Rationale Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities.
Methods The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology—a non-profit international organisation dedicated to consensus methodology in identification of outcome measures—conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF).
Results A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed.
Conclusion Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.
- Connective tissue disease associated lung disease
- Interstitial Fibrosis
- Idiopathic pulmonary fibrosis
- Rheumatoid lung disease
- Systemic disease and lungs
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- Connective tissue disease associated lung disease
- Interstitial Fibrosis
- Idiopathic pulmonary fibrosis
- Rheumatoid lung disease
- Systemic disease and lungs
Why is the key question?
Can a core set of outcome measures that are reliable and feasible be identified by experts for use in future clinical trials in connective tissue disease associated interstitial lung disease (CTD-ILD) and idiopathic pulmonary fibrosis (IPF)?
What is the bottom line?
Using established Delphi and nominal group techniques supplemented by patient input, a preliminary core set of outcome measures in CTD-ILD and IPF have been identified.
Why read on?
To learn the core set of clinically meaningful and feasible measures in CTD-ILD and IPF that were identified and the gaps remaining.
The diffuse idiopathic interstitial pneumonias describe a spectrum of parenchymal lung diseases sharing clinical, physiological, radiological and pathological similarities, including varying degrees of fibrosis, inflammation and vascular injury.1 Idiopathic pulmonary fibrosis (IPF) is associated with usual interstitial pneumonia (UIP), poor survival and limited treatment options.2 Interstitial lung disease (ILD), most typically presenting as non-specific interstitial pneumonitis, is a leading cause of death in systemic sclerosis (SSc)3 and a prominent clinical feature of other connective tissue diseases (CTDs), including idiopathic inflammatory myopathy (IIM) and Sjögren syndrome. UIP is also found in rheumatoid arthritis (RA) and IIM.4 ,5
Current evaluations of therapies focus on patient survival or markers of chronic disease progression, for example, change in forced vital capacity (FVC).6–8 Measures of patient function, for example, 6 min walk test (6MWT), and health-related quality of life (HRQoL) have been variably applied with inconsistent results.6 Therapeutic research has been hampered by lack of consensus on and validation of outcome measures that reliably assess the likelihood of treatment response. Furthermore, extra-pulmonary CTD manifestations may confound measures of ILD activity/severity. Patient-reported dyspnoea is demonstrated to predict time to death, yet a satisfactory dyspnoea instrument for ILD has not yet been identified.7 ,8 Clinically relevant, patient-reported outcome measures (PROMs) exist for obstructive lung disease and, in the absence of disease-specific measures, have been utilised in trials of ILD.
The Outcome Measures in Rheumatology (OMERACT) filter9 (see online supplement) is a dynamic and iterative process/structure through which an instrument's performance can be evaluated under three criteria or points of examination: truth (face, content, construct and criterion validity), discrimination (reliability, sensitivity to change) and feasibility (cost, interpretability, accessibility, safety, time). The ideal instrument satisfies all three while instruments incompletely satisfying the filter may still be immediately useful but require additional study.
The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of the OMERACT international consensus initiative convened to define outcome measures for use in randomised controlled trials (RCTs) in CTD-ILD. Given the major clinical overlap, the same process was used in parallel for IPF. We report the results of a three-component process: medical expert Delphi exercise, patient perspective investigations and a combined medical expert and patient participant nominal group technique (NGT) meeting leading to identification of preliminary core sets of domains with corresponding instruments that are clinically meaningful and feasible in the context of a 1-year multi-centre RCT for each CTD-ILD and IPF. These sets of instruments are proposed as the minimum outcome measures to be used in future RCTs and registries.
Medical expert Delphi process
International experts (n=270) were identified by authorship in peer-reviewed journals, specialty society membership and peer recommendations, and invited to participate in the web-based Delphi process.10–12 This began with an ‘item-collection’ stage called Tier 0, wherein participants nominated an unrestricted number of potential domains (qualities to measure) and instruments (specific tools for use as a measure) perceived as relevant for inclusion in a hypothetical 1-year RCT. This exercise produced a list of >6700 items—reduced only for redundancy, organised into 23 domains and 616 instruments and supplemented by expert advisory teams of pathologists and radiologists. The results of Tier 0 provided the content for sequential web-based surveys: Tiers 1, 2 and 3 which progressively reduced the number of voting items as the items with the lowest ratings were dismissed. Survey items for each CTD-ILD and IPF were aligned in parallel and rated along a nine-point Likert scale from 1 (‘not at all important’) to 9 (‘absolutely important’), with ‘insufficiently familiar’ a voting alternative. An extensive online repository of item-related journal articles was available to participants throughout the process.
