Consensus on the definitions and descriptions of the domains of the OMERACT Core Outcome Set for shared decision making interventions in rheumatology trials.

OBJECTIVE: To gain consensus on the definitions and descriptions of the domains of the Outcome Measures in Rheumatology (OMERACT) core domain set for rheumatology trials evaluating shared decision making (SDM) interventions. METHODS: Following the OMERACT Handbook methods, our Working Group (WG), comprised of 90 members, including 17 patient research partners (PRPs) and 73 clinicians and researchers, had six virtual meetings in addition to email exchanges to develop draft definitions and descriptions. The WG then conducted an international survey of its members to gain consensus on the definitions and descriptions. Finally, the WG members had virtual meetings and e-mail exchanges to review survey results and finalize names, definitions and descriptions of the domains. RESULTS: WG members contributed to developing the definitions. Fifty-two members representing four continents and 13 countries completed the survey, including 15 PRPs, 33 clinicians and 37 researchers. PRPs and clinicians/researchers agreed with all definitions and descriptions with agreements ranging from 87% to 100%. Respondents suggested wording changes to the names, definitions and descriptions to better reflect the domains. Discussions led to further simplification and clarification to address common questions/concerns about the domains. CONCLUSION: Our WG reached consensus on the definitions and descriptions of the domains of the core domain set for rheumatology trials of SDM interventions. This step is crucial to understand each domain and provides the foundation to identify instruments to measure each domain for inclusion in the Core Outcome Measurement Set. CLINICAL SIGNIFICANCE: The current study provides consensus-based definitions and descriptions for the domains of the OMERACT core domain set for shared decision making interventions from patients/caregivers, clinicians and researchers. This is a crucial step to understand each domain and provides the foundation to identify instruments to measure each domain for inclusion in the Core Outcome Measurement Set for trials of SDM interventions.

Prognostic implication of pre-transplant FEV1 on long-term outcomes following allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Pre-transplant pulmonary function testing (PFT) is essential before allogeneic hematopoietic stem cell transplant (HCT), yet the optimal cutoff value for affecting transplant outcomes remains poorly defined. STUDY DESIGN: Retrospective analysis of pre-HCT PFT data from 605 consecutive patients at the Princess Margaret Cancer Centre between January 1, 2004 and December 31, 2013 used binary recursive partitioning to identify cutoff values for overall survival (OS) as an endpoint of transplant outcomes. These values were compared to HCT comorbidity index (HCT-CI) FEV1 cutoffs for OS, cumulative incidence of relapse and non-relapse mortality. RESULTS: FEV1 ≥ 81% was the identified cutoff point. The OS rate at 3 years showed 49.8% (FEV1 ≥ 81%) vs. 36.6% (<81%, p < .001). For HCT-CI cutoffs, the OS rate at 3 years for FEV1 ≥ 80%, 66%-80% and ≤65% were 49.0%, 38.1% and 37.6% (p = .011), respectively. Multivariate analysis confirmed that FEV1 ≥ 81% predicted reduced mortality (HR 0.682, p = .001). Subgroup analysis showed both FEV1 ≥ 81% and FEV1 by HCT-CI cutoffs may stratify patients according to OS and NRM risk in subgroups receiving myeloablative, but not reduced intensity conditioning. CONCLUSION: FEV1 ≥ 81% can predict OS and NRM in our cohort and is potentially simpler when risk stratifying patients undergoing allogeneic HCT, particularly those receiving myeloablative conditioning.

Nintedanib in Patients With Autoimmune Disease-Related Progressive Fibrosing Interstitial Lung Diseases: Subgroup Analysis of the INBUILD Trial.

