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Review
Idiopathic inflammatory myopathies: state of the art on clinical practice guidelines
  1. Alain Meyer1,2,
  2. Carlo Alberto Scirè3,
  3. Rosaria Talarico4,
  4. Tobias Alexander5,
  5. Zahir Amoura6,
  6. Tadej Avcin7,
  7. Simone Barsotti8,9,
  8. Lorenzo Beretta10,
  9. Jelena Blagojevic11,
  10. Gerd Burmester5,
  11. Ilaria Cavazzana12,
  12. Patrick Cherrin6,
  13. Laura Damian13,
  14. Andrea Doria14,
  15. João Eurico Fonseca15,
  16. Federica Furini16,
  17. Ilaria Galetti17,
  18. Frederic Houssiau18,
  19. Thomas Krieg19,
  20. Maddalena Larosa14,
  21. David Launay20,
  22. Raquel Campanilho-Marques15,
  23. Thierry Martin21,
  24. Marco Matucci-Cerinic11,
  25. Pia Moinzadeh19,
  26. Carlomaurizio Montecucco22,
  27. Maria Francisca Moraes-Fontes23,
  28. Luc Mouthon24,
  29. Rossella Neri4,
  30. Sabrina Paolino25,
  31. Yves Piette26,
  32. Simona Rednic13,
  33. Farah Tamirou18,
  34. Angela Tincani12,
  35. Natasa Toplak7,
  36. Stefano Bombardieri27,
  37. Eric Hachulla20,
  38. Ulf Mueller-Ladner28,
  39. Matthias Schneider29,
  40. Vanessa Smith26,
  41. Ana Vieira30,
  42. Maurizio Cutolo25,
  43. Marta Mosca4,8 and
  44. Lorenzo Cavagna22
  1. 1Centre National de Référence des Maladies Systémiques et Auto-immunes Rares Grand-Est Sud-Ouest (RESO), Service de humatologie, Service de physiologie, Unité d’explorations fonctionnelles musculaires, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  2. 2EA3072, Fédération de Médecine Translationelle, Université de Strasbourg, Strasbourg, France
  3. 3Section of Rheumatology, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
  4. 4Rheumatology Unit, AOU Pisana, Pisa, Italy
  5. 5Department of Rheumatology and Clinical Immunology, Charité University Hospital Berlin, Berlin, Germany
  6. 6Department of Internal Medicine, Hospital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
  7. 7Department of Allergology, Rheumatology and Clinical Immunology, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
  8. 8Rheumatology Unit, University of Pisa, Pisa, Italy
  9. 9Department of Medical Biotechnology, University of Siena, Siena, Italy
  10. 10Referral Center for Systemic Autoimmue Diseases, Referral Center for Systemic Autoimmue DiseasesFondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
  11. 11Department of Clinical and Experimental Medicine, Department of Geriatric Medicine, Division of Rheumatology and Scleroderma Unit, University of Florence, AOUC, Florence, Italy
  12. 12Rheumatology and Clinical Immunology Unit, Civil Hospital, Brescia, Italy
  13. 13Department of Rheumatology, Emergency County Teaching Hospital, Cluj-Napoca, Romania
  14. 14Rheumatology Unit, Department of Medicine, AO Padova and University of Padua, Padua, Italy
  15. 15Rheumatology Department, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon Academic Medical Centre, Lisbon, Portugal
  16. 16Section of Rheumatology, Department of Medical Sciences, Sant’Anna University Hospital, Ferrara, Italy
  17. 17FESCA, Federation of European Scleroderma Associations, Milan, Italy
  18. 18Department of Rheumatology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Louvain-la-Neuve, Belgium
  19. 19Department of Dermatology, Universitätsklinikum Köln, Cologne, Germany
  20. 20Département de Médecine Interne et Immunologie Clinique, Centre de Référence des Maladies Systémiques et Auto-Immunes Rares du Nord-Ouest (CERAINO), Université de Lille, CHU Lille, LIRIC, INSERM, Lille, France
  21. 21Departement of Internal Medicine, Centre National de Référence des Maladies Systémiques et Auto-immunes Rares Grand-Est Sud-Ouest (RESO), Hôpitaux Universitaires de Strasbourg, France, Strasbourg, France
  22. 22Division of Rheumatology, University and IRCCS Policlinico S. Matteo Foundation, Pavia, Italy
  23. 23Unidade de Doenças Auto-imunes/Medicina 7.2, Hospital de Curry Cabral, Centro Hospitalar de Lisboa Central, Lisbon, Portugal
  24. 24Service de Médecine Interne, Centre de Référence Maladies systémiques Autoimmunes Rares d’Ile de France, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Cochin, Université Paris Descartes, Paris, France
  25. 25Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, IRCCS Polyclinic Hospital San Martino, University of Genoa, Genoa, Italy
  26. 26Department of Rheumatology, Department of Internal Medicine, Ghent University Hospital, Ghent University, Ghent, Belgium
  27. 27University of Pisa, Pisa, Italy
  28. 28Department of Rheumatology and Clinical Immunology, Kerckhoff Klinik, Justus-Liebig University of Giessen, Bad Nauheim, Germany
  29. 29Department of Rheumatology, Universitätsklinikum Düsseldorf, Düsseldorf, Germany
  30. 30Liga Portuguesa Contra as Doenças Reumáticas, Núcleo Síndrome de Sjögren, Lisbon, Portugal
  1. Correspondence to Dr Alain Meyer; alain.meyer7{at}gmail.com