A cut-off of <4 (median rating) was applied to ratings from the large number of voting items in Tier 1. Cluster analyses were applied to the ratings in Tiers 2 and 3 avoiding the use of an arbitrary cut-off, thus allowing items to aggregate independently providing an unbiased analysis of agreement among raters.12 A nine-cluster analysis was initially applied and reduced to three clusters for all items during both tiers.
Patient perspective investigation
Patient participation is recognised as integral to development of outcome measures by OMERACT, the US Food and Drug Administration and European Medicines Agency.9 ,13 To investigate the patient perspective in CTD-ILD, a set of qualitative studies were conducted: focus groups (60–90 min) of 8–12 consented participants with CTD-ILD were selected by convenience sampling and asked 1) how their life has changed since the diagnosis of their lung disease? and 2) how their lung disease has changed over time? Patient perspective data in 20 English-speaking patients with IPF were previously available.14 Content was extracted from verbatim transcripts and inductive analysis was applied to minimise investigator bias.15 Following each focus group, CTD-ILD participants (study patients with IPF were not available) rated on a seven-point Likert scale the importance of the domains identified in Tier 0 of the medical expert Delphi process.
At the 2012 OMERACT 11 conference and the 2012 American Thoracic Society (ATS) International Conference, data from the Delphi and the patient perspective investigations were reviewed by medical and patient experts. Following this, a face-to-face meeting was held to apply NGT to the overall results.
At the NGT, evaluation of each domain was led by assigned teams of medical and patient participants who presented evidence-based reviews focusing on instrument validation in accordance with the OMERACT filter.9 ,12 Several weeks prior to team assembly, interactive educational sessions with the patient participants examined each domain and instrument. The teams served as a resource for evidence-based information during the discussion phases.
After each team presentation, all participants engaged in a ‘round-robin’ discussion allowing equal speaking time per participant10–12 over two to three rounds examining acceptance or rejection of an item, potential clinical endpoint assignment, and determination for new instrument development within that domain. Each round of discussions was followed by group voting.
All participants were requested to register a vote for each item. With participants’ full knowledge, responses from all physicians and patients with CTD-ILD were tabulated for CTD-ILD, with only those from pulmonologists and patients with IPF for IPF. All votes were recorded. (The radiologist voting was tabulated as a pulmonologist.) A priori, acceptance was agreed upon as ≥70% affirmative votes.16 Voting addressed inclusion/exclusion of items based on the OMERACT filter and whether the patient perspective and evidence-based data warranted the need for new instrument development for that corresponding domain.
Medical expert Delphi
A total of 254 (137 pulmonologists, 113 rheumatologists and 4 cardiologists) engaged in the Delphi process. Seventy-four per cent reported their primary field of interest being ILD. Participation through all stages exceeded 97%. Six domains identified were: Dyspnoea, HRQoL, Lung Physiology/Function, Lung Imaging and Survival, and Medications for each CTD-ILD and IPF. Eighteen instruments were identified for each CTD-ILD and IPF (tables 1⇓⇓–4).
Focus groups were conducted with patients (n=45) in IIM-ILD (n=11), RA-ILD (n=13), SSc-ILD (n=17) and other CTD diagnoses (n=4) (table 5). Patient participants attributed importance to cough, dyspnoea, fatigue, participation (in family, social and leisure activities, work within and outside the home), physical function, self-care and sleep in the questionnaire and the focus groups. Changes in cough were perceived as reflecting potential worsening ILD. Dyspnoea largely carried descriptors different from current instruments. Patients with IPF identified cough, dyspnoea and HRQoL effects as central symptoms.14
OMERACT 11/ATS 2012/Domain Team meetings
Discussions and voting at the OMERACT 11/ATS 2012/Domain Team meetings resulted in the following changes based on the patient perspective data or strong evidence in recent literature (detailed in online supplement):
Cough was reintroduced, discussed and voted upon at the NGT.
To satisfy the reintroduction of Cough, Leicester Cough Monitor (LCM) was introduced as an interim instrument to assess Cough.
The Mahler Dyspnea Index (MDI) and University of California San Diego Shortness of Breath Questionnaire (UCSD-SBQ) were reintroduced under Dyspnoea for use in CTD-ILD and IPF, respectively, based on substantive findings in an updated literature review.
For feasibility, HRQoL would capture ‘fatigue’, ‘participation’, ‘physical function’, ‘self-care’ and ‘sleep’ until disease-specific investigations into these components were conducted.
NGT voting would include whether development of new instruments for Dyspnoea, Cough and HRQoL are needed.
Owing to variability of therapies, concern regarding Medications as a core domain was expressed. However, being identified as important in the Delphi, a statement of clarification would be constructed at the NGT.
‘All-Cause Mortality’ was introduced as an assessment of ‘Survival’.
Table 6 displays the voting results on instruments for CTD-ILD and IPF with striking concurrence in all domains except for HRQoL, for which Patient Global Assessment (PtGA) was not accepted by the pulmonary experts for IPF.
