Reconciling Healthcare Professional and Patient Perspectives in the Development of Disease Activity and Response Criteria in Connective Tissue Disease Related Interstitial Lung Diseases

Abstract

Interstitial lung diseases (ILD), including connective tissue disease (CTD) related and idiopathic pulmonary fibrosis (IPF), carry a high morbidity and mortality. Great efforts are underway to develop and investigate meaningful treatments in the context of clinical trials. However, these efforts have been challenged by the lack of validated outcome measures and inconsistent use of measures in the context of clinical trials. This lack of consensus has fragmented effective use of investigative in CTD-ILD and IPF with a history of resultant difficulties in agency approval of treatment interventions.

Patient perspective in determination of domains and outcome measures in CTD-ILD and IPF, prior to this effort, has never occurred. These efforts demonstrate unequivocally the value and impact of patient involvement on core set development. Regarding CTD-ILD, this is the first OMERACT working group to directly address a manifestation/co-morbidity of a rheumatic disease (ILD) as well as a disease not considered rheumatic (IPF). The OMERACT 11 proceedings of the CTD-ILD Working Group describe the forward and lateral process to include both the medical and patient perspectives in the urgently needed identification of a core set of preliminary domains and outcome measures in CTD-ILD and IPF.

Background

The Connective Tissue Disease Interstitial Lung Disease (CTD ILD) Working Group convened as a special interest group (SIG) during the OMERACT 11 conference to examine concurrence of results between the DELPHI among health care professionals and focus group sessions with patient participants. The SIG included, in addition to OMERACT participants, 2 patient research partners with ILD (DL, CS), the principal investigator (LAS), the director of the patient expert investigation (SM), a director of the medical expert investigation (ELM) and the representative from the OMERACT executive (VS).

The CTD ILD Working Group of OMERACT is an international multidisciplinary effort to develop consensus on criteria to measure disease activity and therapeutic response in CTD-ILD. The group first met in November 2008 to address outcomes measures in CTD-ILD by developing a multi-tiered Delphi process to obtain opinions from a broad array of expert pulmonologists, rheumatologists, and cardiologists and a patient perspective strategy.

Interstitial lung disease (ILD) one of the leading causes of mortality related to underlying CTD pulmonary disease in systemic sclerosis (SSc)^1,2 and is a major cause of morbidity and mortality in connective tissue diseases (CTD) such as rheumatoid arthritis (RA), idiopathic inflammatory myopathy (IIM), and Sjogren’s syndrome. Recent studies suggest that while mortality rates associated with some CTDs have declined, mortality rates associated with CTD-associated pulmonary disease is increased^3,4.

Many complexities of CTD ILD exist, however presently there is no consensus on measures to use for assessment of disease activity or treatment response in CTD-ILD. Drug development and assessment of treatment efficacy has been diminished by a relative paucity of data on validated outcome measures in CTDs.

Traditional measures of disease activity in ILD are easily confounded by extra-pulmonary manifestations of underlying CTD, and though instruments are imperfect even in a disease like IPF whose characteristics are limited to the lung, the group embarked on simultaneously addressing IPF in comparison to CTD ILD simultaneously provide opinions on outcome measures for both disease groups. The CTD-ILD SIG is the first working group to take an interest in a co-morbid manifestation of a rheumatic disease.

During OMERACT 11, the CTD-ILD SIG presented results to date and engaged participants (providers and patients) of the meeting in further discussions regarding this progress.

Summarized here is development of the studies conducted to develop response criteria, domains identified, and progress leading up to the OMERACT 11.

Medical Expert Consensus

A group of rheumatology, pulmonary, cardiology, radiology and pathology specialists with expertise in idiopathic pulmonary fibrosis (IPF) and/or connective tissue disease-interstitial lung disease (CTD-ILD) and statisticians advised in construction of and participated in a structured 3-tiered internet based Delphi process to develop consensus on outcome measures reflective of disease activity and therapeutic responsiveness.

