A complex interaction between demographic, environmental and genetic mechanisms impact the onset, severity and outcome of ILD-SARDs through dysregulation of the immune system and lung pro-biotic pathways. Comorbidity and genetic risk indicate that there are overlapping pathogenic mechanisms among SARDs, some of which underlie ILD in different SARDs. The purpose of this biobank is to study the clinical, pathological, laboratory, and imaging characteristics of SARDs patients with lung involvement. This will help identify as unique features underlying lung involvement in SARDs. In addition, this may lead to the discovery of novel mechanisms of disease and potentially novel targets of treatment for SARDs patients with lung disease.
1\. BACKGROUND AND STUDY RATIONALE: Characterized by immune dysregulation with disrupted self-tolerance, systemic autoimmune rheumatic diseases (SARDs) result in inflammation and auto-antibody formation that cause multi-tissue damage. The prototypic SARDs are rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and autoimmune myositis (AIM). The lung is a frequent target of autoimmune-mediated injury in patients with SARDs, and interstitial lung disease (ILD) is a major cause of morbidity and mortality in patients with SARDs. Among patients with SARDs, ILD varies widely in terms of its morphological pattern, time course, severity and the specific immune cells and cytokines that are most responsible for lung damage. Fundamental clinical questions remain unanswered for understanding diagnosis and management of ILD-SARDs: 1. ILD-SARDs prediction: Which patients with SARDs are likely to develop ILD? In retrospective cohorts of patients with RA, a patient's risk of developing ILD can be predicted by their age, sex and presence of auto-antibodies. How these clinical features interact with possible genetic and environmental risk factors needs to be better established to identify SARDs patients most at risk of developing ILD and to design and test interventions that reduce that risk or delay the onset of clinical manifestations in high-risk patients. 2. ILD-SARDs pathogenesis in humans and preclinical models: Why is there considerable heterogeneity in ILD progression and severity in patients with ILD-SARDs? The fundamental changes that occur in the immune system and lungs of patients with ILD-SARDs are still poorly understood. This is in part due to a lack of appropriate pre-clinical models of ILD-SARDs and lung biopsies from patients with ILD-SARDs. Identifying the biologic processes that promote development of ILD in SARDs patients will let the Investigators use drugs for other ILDs to specific patients with ILD-SARDs and promote the development of new targeted therapies. 3. ILD-SARDs treatment: Which are the best therapies for patients with ILD-SARDs? Few proven treatments for patients with ILD-SARDs exist. Many are proposed based only on case reports in specific SARDs. Positive results from studies of anti-fibrotic agents patients show it is possible to reverse the fibrotic process; yet it is unclear whether some patients with ILD-SARDs could also benefit from this approach as it may interact with the immunosuppressive agents the participants already receive. Addressing this issue is critical to changing the natural course of ILD-SARDs, particularly the symptoms and outcomes most important to patients. The conduct of many of the related future studies will require access to genetic material, fresh peripheral blood cells, serum and tissue from a phenotypically well characterized group of patients with ILD-SARDs. Access to patients is required for future clinical research projects and participation in potential clinical trials. Furthermore, the ILD-SARDs Registry and Biorepository is similar to registries and biorepositories that have been developed or are being developed in Germany, Australia, the United States and elsewhere in Canada. These similarities will facilitate national and international collaboration and allow establishment of a global collaborative network that is essential for further advancement of ILD-SARDs. The aforementioned future studies that will benefit from the contributions of this Bank include the identification of cell types, immune modulators and genetic pathways dysregulated in ILD-SARDs patients; pre-clinical in vivo and ex vivo models to assess disease pathobiology and targeted interventions, such as mouse models to assess mechanisms in the initiation and progression of ILD in SARDs, as well as a human ILD-SARDs lung-on-a-chip model to assess and predict treatment effect by evaluation mechanical evolution of the tissue; the ILD-SARDs Patient Preferences study, which consists of the facilitation of focus groups to characterize ILD-SARDs patients' experiences, needs and preferences; and the existing open-label, single arm pilot study of the safety and tolerability of nintedanib in patients with ILD and autoimmune inflammatory myopathy, to assess the effect of nintedanib on the state of activation of AIM patients' blood cells and to define its effect on the immunophenotype of circulating blood cells in patients. 2\. OBJECTIVES, HYPOTHESIS AND STUDY QUESTIONS A complex interplay between demographic, environmental and genetic mechanisms impact the onset, severity and outcome of ILD-SARDs through dysregulation of the immune system and lung pro-biotic pathways. Co-morbidity and extensive sharing of genetic risk indicate that there are overlapping pathogenic mechanisms among SARDs, some of which underlie ILD in different SARDs. The multidisciplinary team will examine this hypothesis through the establishment of a prospective registry of patients with ILD-SARDs to be enrolled and followed longitudinally, combined with a biorepository. 3\. STUDY METHODS The Investigators will develop a longitudinal clinical registry and biorepository of ILD-SARDs patients. Patient recruitment, informed consent, management, storage of data/samples and all other research activities will be done in accordance with the ILD-SARDs Biobank Management Framework. The ILD-SARDs informed consent forms will be used to obtain participant consent. To estimate recruitment in this cohort, the Investigators reviewed the number of patients seen in the multispecialty ILD-SARDs clinic at the McGill University Health Centre (MUHC) over the last year. The Investigators will recruit an inception cohort for biobanking with annual collection of structured clinical data. Clinical data - including clinical rheumatologic and pulmonary assessment, serology, pulmonary function tests, CT imaging, pathology, current treatments - will be collected at every visit. A biorepository will store biological specimens such as blood cells, serum and DNA/RNA for the cohort members. More specifically, the Investigators will collect whole blood samples at visits as defined above. Those belonging to treatment-naive patients will be sent to Dr. David Langlais' lab at the Inflammation Genomics Lab of the McGill University Genome Centre for single cell RNA sequencing and immunophenotyping. A Standard Operating Process (SOP) for blood sampling, shipping and storage has been developed to detail this process. As for whole blood samples coming from non-treatment-naive-patients, those will be sent to Dr. Gregory Fonseca's lab at the Meakins-Christie Lab at the Royal Victoria Hospital to be processed, and the resulting serum will be biobanked. Moreover, patients with an available bronchoalveolar lavage, lung, skin or muscle biopsy, as well as blood samples will be asked for consent for the study staff to access those samples for the purpose of this research. These samples are essential for the mechanisms established in future studies and will help enable them. The PIs, working under different disciplines, will all equally contribute to the study by identifying eligible participants, having medical oversight and study conduct, having written confirmation of inclusion/exclusion criteria, conducting a physical exam, assessing and signing adverse events (AEs) and serious adverse events (SAEs), providing medical care and follow-up to the participant and reviewing, interpreting and signing lab and other test results. Together, this will allow for a larger number of participants to be identified and followed up in this study.