It was agreed that ‘Medications’ (ie, the incremental increase/decrease of glucocorticoid and/or immunosuppressive therapy) should be viewed as protocol specific rather than a core domain. Depending on study design, ‘Medications’ may be either a dichotomous interpretation of treatment efficacy/failure or a reflection of changes in disease activity.
The lack of validated biomarkers was fully discussed. No items for bio-specimen evaluation emerged from the Delphi exercise but the importance of future biomarker research was planned for during the meeting. Consensus is required to define the minimal standards for investigation-related bio-banking and systematic access to samples by investigators.17
These comprehensive international investigations are the first to identify core sets of domains in each CTD-ILD and IPF along with a provisional consensus on a minimum cadre of feasible and clinically meaningful outcome measures/instruments. The proposed measures are intended to be a common denominator across future RCTs, longitudinal observational studies and natural history registries until work can be done that substantiates a truly durable framework. The rigorous consensus methodologies of OMERACT outline the overall status of the field. Importantly, this is the first study in ILD to incorporate patient participants in panel meetings or guidelines. From the synergy of these investigations, domains which require development of new instruments were also identified, thus providing guidance for imminent research.
Based on the current data, FVC (100% acceptance) was the measure that the group favoured most for each CTD-ILD and IPF. Again, we emphasise that the overarching construct of this exercise was limited to that of a hypothetical RCT of 1-year duration. FVC has been shown to be a consistently reliable serial variable in IPF. Declines in FVC correlate with increased risk of subsequent mortality,4 ,7 ,8 ,18–22 although no data exist demonstrating that improvement in FVC correlates with improved survival. Thus, utilising FVC as an endpoint requires consideration of the clinically meaningful magnitude of change independent of potential impact on mortality. This is particularly relevant in studies of short duration.
While changes in FVC have been shown to be reproducible in SSc-ILD, there are insufficient RCT-derived data to evaluate this in other forms of CTD-ILDs.3–5 ,20 There are confounding issues of vasculopathy, pulmonary hypertension, cardiac involvement, chest wall impairment and systemic disease activity that are often coexistent in CTD-ILDs. Nonetheless, FVC may most reliably and sensitively reflect the contribution of parenchymal disease above other endpoints.
Though a relative change from baseline predicted is preferred to absolute change from normal values, these changes are recognised as non-parametric in FVC. Thus a discrete clinically relevant threshold of minimal change was not able to be agreed upon in either IPF or CTD-ILD. Further, efforts to validate serial variables are challenged by variations in the rate of disease progression, with interval changes of FVC20 ,22 more likely to represent a true change in rapidly progressive disease than in less progressive disease that crosses the same threshold. Extrapolation between two value points will provide less reliable information than continuous variables; therefore, identification of a minimal clinically important difference (MCID) would be misleading without accommodating for these non-parametric changes. Panel discussions surrounding Diffusion Capacity of Lung for Carbon Monoxide (DLCO) reflected the multiple confounders for this instrument, with ranking of FVC as being the favoured marker above DLCO. A threshold of clinically meaningful change was not determined for DLCO.
Neither the 6MWT nor measures of oxygen desaturation survived the NGT process; although deemed feasible they were considered weak in discrimination in addition to construct and criterion validity. The need for supplemental oxygen was not accepted; changes in oxygenation, as judged partly by oxygen desaturation, are difficult to interpret since they do not correlate well with the sensation of dyspnoea or changes in disease progression in mild to moderate disease.19 ,23
The importance of patient-reported dyspnoea for assessing prognosis and disease progression are well recognised.1 ,7 ,8 We identified the Dyspnea 1224 and the Medical Research Council Dyspnea Scale18 ,19 as the best currently available instruments in CTD-ILD and in IPF, yet data are essentially lacking in CTD-ILD. Though the MDI has some demonstrated validity in SSc-ILD20, NGT panelists allocated this interviewer-administered instrument to the research agenda for CTD-ILD, voicing concerns of poor feasibility and uncertain reliability. The UCSD-SBQ was accepted for use in studying IPF.21 It was agreed that development of new Dyspnoea instruments is warranted to specifically reflect the restrictive lung processes of CTD-ILD and IPF.
The Short Form 36 (SF-36) was recognised as a generic HRQoL instrument as anxiety, fatigue, participation, physical function, self-care and sleep are important to patients.25 The St George's Respiratory Questionnaire, although endorsed, lacked specificity in CTD-ILD and IPF.26 ,27 It was agreed that a new disease-specific instrument should be developed.