Abstract

Idiopathic inflammatory myopathies (IIMs) encompass a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and inflammation, but in antisynthetase syndrome arthritis and interstitial lung disease are more frequent and often inaugurate the disease. Clinical practice guidelines (CPGs) have been proposed for IIMs, but they are sparse and heterogeneous. This work aimed at identifying: i) current available CPGs for IIMs, ii) patients ’ and clinicians’ unmet needs not covered by CPGs. It has been performed in the framework of the European Reference Network on rare and complex connective tissue and musculoskeletal diseases (ReCONNET), a network of centre of expertise and patients funded by the European Union’s Health Programme. Fourteen original CPGs were identified, notably recommending that: i) extra-muscular involvements should be assessed; ii) corticosteroids and methotrexate or azathioprine are first-line therapies of IIMs. ii) IVIG is a treatment of resistant-DM that may be also used in other resistant-IIMs; iii) physical therapy and sun protection (in DM patients) are part of the treatment; v) tumour screening for patients with DM include imaging of chest, abdomen, pelvis and breast (in woman) along with colonoscopy (in patients over 50 years); vi) disease activity and damages should be monitor using standardised and validated tools. Yet, only half of these CPGs were evidence-based. Crucial unmet needs were identified both by patients and clinicians. In particular, there was a lack of large multidisciplinary working group and of patients ’ preferences. The following fields were not or inappropriately targeted: diagnosis; management of extra-muscular involvements other than skin; co-morbidities and severe manifestations.

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Key messages

What is already known about this subject?

  • Clinical practice guidelines (CPGs) have been proposed for idiopathic inflammatory myopathies (IIMs) but no review of “what we have” and patients’ as well as clinicians’ unmet needs has been performed so far.

What does this study add?

  • Fourteen original CPGs were identified, covering important issues.Yet, only half of these CPGs were evidence-based. and crucial unmet needs were identified both by patients and clinicians.

How might this impact on clinical practice?

  • Future CPGs should include multidisciplinary stakeholders, together with patients, to address the identified unmet needs in myositis care, based on growing evidence in the field.

Introduction

Idiopathic inflammatory myopathies (IIMs) encompass a heterogeneous group of rare autoimmune diseases showing a large degree of overlap1 but also some peculiarities and differences, in particular in the setting of antisynthetase syndrome (ASSD).2 If IIMs affect adults and children, ASSD is generally an adult-onset condition,3 with only few cases reported in paediatric age.4 IIMs are generally characterised by the occurrence of muscle weakness and inflammation, but in ASSD, arthritis and interstitial lung disease (ILD) are more frequently observed and frequently represent the first manifestation of the disease.5 Skin can also be frequently affected by IIMs, with occurrence of lesions such as heliotrope rash, Gottron’s sign/papules, skin ulcers, V-sign, Shawl sign, Hiker’s feet and mechanic’s hands, with these two latter considered as typical ASSD findings.6 7 Additionally, IIMs are associated with cancer,8 the risk of which is increased up to 5.3-fold with respect to general population in males with dermatomyositis (DM).9 Thus, physicians from different specialties are involved in the care (including diagnosis, treatment and monitoring) of these patients. Even if IIMs are potentially treatable diseases, currently, mortality is hardly fourfold increased with respect to general population10 and quality of life is decreased.11 Considering the large number of specialists potentially involved in the daily management of these patients, as well as the different therapeutic approaches available, it is important to homogenise the different approaches, in order to establish a common shared strategy. Clinical practice guidelines (CPGs) are systematically developed statements to assist practitioner and patient decisions about appropriate healthcare for specific clinical circumstances.12 13 CPGs have been proposed for IIMs, but they are sparse and not homogeneous. This work attended to identify currently available CPGs for IIMs, to provide a narrative review of their contents and to identify patients’ and clinicians’ unmet needs. It has been performed in the framework of the European Reference Network on rare and complex connective tissue and musculoskeletal diseases (ERN ReCONNET), a Network of centre of expertise and patients funded by the European Union’s Health Program (reconnet.ern-net.eu).