The Health Care Professionals (HCP) Delphi was designed to identify domains and instruments perceived as important outcomes in the context of a one year multicenter randomized controlled trial (RCT) of a promising treatment for IPF and/or CTD-ILD. This consensus process included 254 medical experts (physicians with research and clinical expertise in ILD) from 36 countries and 6 continents. In an effort to representatively reflect the views maintain the true voice of the expert community, the process was initiated with an unrestricted collection of domains and instruments suggested by the HCPs. This method of data collection created the voting survey. Throughout the consensus process, the Delphi addressed both CTD-ILD and IPF in parallel tracts, to identify commonalities and differences among outcome measures between these two entities.

The Delphi employed a web-based data collection system that featured links to original publications and subsequent articles addressing validation of all instruments that were identified by a comprehensive Medline literature review. An ‘Inter-Expert Educational Component’ allowed participants to upload commentary, articles and links for review as well as to challenge or defend inclusion of a domain or instrument.

Using cluster analyses, the 3 part Delphi resulted in selection of 5 domains each for IPF and CTD-ILD that were further supported by high mean and median ratings (Table 1). Surviving instruments, also analyzed by cluster analysis, are shown in Table 2, with supporting high median and mean scores.

Table 1. Results of Delphi Tier 3 Analysis of Domains.

Results of the cluster analysis of the 3 tiered Health Care Professional Delphi process. Five domains each were identified for IPF and CTD-ILD.

The Five Common Domains of CTD-ILD and IPF
DOMAINS NAME	CTD-ILD (median/mean)	IPF (median/mean)
	ratings on a 9 point Scale
Dyspnea	(8.0/7.8)	(8.0/8.1)
Health Related Quality of Life	(8.0/7.7)	(8.0/7.8)
Lung Imaging	(9.0/8.3)	(9.0/8.3)
Lung Physiology / Function	(9.0/8.7)	(9.0/8.7)
Survival	(8.0/8.2)	(9.0/8.4)

Table 2.

Cluster analysis yielded the above instruments under corresponding domains with median/mean scores reported. [--] signifies this was no longer considered relevant to that disease.

DOMAIN	INSTRUMENTS	CTD ILD Median / mean	IPF Median /mean
Dyspnea	Borg Dyspnea Index	7.0 / 6.9	7.0/7.0
	Dyspnea 12	[7.0 / 6.6]	7.0 / 6.7
	Medical Research Council (MRC) Breathlessness (Chronic Dyspnea) Scale or the Modified MRC Dyspnea Scale	7.0 / 7.0	7.0 / 7.1
	Borg Dyspnea Index - Pre and Post Exercise	7.0 / 7.0	[7.0 / 7.1]
Health Related Quality of Life (HRQoL)	Medical Outcomes Survey Short Form -36 Questionnaire (SF-36)	7.0 / 7.3	7.0 / 7.3
	St. George’s Dyspnea Respiratory Questionnaire	[7.0 /6.6]	7.0 / 6.8
	Visual Analogue Scale of Patient Assessment of Disease Activity	7.0 / 6.8	7.0 / 6.7
	Ability to Carry Out Activities of Daily Living (ADLs)	7.0 / 6.8	Lost Tier1
	Health Assessment Questionnaire Disability Index (HAQ-DI)	7.0 / 7.0	Lost Tier 1
Lung Imaging	Extent of Honeycombing on HRCT	7.0 / 7.1	8.0 / 7.4
	Extent of Reticulation on HRCT	[7.0 / 6.9]	7.0 / 6.9
	Extent of Ground Glass Opacities on HRCT	7.0 / 7.2	[7.0 / 6.7]
	Overall Extent of Interstitial Lung Disease on HRCT	8.0 / 7.7	8.0 / 7.7
Lung Physiology / Function	Supplemental Oxygen Requirement	7.0 / 7.3	8.0 / 7.5
	Forced Vital Capacity on Spirometry	8.0 / 8.3	9.0 / 8.3
	Diffusion Capacity of Lung for Carbon Dioxide	8.0 / 7.9	8.0 / 7.9
	6 MWT with Maximal Desaturation on Pulse Oximetry	7.0 / 6.8	7.0 / 7.0
	6 MWT for Distance	[7.0 / 6.5]	7.0 / 7.0
Survival	Time to Decline in Forced Vital Capacity	7.0 / 7.3	7.0 / 7.0
	Progression Free Survival	8.0 / 8.2	8.0 / 8.3
	Time to Death	7.0 / 7.1	8.0 / 7.3

In addition surviving instruments of “increasing or decreasing steroids and/or immunosuppressive medications” survived as a marker of disease activity in the ‘Medications’ domain. Please see discussion under ‘Proceedings’.