PtGA, previously validated across rheumatic and non-rheumatic diseases, correlates with dyspnoea in CTD-ILD28 ,29 and was accepted as a measure in CTD-ILD with improvements greater than 10 mm agreed upon as an MCID. PtGA not being validated in IPF was allocated to the research agenda in IPF. PtGA may also serve as an ‘anchor’ to determine MCIDs for recently developed PROMs, such as the King's Brief ILD Health Assessment Questionnaire (K-BILD).30
The extent of ground-glass opacities, honeycombing and/or reticulations on high-resolution CT (HRCT) scan each merited careful consideration as outcome measures. However, taken separately each was felt to incompletely capture disease progression in either CTD-ILD or IPF. The overall extent of ILD on HRCT was accepted to provisionally describe the most appropriate and feasible composite of radiological abnormalities to monitor for disease progression.31 ,32 No specific assessment tool at this time was able to be confidently identified as it is not yet clear whether subjective or automated objective assessment is the more accurate approach. Though serial HRCT raises concern for patient safety, validation studies of less radio-intense methods of HRCT serial assessment33 are underway.
Progression-free survival in IPF was agreed to have merit,34 however the group was undecided as to the practicality of this endpoint in the context of a trial limited to 1 year's duration. Mortality was minimal or absent in two recent RCTs of SSc-ILD.35 ,36 There are cogent arguments for and against survival as the primary outcome in studies of IPF.34 ,37 Regardless of this unresolved debate, mortality was recognised as an essential endpoint in all treatment trials as it provides a harm signal,34 ,37 with all-cause mortality identified as a valid measure of survival in CTD-ILD and IPF. The utility of other measures of progression-free survival in RCTs requires further investigation of candidate instruments before recommending their use in RCTs.
While the domain of Cough did not survive the Delphi process, it was important to patient participants. Additionally, there is a correlation between cough and IPF progression38 and with ILD severity in SSc.39 In SSc-ILD, cough adversely impacted HRQoL and improved with treatment.39 The LCM was selected as an interim measure as it was deemed more able to capture frequency, quality and intensity, and impact on HRQoL. It was also most feasible to administer.40
Primary and secondary endpoint status of the proposed measures were considered, intensely discussed and even voted upon during the NGT. However, at this preliminary stage and given the lack of full validation of the core measures, the consensus was to pursue further data. A more careful approach to endpoint status declarations entails ad hoc and prospective performance analyses of these measures.
Though we recommend these proposed measures for all future research ventures, continued use of measures outside this core set, for clinical practice and research purposes, is fully expected with further research into their performance anticipated and necessary. Rather, this endeavour defines the currently available, best validated and feasible instruments while providing a much needed prioritised research agenda focus to the research community.
This project applied rigorous multi-investigational processes that captured the perspectives of the international ILD expert community and the life experience of patients with ILD to identify a set of domains and measures. Participation remained robust through all tiers of the consensus process.
The importance of patient participation is supported by the incorporation of HRQoL, Participation and Fatigue in the RA core set for RCTs. From a practical perspective, qualitative data collection involved only English-speaking patients from North America, and results may be affected by cultural, environmental and resource-related effects requiring further investigations to follow up our reported findings. Nevertheless, the engagement of patients as partners in the iterative process was important in identifying and re-capturing areas of potentially meaningful measures of disease activity.
It is critical that valid and clinically useful instruments be developed and validated to assess the likelihood of treatment response in these disorders. Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field. However, none of the provisional endpoints were ultimately felt to be either ideal or fully validated. Feasible endpoints like FVC are not perfect; more rigorous endpoints like mortality, particularly in the setting of CTD-ILD, lack feasibility. Thus, selecting the best non-ideal endpoints from a larger group of non-ideal endpoints still leaves us with much work which includes further validation of existing and development of new instruments.
Acknowledgements of thanks for essential and gracious assistance: Kourtnie Augustin, Louisiana State University Health Sciences Center – New Orleans, USA; Reed Barrios, Patient Expert, New Orleans, USA; Bennett deBoisblanc, Louisiana State University Health Sciences Center – New Orleans, USA; Kerri Connolly, Scleroderma Foundation, Danvers, MA, USA; Luis R Espinoza, Louisiana State University Health Sciences Center – New Orleans, USA; Daniel E and Elaine Furst, University of California – Los Angeles, CA, USA; Robert Hedlund, Patient Expert, Virginia, USA; Matthew R Lammi, Louisiana State University Health Sciences Center – New Orleans, USA; Steve Nathan, Innova, Fairfax, Virginia, USA; Karen Nichols, Patient Expert, Virginia, USA; Frank Smart, Louisiana State University Health Sciences Center – New Orleans; Virginia Steen, Georgetown University, Washington DC, USA; Valorie Thompson, DINORA; Pieter van den Assum, Patient Expert, Virginia, USA. Ms LeSage and Ms Sarver are co-investigators and have contributed their expertise as patients to key decision-making in the design, implementation as well as analysis and interpretation of data and thus listed as authors. Research assistance with analysis and coding of patient perspective manuscripts provided by: Sophia L Cenac and Harmanjot K Grewal from LSU – New Orleans, USA; Angela M Christensen and Sancia Ferguson from Tulane University and Maithy Tran from University of Toronto.
