field has limited this selection bias, and new studies published after October 2014 were included for these new outcomes. ACR/EULAR 2013 classification criteria could not be retrospectively applied in all studies published prior to 2013.33

    This SRL also has several strengths. Each step was supervised by a dedicated methodologist. Three databases were searched, and search terms were designed by a dedicated librarian, informed by the task force leaders. This SLR was based on a comprehensive literature search despite the complexity of the task considering the high number of interventions, the high number of outcomes and the lack of RCTs leading to the analysis of observational studies as well. This SLR also took into account the previous set of recommendations, and updated previous data extraction with new outcomes as deemed appropriate by the Delphi exercise, reflecting the evolution of knowledge and practice. This SLR was performed by an international team of reviewers supervised by international experts in the field. Data extraction was supervised by the same researcher (AL), ensuring the consistency of the approach and methods. Two rounds of SLR ensured a most up-to-date screening of the literature.

    Based on a robust methodology, as per EULAR guidelines, this SLR provides and summarises the highest level of evidence to address questions prioritised in the update of EULAR recommendations for the treatment of SSc, providing an unprecedented comprehensive overview of recent knowledge on SSc treatments and participating in defining the future research agenda for SSc management. This SLR manuscript also provides the most updated and highest level of evidence on interventions and/or outcomes that were not ultimately included in the final version of the recommendations. However, evidence on these outcomes and interventions may still be relevant for clinicians seeking guidance and references, making this SLR an essential complement to the statements provided in the recommendations manuscript.

    Ethics statements

    Patient consent for publication

    Ethics approval

    Not applicable.

    Acknowledgments

    The authors would like to acknowledge Jerome Avouac, Mike Becker, Maurizio Cutolo, Laszlo Czirjak, Nemanja Damjanov, Jörg H W Distler, Ivan Foeldvari, Daniel E Furst, Serena Guiducci, Nicolas Hunzelmann, Dinesh Khanna, Jacob M van Laar, Gabriela Riemekasten, Richard Silver, Vanessa Smith, Alberto Sulli, Ulrich A Walker, Francesco Zulian, Marco Matucci-Cerenic, Armando Gabrielli, Oliver Distler, Anna-Maria Hoffmann-Vold, Ivan Castellvi, Alexandra Balbir-Gurman, Madelon C Vonk, Lydia Ananyeva, Simona Rednic, Anna Tarasova, Predrag Ostojic, Vladimira Boyadzhieva, Khadija El Aoufy, Sue Farrington, Ilaria Galetti, Christopher P Denton, Otylia Kowal-Bielecka, Ulf Mueller-Ladner for their contribution to the discussion on the recommendations. The authors especially thank patient partners and representatives (Ilaria Galetti and Sue Farrington) from the task force for their valuable comments and for helping prioritise the most important questions and research avenues.

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    Footnotes

    • Handling editor Josef S Smolen

    • X @delgaldoFrances

    • EB, JČoć, TS and YAS contributed equally.

    • Contributors AL coordinated the SLR and drafted the manuscript. EB, JČ, TS and YAS performed the SLR as equal contributors. JE served as librarian. PGC, YA and FdG supervised the entire process and critically reviewed the manuscript.

    • Funding FdG and PGC are supported in part by the National Institute for Health and Care Research (NIHR) Leeds Biomedical Research Centre (BRC) (NIHR203331).

    • Disclaimer The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

    • Competing interests EB: grants or contracts from GlaxoSmithKline (GSK) (master scholarship), support for attending meetings and/or travel from Boehringer Ingelheim, Eli Lilly. TS: grants or contracts from Janssen, Boehringer Ingelheim, AbbVie, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen, Boehringer Ingelheim; support for attending meetings and/or travel from AbbVie. PGC: consulting fees from AbbVie, BMS, Eli Lilly, Eupraxia, Galapagos, Genascence, GSK, Grunenthal, Janssen, Levicept, Moebius Medical, Novartis, Pacira, Stryker, Takeda and TrialSpark; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, Eli Lilly, Novartis. YA: consulting fees from Topadur, Boehringer Ingelheim, AstraZeneca, Galderma, Prometheus, Medsenic; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen, Horizon, Boehringer Ingelheim, Sandoz; support for attending meetings and/or travel from AstraZeneca and Boehringer Ingelheim. FdG: grants or contracts from AbbVie, Boehringer Ingelheim. AL, JČ, YAS and JE have nothing to declare.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.