Patient Perspective Investigation

The patient-centered investigation was planned with the following objectives: to collect information relevant to the patient experience to determine domains important to patients in assessing disease activity and its impact, provide their perspective on currently utilized instruments in IPF/CTD-ILD, to recognize aspects of these diseases relevant to patients potentially not considered by investigators. This strategy was intended to learn about the disease based on the priorities, central experiences and subtle day-to-day challenges faced by patients that investigators rarely witness.

The investigative team included 3 rheumatologists with expertise in CTD-ILD, a pulmonologist, a patient research partner and a senior qualitative researcher. All members engaged in study design, implementation, analysis and interpretation of the results. No preconceived themes or codification were imposed upon the data collected for deductive analysis. Rather, the team adopted an inductive methodology to preserve views expressed by the patients within their own frames of reference, whereby data collected through focus group interviews underwent iterative analyses from which a codification system emerged. Each transcript from each focus groups was individually analyzed by 5 or more independent evaluators – one of whom was a patient research partner - with subsequent comparative analysis across transcripts. Throughout the process, the patient-research partner provided expert guidance in interpretation and theme development, and prioritization of themes.

Focus groups were followed by a questionnaire requesting patient partners to rate and prioritize the importance of a series of domains presented in lay terminology. The question was asked “On a scale from 1 to 7, how much do you care about the following item as it relates to your lungs?” Some examples included: ‘how much you cough?’ and ‘how good the results of your chest x-ray or CT scan are?’

At the time of OMERACT 11, data from 6 focus groups including 45 English-speaking participants were available. Two groups included patients with various underlying CTDs: one with rheumatoid arthritis and ILD, one with idiopathic inflammatory myositis (IIM) and ILD and 2 with systemic sclerosis (SSc) and ILD. Moderation of focus groups necessitated a knowledge of ILD, with both script and moderation guiding discussion of lung disease as a primary topic or a comparateur topic to the underlying disease. From these groups a preliminary set of congruent themes and issues important to inform synthesis with the HCP Delphi process for identifying domains and outcome measures emerged:

• Cough, originally lost in HCP Delphi process, was found to:

  • ◦
    Be central to the experience of patients with ILD
  • ◦
    Adversely impact physical functional, sleep and social aspects of HRQoL
  • ◦
    Be well articulated by patients who could:

    • ▪
      Describe its quality and distinguish between types of cough
    • ▪
      Recognize various triggers of cough
    • ▪
      Identify changes in cough relevant to breathing and presumably reflecting changes in the underlying lung disease

Dyspnea, a central experience to patients, and although it had survived the HCP Delphi process, revealed important areas of discordance with concepts of “difficulty in breathing”, that:

• It rarely referred to the act of breathing itself

• Descriptors such as ‘shortness of breath’ were rarely used to describe difficulty in breathing; rather descriptors such as “winded”, ‘wind cut’, trouble “getting a deep breath in”, “can’t catch a breath”, “losing your breath” were used

• It was described in the context of the ability to carry out a central life activity, such as

  • ◦
    Not being able to finish reading or singing a song to children/grandchildren
  • ◦
    Not being able to accomplish activities of daily living, care for others and surroundings
  • ◦
    Length of recovery time between tasks.
• The limitations arising from dyspnea generate:

  • ◦
    Feelings of frustration, shame, anger, and isolation
  • ◦
    Disturbances in sleep
  • ◦
    Loss of connectedness/participation in family, employment, social and pleasurable activities

The impact on distinct components of HRQoL were described such as mental health, fatigue, sleep, participation etc. Such distinction had not been identified in the HCP Delphi process. Cough, dyspnea and HRQoL have been identified as important health areas idiopathic pulmonary fibrosis⁶.