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Files in this Data Supplement:
- Data supplement 1 - Online supplement
Contributors LAS: PI, methodologist and project leader of all three components, author of manuscript. SM: Co-PI of patient perspective, NGT panel member (content, data collection, analysis), manuscript reviewer (MR). DH: Steering Committee for Delphi, Joint Analysis Decision, Interpretation of Delphi Data (SC1), methodologist, designer of Delphi database, statistician to all three components, MR. DK: SC1, NGT panel member, MR. PFD: SC1, NGT panel member, MR. OD: SC1, NGT panel member, methodology, MR. KRF: SC1, NGT panel member, MR. SF: Steering Committee for Patient Perspective, Qualitative analyses, Coding, Interpretation (SC2), methodology, analysis, MR. CVO: SC1, NGT panel member, MR. CPD: SC1, NGT panel member, MR. AF: SC2, NGT panel member, MR. OMK-B: SC1, database design, NGT panel member, MR. DL: SC2, patient research partner (assist with design, analysis, interpretation), analysis, NGT panel member, MR. PAM: SC1, NGT panel member, MR. KP: SC1, MR. DP: SC1, database construction, MR. JS: SC2, NGT panel member, MR. KA: NGT panel member, MR. RPB: NGT panel member, MR. FVC: SC2, patient data collection, analysis. RBC: literature review, database content collection and assembly, MR. LC-S: SC2, patient data collection, analysis, MR. HRC: content, analysis, interpretation, MR. VC: content, analysis, interpretation, MR. SD: SC2, patient data collection, analysis, MR. KBH: NGT panel member, MR. LH: SC2, patient data collection, analysis, MR. AAS: SC2, patient data collection, analysis, MR. DSK: NGT panel member, MR. DAL: NGT panel member, MR. FWM: NGT panel member, MR. SMP: NGT panel member, MR. LR: NGT panel member, MR. JHR: NGT panel member, MR. NS: literature review, database content collection and assembly, MR. CS: SC2, patient research partner, analysis NGT panel member, MR. AUW: SC1, NGT panel member, MR. VS: SC1, NGT panel member, MR. ELM: SC1, NGT panel member, MR. KKB: SC1, NGT panel member, MR. JRS: SC1, NGT panel member, MR.
Collaborators Delphi Co-Authors: *indicates Disease Committee Member. Rohit Aggarwal*, University of Pittsburgh School of Medicine, USA; Gillian Ainslie, University of Cape Town & Groote Schuur Hospital, South Africa; Firas Alkassab, University of North Carolina-Chapel Hill, Charlotte, USA; Yannick Allanore*, Université Paris Descartes, France; Marina E Anderson, University of Liverpool, UK; Andrew P Andonopoulos, University of Patras School of Medicine, Greece; Danielle Antin-Ozerkis, Yale University School of Medicine, USA; Ana Arrobas, Centro Hospitalar de Coimbra, Portugal; Dana P Ascherman*, University of Miami Miller School of Medicine, USA; Shervin Assassi, University of Texas Health Science Center at Houston, USA; Murray Baron, Jewish General Hospital, McGill University, USA; Joan M Bathon*, Columbia University College of Physicians & Surgeons, USA; Juergen Behr, Ludwig-Maximilians University, Munich, Germany; Lorenzo Beretta, Referral Center for Systemic Autoimmune Diseases-Milan, Italy; Clifton O Bingham III, Johns Hopkins University, USA; Matthew Binnie, St. Michael's Hospital, Toronto, Canada; Surinder S Birring, King's College Hospital, UK; Francesco Boin, Johns Hopkins University; USA; Tim Bongartz*, Mayo Clinic College of Medicine, USA; Arnaud Bourdin, Département de Pneumologie et Addictologie INSERM U1046 - Université Montpellier; Demosthenes Bouros, Democritus University of Thrace, Greece; Richard Brasington, Washington University, St Louis, USA; Paul Bresser, Onze Lieve Vrouwe Gasthuis, Netherlands; Maya H Buch, University of Leeds, UK; P Sherwood Burge, Birmingham Hearlands Hospital, UK; Loreto Carmona, Universidad Camilo José Cela and Institute for Musculoskeletal Health, Spain; Patricia E Carreira, Hospital Universitario, Spain; Carlos RR Carvalho, University of Sao Paulo Medical School, Brasil; Luis J Catoggio, Hospital Italiano de Buenos Aires, Argentina; Kevin M Chan, University of Michigan Health Systems, USA; Jeffrey Chapman, Cleveland Clinic, USA; Soumya Chatterjee, Cleveland Clinic, USA; Felix Chua*, St. George's Hospital NHS Trust, UK; Lorinda Chung, Stanford University School of Medicine, USA; Matthew