OBJECTIVE: To analyze the efficacy and safety of nintedanib in patients with fibrosing autoimmune disease-related interstitial lung diseases (ILDs) with a progressive phenotype. METHODS: The INBUILD trial enrolled patients with a fibrosing ILD other than idiopathic pulmonary fibrosis, with diffuse fibrosing lung disease of >10% extent on high-resolution computed tomography, forced vital capacity percent predicted (FVC%) ≥45%, and diffusing capacity of the lungs for carbon monoxide percent predicted ≥30% to <80%. Patients fulfilled protocol-defined criteria for progression of ILD within the 24 months before screening, despite management deemed appropriate in clinical practice. Subjects were randomized to receive nintedanib or placebo. We assessed the rate of decline in FVC (ml/year) and adverse events (AEs) over 52 weeks in the subgroup with autoimmune disease-related ILDs. RESULTS: Among 170 patients with autoimmune disease-related ILDs, the rate of decline in FVC over 52 weeks was -75.9 ml/year with nintedanib versus -178.6 ml/year with placebo (difference 102.7 ml/year [95% confidence interval 23.2, 182.2]; nominal P = 0.012). No heterogeneity was detected in the effect of nintedanib versus placebo across subgroups based on ILD diagnosis (P = 0.91). The most frequent AE was diarrhea, reported in 63.4% and 27.3% of subjects in the nintedanib and placebo groups, respectively. AEs led to permanent discontinuation of trial drug in 17.1% and 10.2% of subjects in the nintedanib and placebo groups, respectively. CONCLUSION: In the INBUILD trial, nintedanib slowed the rate of decline in FVC in patients with progressive fibrosing autoimmune disease-related ILDs, with AEs that were manageable for most patients.

Utility of anti-neutrophil cytoplasmic antibody screening in idiopathic interstitial lung disease.

BACKGROUND: Interstitial lung disease (ILD) is an established manifestation of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Autoimmune serologic screening is recommended by international consensus guidelines during the evaluation of idiopathic ILD, but ANCA testing only on a case-by-case basis. OBJECTIVE: We aimed to evaluate the role of ANCA screening in patients with idiopathic ILD. METHODS: We performed a retrospective review of patients seen between September 2015 and April 2017 in the ILD clinic at Toronto General Hospital. Patients referred with confirmed or suspected connective tissue disease were excluded. Patient demographics, symptoms, chest imaging, and pulmonary function testing was collected. We performed descriptive statistics based on the presence of ANCAs and estimated operating characteristics for ANCA screening. RESULTS: In total, 360 patients with idiopathic ILD were reviewed, 159 met study inclusion criteria and 4 (2.5%) tested positive for ANCAs. Two patients (1.2%) had elevated myeloperoxidase-ANCAs (MPO-ANCA) and 2 (1.2%) had elevated proteinase-3-ANCAs (PR3-ANCA). There were no significant associations between patient demographics and ANCAs. One patient (0.6%) with PR3-ANCAs was diagnosed with vasculitis following rheumatologic evaluation. Despite negative ANCA testing, 1 patient (0.6%) was diagnosed with vasculitis following rheumatologic evaluation. The sensitivity and specificity of ANCA screening for vasculitis in patients with ILD was calculated as 50% (95% CI, 1.3%-98.7%) and 98% (95%CI, 4.4-155.5) respectively. Negative and positive likelihood ratios were 0.5 (95%CI 0.1-2.0) and 26.2 (95%CI 4.4-155.5) respectively. CONCLUSION: ANCA screening in patients with idiopathic ILD rarely yields positive results. These results support an individualized approach to ANCA testing as opposed to widespread screening.

Endorsement of the OMERACT core domain set for shared decision making interventions in rheumatology trials: Results from a multi-stepped consensus-building approach.

OBJECTIVE: To gain consensus on the Outcome Measures in Rheumatology (OMERACT) core domain set for rheumatology trials of shared decision making (SDM) interventions. METHODS: The process followed the OMERACT Filter 2.1 methodology, and used consensus-building methods, with patients involved since the inception. After developing the draft core domain set in previous research, we conducted five steps: (i) improving the draft core domain set; (ii) developing and disseminating white-board videos to promote its understanding; (iii) conducting an electronic survey to gather feedback on the draft core domain set; (iv) finalizing the core domain set and developing summaries, a plenary session video and discussion boards to promote its understanding; and (v) conducting virtual workshops with voting to endorse the core domain set. RESULTS: A total of 167 participants from 28 countries answered the survey (62% were patients/caregivers). Most participants rated domains as relevant (81%-95%) and clear (82%-93%). A total of 149 participants (n = 48 patients/caregivers, 101 clinicians/researchers) participated in virtual workshops and voted on the proposed core domain set which received endorsement by 95%. Endorsed domains are: 1- Knowledge of options, their potential benefits and harms; 2- Chosen option aligned with each patient's values and preferences; 3- Confidence in the chosen option; 4- Satisfaction with the decision-making process; 5- Adherence to the chosen option and 6- Potential negative consequences of the SDM intervention. CONCLUSION: We achieved consensus among an international group of stakeholders on the OMERACT core domain set for rheumatology trials of SDM interventions. Future research will develop the Core Outcome Measurement Set. CLINICAL SIGNIFICANCE: Prior to this study, there had been no consensus on the OMERACT core domain set for SDM interventions. The current study shows that the OMERACT core domain set achieved a high level of endorsement by key stakeholders, including patients/caregivers, clinicians and researchers.