In summary, ‘cough’ was clearly important to patients, although it did not survive as a domain in the HCP Delphi process. ‘Dyspnea’, although included as a domain, revealed important areas of discordance between the language and concepts reflected in current instruments and those expressed by patients. Discrete areas of HRQoL were identified as important to patients. Additionally, patient participants identified previously unanticipated and important insights regarding the impact of these diseases: living with uncertainty, challenges in physician communication, struggle over new self, coping strategies and self-efficacy.

OMERACT 11 Proceedings (Table 3)

Table 3.

Domains Ratified During OMERACT 11 Proceedings - Forging Consensus Between Distinct Stakeholders with Special Considerations

Domains from Combined Investigations	Special Considerations
DYSPNEA	Unexpected language and contextual factors Consider need for disease-specifics instrument development
COUGH	Pervasive impact on Dyspnea and HRQoL Core Set inclusion received 100% endorsement Consider need for disease-specific instrument development
HEALTH RELATED QUALITY of LIFE (also captures patient global assessment)	Consider need for disease-specific instrument development HRQoL is impacted by uncertainty surrounding disease outcome HRQoL may be impacted by physician-patient communication
LUNG PHYSIOLOGY/FUNCTION	Patients and physicians care about this domain Patients are anxious about performance-related results (re: poor result of spirometry because of ‘effort’ or a ‘bad day’)
LUNG IMAGING	Patients and physicians care about this domain
SURVIVAL	Patients and physicians care about this domain Patients want to communicate about prognosis and handling episodic exacerbations
MEDICATIONS	Important to both stakeholder groups Incremental increase/decrease may be useful as a disease activity marker but depends on targeted therapy

At the CTD-ILD SIG at OMERACT 11 data from both the HCP Delphi and patient focus groups were presented to attendees. The main objectives of the meeting were to examine crucial issues arising from the preliminary comparative synthesis of data from both investigations. In addition, an in-depth analysis of data relating to psychosocial concepts that fell outside the primary goal of developing outcome measures in RCTs was discussed by Drs. Frankel and Mittoo. Ms. LeSage and Ms. Sarver provided poignant summaries regarding the impact of their disease, issues pertaining to healthcare delivery for the patient with ILD, utilization of instruments as well as unique interpretations of the data. This offered unanticipated and significant enhancements to the clinical knowledge of most of the attendees. Dr. Frankel presented results of the patient focus group analyses with interpretations based on careful reconstruction of patient-guided themes - this was expanded upon and corroborated by Ms. LeSage and Ms. Sarver. These presentations promoted understanding of patient response to the Delphi results as well as keen demonstration of lateralization of priorities between the two stakeholder groups and thus an interim consensus.

Results of the patient perspective investigation revealed ‘Cough’ to be central to the patient experience, although it did not survive the HCP Delphi process. Patients were able to articulate subtleties indicating that ‘Cough’ in ILD is associated with distinct qualities not captured in currently available instruments, especially as current instruments of cough were not developed with patient participation nor specifically for patients with ILD. It was hypothesized by the group that ‘Cough’ may have been lost in the medical expert Delphi due to lack of an appropriate instrument. In view of these points, the following received 100% acceptance upon voting:

• ▪Any domain important to either HCP or patient participants should be considered for inclusion in the core sets for CTD-ILD and IPF.
• ▪‘Cough’ should be included in the core sets for CTD-ILD and for IPF.
• ▪Although appropriate instruments may be used in the interim, new instruments should be developed for “Cough” specific for CTD ILD and/or IPF with patient participation.

‘Dyspnea’ was deemed important in both investigations; although there was important discordance between HCP and patient perspectives. In view of these points, the following received 100% acceptance upon voting:

• ▪Although appropriate instruments may be used in the interim, new instruments should be developed for “dyspnea” specific for CTD ILD and/or IPF with patient participation.

Although HRQoL was collapsed into a single domain during the HCP Delphi process, patient participants identified clearly defined importance of each of the discrete components of HRQoL. After discussion, the following was supported by an 82% vote for acceptance:

• ▪Recognition of discrete components of HRQoL is essential, however until these components can be supported by validated instruments for CTD-ILD and/or IPF; interim instruments designed to measure generic and disease-specific HRQoL may be utilized.