Conron, St Vincent's Hospital, Australia; Tamera Corte, University of Sidney, Australia; Gregory Cosgrove, National Jewish Health, USA; Ulrich Costabel, University of Duisburg-Essen, Germany; Gerard Cox, McMaster University, Canada; Bruno Crestani, Centre de Compétences Maladies Rares Pulmonaires, Paris, France; Leslie J Crofford, University of Kentucky College of Medicine, USA; Mary E Csuka, Medical College of Wisconsin, USA; Pablo Curbelo, Universidad de la República, Montevideo, Uruguay; László Czirják, University of Pécs, Hungary; Zoe Daniil, University of Thessaly, Larissa, Greece; Christine L D'Arsigny, Queen's University, Canada; Gerald S Davis, College of Medicine University of Vermont, USA; Joao A de Andrade, University of Alabama at Birmingham, USA; Paul De Vuyst, Hopital Erasme, Université Libre de Bruxelles, Belgium; Owen J Dempsey, Aberdeen Royal Infirmary Foresterhill, Scotland, UK; Chris T Derk, University of Pennsylvania, USA; Jörg Distler, University of Erlangen-Nuremberg, Germany; William G Dixon*, University of Manchester, UK; Gregory Downey, National Jewish Health, USA; Mittie K Doyle, Alexion Pharmaceuticals Inc, Cambridge, USA; Marjolein Drent, Maastricht University, Maastricht, Netherlands; Lakshmi Durairaj, Carver College of Medicine, University of Iowa, USA; Paul Emery, University of Leeds, UK; Luis R Espinoza, Louisiana State University Health Sciences Center, New Orleans, USA; Dominique Farge, St. Louis Hospital, Paris, France; Maryam Fathi, Karolinska Institutet, Sweden; Charlene D Fell, University of Calgary, Canada; Barri J Fessler, University of Alabama at Birmingham, USA; John E Fitzgerald, University of Texas Southwestern Medical Center, USA; Ivan Foeldvari, University of Hamburg, Germany; George A Fox, Memorial University of Newfoundland, Canada; Tracy M Frech, University of Utah, USA; Sara Freitas, Coimbra Hospital and University Center, Portugal; Daniel E Furst*, University of California Los Angeles, USA; Armando Gabrielli, Università Politecnica delle Marche, Ancona, Italy; Rosario García-Vicuña, Hospital Universitario de la Princesa. IISP; Ognian B Georgiev, University Hospital Alexandrovska, Sofia, Bulgaria; Anthony Gerbino, Virginia Mason Medical Center, USA; Adrian Gillisen, General Hospital Kassel, Germany; Dafna D Gladman, University of Toronto, Canada; Marilyn Glassberg, University of Miami Miller School of Medicine, USA; Bernadette R Gochuico, National Human Genome Research Institute, National Institutes of Health, USA; Athena Gogali, University Hospital of Ioannina, Greece; Nicole S Goh*, Alfred Hospitals, Melbourne, Australia; Avram Goldberg, Hofstra North Shore LIJ School of Medicine, USA; Hilary J Goldberg, Brigham and Women's Hospital, Harvard Medical School, USA; Mark F Gourley*, National Institutes of Health, USA; Leroy Griffing, Mayo Clinic College of Medicine, USA; Jan C Grutters, University Medical Center Utrecht, Netherlands; Ragnar Gunnarsson, Oslo University Hospital, Norway; Eric Hachulla, Claude Huriez Hospital, University of Lille, France; Frances C Hall, University of Cambridge, UK; Sergio Harari, U.O. di Pneumologia Ospedale San Giuseppe MultiMedica, Milan, Italy; Ariane L Herrick, University of Manchester, UK; Erica L Herzog, Yale University School of Medicine, USA; Roger Hesselstrand, Lund University, Sweden; Nikhil Hirani, University of Edinburgh, UK; Ulla Hodgson, Helsinki University Hospital, Finland; Helen M Hollingsworth, Pulmonary Center, Boston University School of Medicine, USA; Robert J Homer, Yale University School of Medicine Department of Pathology, USA; Rachel K Hoyles, Oxford Centre for Respiratory Medicine, UK; Vivien M Hsu, University of Medicine and Dentistry of New Jersey, USA; Richard B Hubbard, University of Nottingham, UK; Nicolas Hunzelmann, Deptartment of Dermatology, University of Cologne, Germany; Maria Eloisa Isasi, Hospital Maciel. Montevideo. Uruguay; Elida Susana Isasi, Hospital Maciel. Montevideo. Uruguay; Soren Jacobsen, Rigshospitalet, Copenhagen University Hospital, Denmark; Sergio A Jimenez, Jefferson University, USA; Sindhu R Johnson, University of Toronto, Toronto, Canada; Christine H Jones, University of Vermont College of Medicine, Fletcher Allen Health Care, USA; Bashar