Cytokine Storm in COVID-19-Immunopathological Mechanisms, Clinical Considerations, and Therapeutic Approaches: The REPROGRAM Consortium Position Paper.

Cytokine storm is an acute hyperinflammatory response that may be responsible for critical illness in many conditions including viral infections, cancer, sepsis, and multi-organ failure. The phenomenon has been implicated in critically ill patients infected with SARS-CoV-2, the novel coronavirus implicated in COVID-19. Critically ill COVID-19 patients experiencing cytokine storm are believed to have a worse prognosis and increased fatality rate. In SARS-CoV-2 infected patients, cytokine storm appears important to the pathogenesis of several severe manifestations of COVID-19: acute respiratory distress syndrome, thromboembolic diseases such as acute ischemic strokes caused by large vessel occlusion and myocardial infarction, encephalitis, acute kidney injury, and vasculitis (Kawasaki-like syndrome in children and renal vasculitis in adult). Understanding the pathogenesis of cytokine storm will help unravel not only risk factors for the condition but also therapeutic strategies to modulate the immune response and deliver improved outcomes in COVID-19 patients at high risk for severe disease. In this article, we present an overview of the cytokine storm and its implications in COVID-19 settings and identify potential pathways or biomarkers that could be targeted for therapy. Leveraging expert opinion, emerging evidence, and a case-based approach, this position paper provides critical insights on cytokine storm from both a prognostic and therapeutic standpoint.

Screening for Myositis Antibodies in Idiopathic Interstitial Lung Disease.

PURPOSE: International guidelines recommend screening for connective tissue disease (CTD) with autoantibodies when evaluating patients with idiopathic interstitial lung disease (ILD). Idiopathic inflammatory myositis comprises of a subgroup of CTD diagnosed with myositis antibodies (MA), often presenting with ILD. Our aim was to evaluate the utility of MA screening in patients with idiopathic ILD. METHODS: A retrospective analysis was conducted on patients referred with idiopathic ILD to a tertiary centre ILD clinic who were screened for MA. Patients with known or suspected CTD were excluded. Descriptive statistics, univariate analysis and multivariable logistic regression were used to detect associations between MA and patient characteristics. RESULTS: Of 360 patients, 165 met inclusion criteria and 44 (26.7%) were identified to have MA. Fourteen patients (8.5%) had a change in diagnosis as a result of MA screening. Multivariable logistic regression identified the presence of MA to be associated with current smoking [OR 6.87 (1.65-28.64), p = 0.008] and a diffusing capacity of < 70% predicted [OR 2.55 (1.09-5.97), p = 0.03]. In patients with a change in diagnosis due to MA screening, 3 (1.8%) underwent a surgical lung biopsy and 2 (1.2%) were previously treated with antifibrotic therapy. CONCLUSIONS: Screening for MA in patients with idiopathic ILD can contribute to a change in patient diagnosis, and may prevent invasive testing and unproven use of antifibrotic therapy. These results support the addition of MA to CTD screening panels during the initial evaluation of idiopathic ILD.

OMERACT Development of a Core Domain Set of Outcomes for Shared Decision-making Interventions.

OBJECTIVE: The Outcome Measures in Rheumatology (OMERACT) Shared Decision Making (SDM) Working Group aims to determine the core outcome domain set for measuring the effectiveness of SDM interventions in rheumatology trials. METHODS: A white paper was developed to clarify the draft core domain set. It was then used to prepare for interviews to investigate reasons for lack of consensus on it and to suggest further improvements. RESULTS: OMERACT scientists/clinicians (n = 13) and patients (n = 10) suggested limiting the core domain set to outcome domains, removing process domains, and clarifying remaining domains. CONCLUSION: A revised core domain set will undergo further consensus-building.