Strong support in the HCP Delphi for results led to the proposal that strategies in the handling of adjuvant immunosuppressant agents be decided depending on the targeted therapy. It was acknowledged that in the present state of uncertainty about the benefits of the medication and management of ILD; this is a complex concept. However, after discussion the following was supported by an 82% vote for acceptance:

• ▪Both strategies: a) dichotomous treatment failure / success defined by increase or decrease in immunosuppressive agents and b) incremental increases or decreases in immunosuppressive agents over time be considered as outcome measures, on a protocol specific basis.

During OMERACT 10 discussions during the CTD ILD SIG included consideration of cohort enrichment as well as alternate models of efficacy and clinically meaningful end-points particularly in a condition that typically results irreversible damage⁵. Subsequent discussions during OMERACT 11 resulted in 100% voting for acceptance:

• ▪“Lack of progression” should be considered a clinically meaningful end-point in RCTs in CTD-ILD and IPF.
• ▪Definitions of ‘Progression Free Survival’ should be a goal of the CTD-ILD Working Group for use in RCTs.

These points were important for future efforts of this CTD ILD Working Group.

Future Directions

The next step in the process is a meeting including HCPs and patient participants, employing nominal group technique (NGT), to identify currently available instruments most appropriate to measure the domains selected from the HCP Delphi process and patient participant focus groups, examine the degree to which they meet the “OMERACT filter”⁷and to outline the research agenda.

The selected domains which include the reinstatement of ‘Cough’, ‘Dyspnea’ as voted upon in the OMERACT proceedings as well as ‘patient global assessment of disease activity’ will be evaluated by a panel of experts consisting of patients as well as pulmonary, rheumatology and radiology specialists in the fields of IPF and CTD-ILD. A domain to capture the above called ‘Signs and Symptoms’ is under consideration.

‘Domain teams’ including representation from each expert group according to expertise will be assigned to present the most updated information regarding the instruments and how well they fulfill the OMERACT filter; each team will also responsible for ensuring that patient perspective results are included. As an example, a concept central to the OMERACT Filter 2.0: a core domain of “survival” or death will be considered. Importantly it encompasses the length of time a patient lives; but also includes the concept of ‘progression free survival’. Additional discussion and voting will include addressing whether and how ‘Lung Physiology / Function’ measures should be part of the core set. For each accepted instrument, experts will determine whether they should be considered primary or secondary endpoints and whether a preliminary threshold of change (e.g. > 10% decline in DLCO regarded as significant) can be assigned.

In addition to the pre-meeting endeavors of the ‘domain teams’, pre-meeting educational sessions on the meeting process and OMERACT methodology⁷ are planned, allowing for clarification and review of the combined results. A subsequent meeting in San Francisco in May 2012 is dedicated to review the NGT content and process review for the pulmonary experts on the panel. This meeting also provides a forum to discuss the results of these OMERACT proceedings. Patient experts will attend a pre-meeting teleconference / web series that deconstructs domains and potential instruments importance perceived by medical experts as well as a devoted forum to reviewing the patient-centered data with continual open discussion of experiences and perceptions related to the instruments.

Future direction necessitates a priority-tiered research agenda to guide inclusion and testing of non-core set items which did not survive the Delphi tier-filtered exercise but may nonetheless be considered important for examination within the context of randomized clinical trials, clinical practice, and registry studies. Continued work will necessarily non-physician HCPs who provide expertise from, such as nurse specialists in ILD and pulmonary rehabilitation therapists who see the disease process from a unique angle and continuum.

Summary

Perspectives from and results of the HCP Delphi process and patient perspective focus groups will be reconciled in the evaluation of domains and instruments appropriate for their assessment in one year RCTs in CTD-ILD and IPF at an upcoming NGT meeting. Following this and an outline of the research agenda the CTD-ILD group will work over time to develop a responder analysis utilizing the core set of domains and recommended and validated instruments.