Kahaleh, University of Toledo Medical Center, USA; Ronaldo A Kairalla, Heart Institute (InCor), University of São Paulo Medical School, Brazil; Meena Kalluri, University of Alberta, Canada; Sanjay Kalra, Mayo Clinic, USA; Robert J Kaner, Cornell University School of Medicine, USA; Brent W Kinder, University of Cincinnati College of Medicine; USA Goksel Kiter (Kiter G), Pamukkale University, Turkey; Ross C Klingsberg, Tulane University School of Medicine, USA; Maria Kokosi, Sismanoglio General Hospital; Martin RJ Kolb, Mcmaster University, Canada; Joanna Kur-Zalewska, Military Institute of Medicine, Warsaw, Poland; Masataka Kuwana*, Keio University School of Medicine, Japan; Fiona R Lake, University of Western Australia; Edward V Lally, Brown University, USA; Joseph A Lasky, Tulane University School of Medicine, USA; Ileda M Laurindo, University of Sao Paulo, Brasil; Lawrence Able, Sanjay Gandhi Postgraduate Institute of Medical Sciences, India; Peter Lee, University of Toronto, Canada; Colm T Leonard, University Hospital of South Manchester NHS Foundation Trust, UK; Dale C Lien, University of Alberta, Canada; Andrew H Limper, Mayo Clinic College of Medicine, USA; Stamatis-Nick C Liossis, University of Patras Medical School. Greece; Kristine M Lohr, University of Kentucky College of Medicine, USA; James E Loyd, Vanderbilt University, USA; Ingrid E Lundberg*, Karolinska Institutet, Sweden; Yolanda N Mageto, University of Vermont, USA; Toby M Maher, Royal Brompton Hospital, UK; Tafazzul H Mahmud, Shaikh Zayed Medical complex, Lahore, Pakistan; Helene Manganas, CHUM (Notre-Dame Hospital), Canada; Isabelle Marie, Rouen University, France; Theodore K Marras, University Health Network, Mount Sinai hospital and the University of Toronto; José Antônio Baddini Martinez, Faculdade de Medicina de Ribeirao Preto, Brasil; Fernando J Martinez, University of Michigan, USA; Alessandro Mathieu, Università degli Studi di Cagliari, Italy; Marco Matucci-Cerinic*, University of Florence, Italy; Maureen D Mayes*, University of Texas Health Science Center at Houston, USA; Kevin M McKown, University of Wisconsin School of Medicine and Public Health, USA; Thomas A Medsger, Jr., University of Pittsburgh School of Medicine, USA; Richard T Meehan, National Jewish Health, USA; Mendes Ana Cristina, Serviço de Pneumologia 1, CHLN- Hospital de Santa Maria; Keith C Meyer, University of Wisconsin School of Medicine and Public Health, USA; Ann B Millar, University of Bristol, UK; Nesrin Moğulkoç, Ege University, Izmir, Turkey; Jerry A Molitor, University of Minnesota, USA; António Morais, Pneumology Department, Centro Hospitalar São João; Portugal Luc Mouthon, Hôpital Cochin, Paris, France; Veronika Müller, Semmelweis University, Hungary; Joachim Müller-Quernheim, University of Freiburg, Germany; Oleg Nadashkevich, Lviv National Medical University, Ukraine; Roland Nador, University of Alberta, Canada; Peter Nash, University of Queensland, Australia; Steven D Nathan, Inova Fairfax Hospital, USA; Carmen Navarro, Instituto Nacional de Enfermedades Respiratorias, Mexico; Sofia Neves, Centro Hospitalar Vila Nova de Gaia/Espinho, Portugal; Imre Noth, University of Chicago, USA; Hilario Nunes, Avicenne Hospital, Paris, France; Amy L. Olson, National Jewish Health, USA; Christian F Opitz, DRK Kliniken Berlin-Köpenick, Berlin, Germany; Maria Padilla, Mount Sinai School of Medicine, New York, USA; Dimitrios Pappas, Columbia University College of Physicians & Surgeons, USA; Helen Parfrey, University of Cambridge and Papworth Hospital, UK; José M Pego-Reigosa, Meixoeiro Hospital, Spain; Carlos AC Pereira, Federal University of São Paulo, Brasil; Rafael Perez, University of Kentucky College of Medicine, USA; Janet E Pope*, Western University, Canada; Joanna C. Porter, University College London, UK; Elisabeth A Renzoni, Interstitial Lung Disease Unit, Royal Brompton Hospital, UK; Gabriela Riemekasten, Charité Universitätsmedizin Berlin, Germany; David J Riley, University of Medicine and Dentistry of New Jersey, USA; Maureen Rischmueller, The Queen Elizabeth Hospital and University of Adelaide, Australia; Tatiana S Rodriguez-Reyna, Instituto Nacional de Ciencias Médicas y Nutrición, Mexico; Rojas-Serrano, Instituto Nacional