Study Type
OBSERVATIONAL
Enrollment
252
Blood draws will be performed by personnel that are both qualified and authorized by their employer/institution to perform the procedures. The procedures will be performed with standards expected in the context of clinical care. 40 mL (2-3 tbsp) of blood will be drawn in order to collect DNA, RNA, serum and PBMCs. Blood tubes will be sent to the Bank as per the SOP for patient blood sampling and processing. The blood will be processed, centrifuged and stored by a trained laboratory technician.
If the patient's medical care or their participation in a research project involves a biopsy or surgery to remove tissue, the tissue not required for diagnosis (excess tissue) or hospital archives will be included in the biobank. This may include healthy tissue as well as tissue affected by the patient's health condition. The Investigators will not conduct extra procedures in order to obtain samples for the sole purpose of this study and will only operate on what's available. These may include blood samples, skin, lung and muscle biopsies, and bronchoalveolar lavage, all of which will be obtained from the pathology department.
Participant's relevant medical information from medical records, general health questionnaires and clinical assessments. The data includes gender, date of birth, race/ethnicity, habits, height, weight, vital signs, medical history, family history, pregnancy history, imaging data pertinent to ILDs and SARDs, results of routine blood tests, environmental exposures, medication and treatment exposures and adherence, function and quality of life, patient's assessment of their own health, clinical symptoms.
Results of the DNA or RNA sequencing, conducted for the Biobank and will be made available to future research; possible single nucleotide polymorphism (SNP) assays (including single SNP, low-plex or microarray-based assays).
RI-MUHC
Montreal, Quebec, Canada
RECRUITINGRate of death or lung transplant via Connective Tissue Disease (CTD) ILD Physician Baseline Respirology Only Form, and CTD ILD Physician Follow-Up Form
Date and cause of death, date of lung transplantation and type (bilateral, single)
Time frame: 5 years
Time to acute exacerbations and hospitalizations via ILD-SARDs Additional AcuteSubacute Respiratory Worsening Form, CTD ILD Physician Baseline Respirology Only Form, and CTD ILD Physician Follow-Up Form
Date of worsening symptoms, admission to hospital required (dates of admission and discharge)
Time frame: 5 years
Rate of requirement of interventions during hospital admission via ILD-SARDs Additional AcuteSubacute Respiratory Worsening Form, CTD ILD Physician Baseline Respirology Only Form, and CTD ILD Physician Follow-Up Form
Yes or no questions for required ICU stay, required noninvasive ventilation, required mechanical ventilation, required extracorporeal membrane oxygenation (ECMO), bronchoscopy performed, treatment received
Time frame: 5 years
Rate of reasons for worsening symptoms via CTD ILD Physician Baseline Respirology Only Form, and ILD-SARDs Additional AcuteSubacute Respiratory Worsening Form
List of possible reasons for worsening symptoms/exacerbations
Time frame: 5 years
Rate of outcome of acute exacerbations and hospitalizations via CTD ILD Physician Baseline Respirology Only Form, and ILD-SARDs Additional AcuteSubacute Respiratory Worsening Form
Evaluation of outcome of acute exacerbations and hospitalizations between resolved, plateau with worse symptoms and death
Time frame: 5 years
Patient Global Assessment Questionnaire
To measure quality of life and patient related outcomes, ranging from 0 to 10, and where higher scores mean a worse outcome.
Time frame: 5 years
36-Item Short Form Survey (SF-36 v2)
To measure quality of life, ranging from 1 to 3 or 5 depending on the question, and where higher scores can either mean a better or worse outcome, depending on the question.
Time frame: 5 years
University of California San Diego Medical Center Pulmonary Rehabilitation Program Shortness-of-Breath Questionnaire (UCSD SOBQ)
To measure patient-related outcomes, specifically with dyspnea, ranging from 0 to 5, where higher scores mean a worse outcome.
Time frame: 5 years
Functional Assessment of Chronic Illness Therapy - Dyspnea (FACIT-Dyspnea) Questionnaire
To measure patient-related outcomes, specifically with dyspnea, ranging from "No shortness of breath" to "Severely short of breath", including "I did not do this in the past 7 days" with possibility to indicate reason why.
Time frame: 5 years
Patient-Reported Outcomes Measurement Information System 29 (PROMIS-29) Questionnaire
To measure patient-related outcomes, specifically with dyspnea, ranging from 1 to 5, where higher scores can mean a better or worse outcome, depending on the question.
Time frame: 5 years
King's Brief Interstitial Lung Disease (KBILD) Questionnaire
To measure patient-related outcomes, specifically with dyspnea, ranging from 1 to 7, where higher scores mean a better outcome.
Time frame: 5 years
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