Methods

Objective and management of first work package of ERN ReCONNET

The aim of the first work package of ERN ReCONNET was the identification of field of application of identified CPGs, looking for potential unmet needs.

Planning and evaluation of the work was driven by regular interaction between participants of the working group during meetings (European League Against Rheumatism (EULAR) Congress 2017, American College of Rheumatology (ACR) Congress 2017, ERN ReCONNET Meeting, Pisa, 4–6 February 2018), web conferences, electronic letters and ERN Collaborative Platform (https://webgate.ec.europa.eu).

Systematic literature search

Between June 2017 and February 2018, we carried out a search in PUBMED and EMBASE based on controlled terms (MeSH and Emtree), keywords of the disease and publication type (CPGs). All published articles were reviewed in order to identify existing CPGs on diagnosis, monitoring and treatment of IIMs, according to the Institute of Medicine 2011 definition (clinical practice guidelines are statements that include recommendations intended to optimise patient care that are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options).

The Disease Coordinators (DCs) (LC and AM) of the ERN ReCONNET for IIMs have assigned the work on CPGs to the Healthcare Providers involved. Moreover, in order to implement the list of guidelines provided by Medline and Embase search, the group performed also a hand search. A first screening of evidence-based medicine guidelines (regardless its level) was performed on the basis of their title and abstract (systematic search and hand search). A discussion group was set for the effective inclusion and evaluation of the existing CPGs, in order to identify the unmet needs.

Here is the search strategy: Medline (Pubmed): (“polymyositis” [MeSH Terms] OR “polymyositis” [All Fields] OR “dermatomyositis” [MeSH Terms] OR “dermatomyositis” [All Fields] OR “myositis” [MeSH Terms] OR “myositis” [All Fields] OR (“idiopathic” [All Fields] AND “inflammatory” [All Fields] AND “myopathies” [All Fields]) OR “idiopathic inflammatory myopathies” [All Fields]) AND (“Practice Guideline” [Publication Type] OR “Practice Guidelines As Topic” [MeSH Terms] OR Practice Guideline [Publication Type] OR “Practice Guideline” [Text Word] OR “Practice Guidelines” [Text Word] OR “Guideline” [Publication Type] OR “Guidelines As Topic” [MeSH Terms] OR Guideline [Publication Type] OR “Guideline” [Text Word] OR “Guidelines” [Text Word] OR “Consensus Development Conference” [Publication Type] OR “Consensus Development Conferences As Topic” [MeSH Terms] OR “Consensus” [MeSH Terms] OR “Consensus” [Text Word] OR “Recommendation” [Text Word] OR “Recommendations” [Text Word] OR “Best Practice” [TextWord] OR “Best Practices” [TextWord]). Embase: (‘myositis’/exp OR ‘idiopathic inflammatory myopathy’ OR ‘inflammatory myopathy’ OR ‘muscle inflammation’ OR ‘myopathy, inflammatory’ OR ‘polymyositis’/exp OR 'fibromyositis’ OR 'polymyositis’ OR 'dermatomyositis’/exp OR ‘dermatomyositides’ OR ‘dermatomyositis’ OR ‘polymyositis arthropathica’) AND (‘practice guideline’/exp OR ‘practice guideline’ OR ‘practice guidelines’/exp OR ‘practice guidelines’ OR ‘clinical practice guideline’/exp OR ‘clinical practice guideline’ OR ‘clinical practice guidelines’/exp OR ‘clinical practice guidelines’ OR ’clinical practice guidelines as topic’/exp OR ‘clinical practice guidelines as topic’ OR ‘guideline’/exp OR ‘guideline’ OR ‘guidelines’/exp OR ‘guidelines’ OR ‘guidelines as topic’/exp OR ‘guidelines as topic’ OR ‘consensus development’/exp OR ‘consensus development’ OR ‘consensus development conference’/exp OR ‘consensus development conference’ OR ‘consensus development conferences’/exp OR ‘consensus development conferences’ OR ‘consensus development conferences as topic’/exp OR ‘consensus development conferences as topic’ OR ‘consensus’/exp OR ‘consensus’ OR ‘recommendation’ OR ‘recommendations’) AND [embase]/lim NOT [medline]/lim.