de Enfermedades Respiratorias, Mexico; Jesse Romam, University of Louisville Health Sciences Center, USA; Glenn D Rosen, Stanford University School of Medicine, USA; Milton Rossman, University of Pennsylvania, USA; Naomi Rothfield, University of Connecticut Health Center, USA; Steven A Sahn, Medical University of South Carolina, USA; Alessandro Sanduzzi, Università degli Studi di Napoli "Federico II", Italy; Mary Beth Scholand (Scholand MB for Medline, University of Utah, USA; Moises Selman, Instituto Nacional de Enfermedades Respiratorias, Mexico; Jean-Luc Senécal, University of Montreal, Canada; Philip Seo, Johns Hopkins University, USA; Richard M Silver*, Medical University of South Carolina, USA; Joshua J Solomon, National Jewish Health, USA; Virginia Steen*, Georgetown University, USA; Wendy Stevens, St. Vincent's Hospital, Melbourne, Australia; Charlie Strange, Medical University of South Carolina, USA; Robert Sussman, Pulmonary and Allergy Associates, Summit, NJ, USA; Evelyn D Sutton, Dalhousie University, Canada; Nadera J Sweiss, University of Illinois, Chicago, USA; Göran Tornling, Karolinska Institutet, Sweden; George E Tzelepis, University of Athens Medical School, Greece; Alvaro Undurraga, Thorax National Institute, Santiago, Chile; Allessandra Vacca, University and A.O.U. of Cagliari, Italy; Carlo Vancheri, University of Catania, Italy; Janos Varga, National Koranyi Institute of TB and Pulmonology, Hungary; Douglas J Veale, University College Dublin, Ireland; Suncica Volkov, University of Illinois, Chicago, USA; Ulrich A Walker, Basel University Deptartment of Rheumatology, Felix Platter-Spital, Switzerland; Mark Wencel, Via Christi Clinic, University of Kansas Medical Center – Wichita, USA; Lewis J Wesselius, Mayo Clinic Arizona, USA; Melissa Wickremasinghe, St. Mary's Hospital, London, UK; Pearce Wilcox, University of British Columbia, Canada; Margaret L Wilsher, Auckland District Health Board and University of Auckland, New Zealand; Frank A Wollheim, Lund University, Sweden; Wim A Wuyts, University Hospitals Leuven, Netherlands; Gordon Yung, University of California - San Diego, USA; Pietro Zanon, Ospedale di Circolo di Busto Arsizio, Italy; Christopher J Zappala, Royal Brisbane & Women's Hospital, Brisbane QLD Australia Pathology Advisory Team Steve D Groshong, National Jewish Health, USA; Kevin O Leslie, Mayo Clinic College of Medicine, USA; Jeffrey L Myers, University of Michigan, USA; Robert F Padera, Brigham and Women's Hospital, USA Radiology Advisory Team Sujal R Desai, King's College Hospital, London, UK; Jonathan Goldin, David Geffen School of Medicine, UCLA, USA; Ella A Kazerooni, University of Michigan, Ann Arbor, USA; Jeffrey S Klein, Fletcher Allen Health Care, University of Vermont, USA; David A Lynch, National Jewish Health, Denver, USA Additional Statistical Support Kevin J Keen, University of Northern British Columbia, Prince George, Canada
Funding Non-profit support: These studies were supported in part by the intramural division of the National Institute of Environmental Health Sciences, National Institutes of Health; and the following non-profit organisations: Brigham and Women's Hospital, Charité Hospital—Berlin, German Rheumatism Research Centre, Ira J Fine Discovery Fund, Jonathan and Lisa Rye Scleroderma Research Foundation, Louisiana State University Health Sciences Center—New Orleans, Mayo Clinic—Rochester, National Jewish Hospital Denver, Louisiana State Office of Public Health—New Orleans, OMERACT (Outcome Measures in Rheumatology), Scleroderma Foundation, Sibley Hospital Foundation, and Sonia Roth AARC Foundation. Commercial Interest Support: Abbott Laboratories Canada, Actelion, Boehringer–Ingelheim Pharmaceuticals, Celgene, Intermune, Sigma Tau, UCB and United Therapeutics.
Competing interests None.
Ethics approval Louisiana State University School of Medicine Institutional Review Board for all components. Patient perspective studies also included approval from Johns Hopkins University, Massachussets General Hospital, University of Manitoba and University of Toronto.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement We have made all data visible in the online supplement.
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