Appendix A. Co-Authors

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;

Katerina Antoniou*, University of Crete, Greece;

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;

Robert P. Baughman*, University of Cincinnati, OH, 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;

Kevin K. Brown*, National Jewish Health; Denver, CO, USA;

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;

Flavia V. Castelino*, Massachusetts General Hospital, Boston, MA, USA;

Patricia E Carreira, Hospital Universitario, Spain;

Carlos R. R. 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

Romy B. Christmann*, Boston University School of Medicine, Boston, MA, USA;

Lisa Christopher-Stine*, Johns Hopkins University, Baltimore, MD, 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;

Vincent Cottin*, Claude Bernard University, Lyon, France;

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;

Sonye Danoff*, Johns Hopkins University, Baltimore, MD, USA;

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 F. Dellaripa*, Brigham and Womens Hospital, Boston, MA, USA;

Paul De Vuyst, Hopital Erasme, Université Libre de Bruxelles, Belgium;

Owen J Dempsey, Aberdeen Royal Infirmary Foresterhill, Scotland, UK;

Christopher P. Denton*, Royal Free Hospital, London, UK;

Chris T. Derk, University of Pennsylvania, USA;

Jörg Distler, University of Erlangen-Nuremberg, Germany;

Oliver Distler*, University Hospital Zurich, Switzerland;

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;

Aryeh Fischer*, National Jewish Health; Denver, CO, USA;

John E. Fitzgerald, University of Texas Southwestern Medical Center, USA;

Kevin R. Flaherty*, University of Michigan, Ann Arbor, USA, MI;

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;

Kristin Highland*, Cleveland Clinic, Cleveland, OH, USA

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;

Laura Hummers*, Johns Hopkins University, Baltimore, MD, USA;Nicolas Hunzelmann, Dept. of Dermatology, University of Cologne, Germany;

Dörte Huscher*, German Rheumatism Research Centre, Berlin, Germany and Charité Universitaetsmedizin, Berlin, 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;

Dinesh Khanna*, University of Michigan, Ann Arbor, USA, MI;

Dong Soon Kim*, Asan Medical Center University of Ulsan, Korea;

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;

Otylia M Kowal-Bielecka*, Medical University of Bialystok, Bialystok, Poland;

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 (JA Baddini Martinez FOR MEDLINE), 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;

Ana Cristina Mendes, Serviço de Pneumologia 1, CHLN- Hospital de Santa Maria;

Peter A. Merkel*, University of Pennsylvania, Philadelphia, PA, USA;

Keith C. Meyer, University of Wisconsin School of Medicine and Public Health, USA;

Ann B Millar, University of Bristol, UK;

Frederick W. Miller*, National Institutes of Health, Bethesda, MD, USA;

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;

Chester V. Oddis*, University of Pittsburgh, Pittsburgh, PA, USA;

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;

Kristine Phillips*, University of Michigan, Ann Arbor, USA, MI;David Pittrow, University of Dresden, Germany;

Janet E Pope*, Western University, Canada;

Joanna C. Porter, University College London, UK;

Susanna M. Proudman*, University of Adelaide, Australia;

Elisabeth A. Renzoni, Interstitial Lung Disease Unit, Royal Brompton Hospital, UK;

Luca Richeldi*, University Hospital of Modena, Modena, Italy;

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;

Jay H. Ryu*, Mayo Clinic College of Medicine, Rochester, MN, USA;

Steven A. Sahn, Medical University of South Carolina, USA;

Nora Sandorfi*, University of Pennsylvania, USA;

Alessandro Sanduzzi, Università degli Studi di Napoli "Federico II", Italy;

Mary Beth Scholand (Scholand MB for Medline, University of Utah, USA;

James R. Seibold*, Scleroderma Research Consultants, LLC, Avon, CT, USA:

Moises Selman, Instituto Nacional de Enfermedades Respiratorias, Mexico;

Jean-Luc Senécal, University of Montreal, Canada;

Philip Seo, Johns Hopkins University, USA;

Ami Shah*, Johns Hopkins University, Baltimore, MD, 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;

Jeffrey Swigris, National Jewish Health; Denver, CO, 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 Dept. of Rheumatology, Felix Platter-Spital, Switzerland;

Athol U. Wells, Royal Brompton Hospital and National Heart and Lung Institute; London, UK;

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