Inclusion criteria and CPGs identification

CPGs were included if12 13:

  1. Their development was aimed at assisting practitioners’ and patients’ decisions about appropriate healthcare for patients with IIMs and ASSD.

  2. They were based on a systematic review of evidence.

  3. They were written in English.

All papers identified during the literature search were screened for eligibility by two evaluators and by DCs based on title and abstract assessment. Only papers considered eligible by at least one evaluator were included. Papers selected after the first round were then further assessed in order to verify their actual status of CPGs. In case of disagreement in the decision, a further round of discussion involving participants has been performed, in order to uniform the evaluation reaching the 100% of consensus.

Physicians’ and patients’ unmet needs were delineated by focus groups conducted during the ERN meeting followed by written exchange during the redaction process of the present manuscript. Patients were a 51-year-old woman with bachelor’s degree, a 45-year-old man with bachelor’s degree and a 39-year-old woman with higher level of education.

Results: state of the art on CPGs

Identification of existing CPGs

The systematic literature search provided a total of 727 citations. Title and abstract evaluation identified 98 papers suitable for full-text upload and review. After full-text revision, we identified 14 original papers published between 1996 and 201714–32 (figure 1).

Figure 1

Flow chart constructed from Pubmed, Embase and national databases. CPGs, clinical practice guidelines.

In the following sections, these papers will be thus defined as CPGs for practical purpose.

This is the first review providing an overview of currently available CPGs for IIMs whose characteristics and contents are resumed below and in tables 1 and 2.

Table 1

CPGs general characteristics

Table 2

Scope and key recommendations of available CPGs for IIMs

CPGs characteristics

CPGs were written (first and/or last authors) by rheumatologists (n=3), neurologists (n=7), dermatologists (n=3) and pulmonologists (n=1). In four CPGs, co-workers from different specialties than main authors were also involved. No CPGs involved clinicians from more than two different specialties. No CPGs involved patients.

Five CPGs were dedicated to IIMs, while nine covered a broader spectrum of diseases (including IIMs).

Nine CPGs targeted IIMs as a whole (juvenile and adult) although in four of the latter,14–16 23 authors did not state whether the recommendation applied to adult and/or juvenile IM. One paper targeted specifically juvenile IIMs and four specifically adults IIMs.

The majority of CPGs (n=13) focused on therapeutic questions including overall treatment, use of intravenous globulin, management of lung and cutaneous disease. Others addressed disease measurements (tools for clinical assessment and improvement definition), associated conditions (cancer, pregnancy) and overall management. In seven CPGs, evidence was systematically searched and discussed (evidence-based CPGs). In the others, the method for evidence search was not provided (‘eminence-based’ CPGs). There were no specific recommendations focusing on ASSD.

CPGs content

The covered points are as follows. (1) Global management of juvenile dermatomyositis (DM), the most frequent IIMs in children,20 and of IIMs in general.19 23 31 (2) The role of physical therapy in IIMs, focusing on the evaluation of disease-specific quality indicators, outcome measures and guidelines. The establishment of a physical rehabilitation path, in association to the pharmacological treatments, is crucial to obtain the best improvement possible in these patients.15 (3) Screening of cancer, one of the leading causes of death in IIMs.32 (4) Use of intravenous immunoglobulin (IVIG), an expensive treatment that should be reserved only to specific clinical conditions.14 16 17 21 29 (5) Cutaneous manifestations which are debilitating complications of various IIMs,22 in particular in juvenile forms.20 (6) ILD-related treatment,28 the main impacting prognostic factor in IIMs in general and in ASSD in particular. (7) Pregnancy planning and management, in a field in which juvenile forms are common and young people in childbearing age can be affected by these diseases.18

Recommendations of available CPGs are presented in table 2 and notably stated that: (1) extramuscular involvements should be assessed; (2) corticosteroids and methotrexate or azathioprine are first-line therapies of IIMs; (3) IVIG is a treatment of resistant-DM that may be also used in other resistant-IIMs; (4) physical therapy and sun protection (in patients with DM) are part of the treatment; (5) tumour screening for patients with DM include imaging of chest, abdomen, pelvis and breast (in woman) along with colonoscopy (in patients over 50 years); (6) disease activity and damages should be monitored using standardised and validated tools.

Unmet needs

CPGs that are currently available do not cover the entire spectrum of IIMs needs. From the clinical point of view, we think that the identification of uncovered areas could be useful for the establishment of additional CPGs. From the scientific point of view, by considering that CPGs are recommendations based on scientific evidences, some of the unmet needs could indicate areas that deserve future research. Finally, it will be important to critically review the content of existing CPGs, in order to identify their strength and weakness, looking to their improvement, as planned in the next ReCONNET work packages.

Clinicians’ unmet needs

Even if several issues have been addressed, other relevant points are currently not or ineffectively targeted by CPGs IIMs that can be summarised as follows (table 3):

Table 3

Synthesis of the physicians’ unmet needs

Unmet needs related to the stakeholders of CPGs development

  • The lack of large multidisciplinary working group is the first transversal and crucial problem of available CPGs. Indeed, considering that patients with IIMs have multiorgan involvement with different manifestations prevalence and severity levels, CPG for their optimal management cannot be developed without a larger number of different organ specialists as stakeholders. In this regard, a collaboration of ReCONNET with other ERNs concern by IIMs (EURO-NMD and ERN LUNG) has been planned.

  • Second, as IIMs are chronic diseases, patients’ perspective is mandatory for the improvement of daily quality of care. This issue will be overcome by initiatives notably started by the OMERACT (independent initiative of international health professionals interested in outcome measures in rheumatology).33

Unmet needs related to scope and target of the CPGs

  • No CPGs are currently available for diagnosis. Early intervention may be associated with a better outcome34 but treatment is often delayed or not appropriated, because IIMs can be misdiagnosed as numerous other conditions including non-inflammatory myopathies34 and other inflammatory diseases (such as rheumatoid arthritis35 or ILDs with autoimmune features36). On the other hand, mimickers of treatable IIMs include numerous non-inflammatory myopathies and inclusion body myositis.37 Although being an important milestone in the field, the recently published EULAR/ACR IIMs classification criteria did not match the definition of CPGs and were thus not included in this review. Yet, even considering these classification criteria,38 lung, joint and skin (other than DM rash) involvements are not taken into account,39 which is an issue especially for diagnosis of ASSD, as previously suggested by the American, European NEtwork of Antisynthetase Syndrome collaborative group.2 36 39–41 This unmet need will be fixed in next year thanks to CLASS project addressed to the establishment of next EULAR/ACR classification criteria of ASSD.

  • Management of extramuscular organ involvement other than skin is not appropriately targeted by current available CPGs. Of note, four papers address this important point, but have not been included in this review as they are based on expert consensus and thus do not match criteria for CPGs.24–27 Lung disease, one of the most frequent manifestations of IIMs and major cause of death10 is only addressed by one CPG.28 No CPG currently address heart, joints and gastroenterological manifestations, which are yet source of handicap and/or increased mortality.42–44

  • IIMs are a heterogeneous group of diseases. The clinical manifestations, autoantibody profile and muscle histology can be used to distinguish patient subgroups (extending their spectrum far beyond the subdivision between DM and other IIMs) with fairly homogeneous patterns of complications, treatment responses and outcomes. Yet, none of the CPGs identified in this review were specifically dedicated to one of these subgroups.

  • Accurate monitoring of muscle inflammatory activity and damages are mandatory in order to meet the subtle threshold point between undertreatment and overtreatment. This challenge has been taken up by only one CPG. The recently published EULAR/ACR criteria for clinical response in adult and juvenile IIMs45 46 is an important step in this field. Yet, they were not included in this review because they did not match the definition of CPGs.

  • Patients with IIMs may face life or organ-function threatening complications such as severe rapidly progressive ILD, myocarditis, pneumomediastinum, pulmonary hypertension, respiratory failure, prone position complication due to severe muscle weakness dysphagia and ischaemic ulcerative colitis. These situations require peculiarly prompt diagnosis and management. Yet, no CPG currently cover these points.

  • Side-effects of IIMs treatments and comorbidities (such as infections, osteoporosis, cardiovascular events and high-risk pregnancy) are major causes of morbidity and mortality in patients with IIM.10 47 Prevention and management of these associated conditions are currently not or only insufficiently targeted by CPGs.

  • Transition management. IIMs encompass all ages with different disease phenotypes and different patients’ needs, in particular in the transition period. Patients’ approach of adult and paediatric clinicians is generally different, and this may be an additional serious problem to be considered.

Patients’ unmet needs

This paragraph intends to highlight the unmet needs of the IIMs European community. The content of this paragraph has been carefully but hardly realised collecting the voices and the points of view of the patients affected by the disease. The rarity of the disease and the scarcity of patient organisations made this work harder than expected. IIMs spectrum disorders encompass a large number of conditions with a very heterogeneous range of manifestations, not limited to muscle involvement. On this basis, it is evident that patients’ needs are very different and deeply influenced by disease presentation pattern. Furthermore, also the diagnosis is not always easy to reach and this adds further uncertainty to patients, with a large number of doubts about the carried disease: ‘I do not understand what I have?’, ‘What is happening to me?’, ‘What should I expect from the future?’. Even if crucial, these questions have not always an answer in IIMs or, even worse, they have different answers according to the different referring specialist. Patients experience a lack of harmonisation in the medical approach and a scarce involvement in developing a common path. Being the diseases so heterogeneous, each patient would bring its own experiences and suggestions adding further useful information and improving the care of these conditions. Unfortunately, only few clinicians are aware that patients need more direct support and attention: a continuous process of discussion and dialogue with physicians could be surely relevant to this purpose. Furthermore, patients refer that they need more personalised assistance from the national health systems, in term of social demands and attention. The lack of harmonisation of assistance creates differences in the European Countries and ERN ReCONNET is perceived to possibly fill this gap.

Conclusions

We identified the currently IIMs available CPGs, showing a large area of unmet needs. A further effort is necessary and it has been planned by the ERN ReCONNET in order to evaluate the intrinsic validity and applicability of available recommendations. The standardisation and sharing of CPGs, from diagnosis to treatment, are crucial to really improve the prognosis of these patients. We need therefore to work intensively together with patients focusing on the global improvement of their daily life that represents a shared objective of patients and clinicians. We propose that future CPGs should include multidisciplinary stakeholders, together with patients, to address the identified unmet needs in myositis care, based on growing evidences.

Acknowledgments

Thanks to all the members of the Steering Committee of the ERN ReCONNET for the huge commitment during this work. A special thank goes to all the members of the ERN ReCONNET team for providing support during all the phases of the Work Package 3.

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View Abstract

Footnotes

  • Contributors AM, SCA,TR, CM, MM and LC contributed to the conception and design of the work, acquisition of data, drafting the work and revising it critically for important intellectual content. All authors contributed to the analysis and interpretation of data, final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Funding This publication was funded by the European Union’s Health Programme (2014-2020), Framework Partnership Agreement number: 739531 – ERN ReCONNET. The content of this publication represents the views of the authors only and it is their sole responsibility; it cannot be considered to reflect the views of the European Commission and/or the Consumers, Health, Agriculture and Food Executive Agency (CHAFEA) or any other body of the European Union. The European Commission and the Agency do not accept any responsibility for use that may be made of the information it contains.

  • Disclaimer ERN ReCONNET is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States. The ERNs are co-funded by the European Commission. The content of this publication represents the views of the authors only and it is their sole responsibility; it cannot be considered to reflect the views of the European Commission and/or the Consumers, Health, Agriculture and Food Executive Agency (CHAFEA) or any other body of the European Union. The European Commission and the Agency do not accept any responsibility for use that may be made of the information it contains.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Data sharing statement No additional data are available.

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