The Dorsal 4-finger Technique: A Novel Method to Examine Metacarpophalangeal Joints in Patients with Rheumatoid Arthritis.

OBJECTIVE: To describe the dorsal 4-finger technique (DFFT) in examining metacarpophalangeal (MCP) joints of patients with rheumatoid arthritis (RA) and compare it to the traditional 2-finger technique (TFT) using ultrasound (US) as a gold standard. METHODS: Four rheumatologists evaluated 180 MCP joints of 18 patients with RA. All patients underwent US for greyscale (GSUS) and power Doppler US (PDUS). Agreements between rheumatologists, the 2 techniques, and US were evaluated using Cohen κ and the first-order agreement coefficient (AC1) κ methods. RESULTS: The population comprised 17 females (94.4%) with a mean (SD) age and disease duration of 56.8 (14.4) and 21.8 (12.9) years, respectively. Eight patients (44.4%) were taking methotrexate monotherapy, while 10 patients (55.6%) were receiving biologics. US evaluation revealed 69 (38.3%) and 30 (16.7%) joints exhibited synovitis grade 2-3 by GSUS and PDUS, respectively. Effusion was documented in 30 joints (16.7%). The mean intraobserver agreement using the DFFT and TFT were 80.5% and 86%, respectively. The mean interobserver agreements using the DFFT and TFT were 84% and 74%, respectively. κ agreement with US findings was similar for both techniques in tender joints but was higher for the DFFT in nontender joints (0.33 vs 0.07, p = 0.015 for GSUS) and (0.48 vs 0.11, p = 0.002 for PDUS). The DFFT had a higher sensitivity in detecting ballottement by GSUS (0.47 vs 0.2, p < 0.001) and PDUS (0.60 vs 0.27, p < 0.001). CONCLUSION: The DFFT is a novel, reproducible, and reliable method to examine MCP joints, and it has a better correlation with US than the traditional TFT.

The Canadian Registry for Pulmonary Fibrosis: Design and Rationale of a National Pulmonary Fibrosis Registry.

Background. The relative rarity and diversity of fibrotic interstitial lung disease (ILD) have made it challenging to study these diseases in single-centre cohorts. Here we describe formation of a multicentre Canadian registry that is needed to describe the outcomes of fibrotic ILD and to enable detailed healthcare utilization analyses that will be the cornerstone for future healthcare planning. Methods. The Canadian Registry for Pulmonary Fibrosis (CARE-PF) is a prospective cohort anticipated to consist of at least 2,800 patients with fibrotic ILD. CARE-PF will be used to (1) describe the natural history of fibrotic ILD, specifically determining the incidence and outcomes of acute exacerbations of ILD subtypes and (2) determine the impact of ILD and acute exacerbations of ILD on health services use and healthcare costs in the Canadian population. Consecutive patients with fibrotic ILD will be recruited from five Canadian ILD centres over a period of five years. Patients will be followed up as clinically indicated and will complete standardized questionnaires at each clinic visit. Prespecified outcomes and health services use will be measured based on self-report and linkage to provincial health administrative databases. Conclusion. CARE-PF will be among the largest prospective multicentre ILD registries in the world, providing detailed data on the natural history of fibrotic ILD and the healthcare resources used by these patients. As the largest and most comprehensive cohort of Canadian ILD patients, CARE-PF establishes a network for future clinical research and early phase clinical trials and provides a platform for translational and basic science research.

Connective tissue disease-related interstitial lung disease.

Interstitial lung disease (ILD) is commonly present in patients with an underlying connective tissue disease (CTD), particularly those with systemic sclerosis, rheumatoid arthritis, and inflammatory myositis. The clinical spectrum can range from asymptomatic findings on imaging to respiratory failure and death. Distinguishing features in the clinical, radiographic, and histopathologic characteristics of CTD-ILD subsets can predict prognosis and treatment response. Treatment often consists of combinations of immunosuppressive medications, but there is a paucity of guidance in the literature to help clinicians determine appropriate screening and management of CTD-ILD. As such, there is a critical need for studies that can elucidate the natural history of the CTD-ILD, as well as clarify optimal therapies for CTD patients with ILD.

Patient Perspectives in OMERACT Provide an Anchor for Future Metric Development and Improved Approaches to Healthcare Delivery in Connective Tissue Disease Related Interstitial Lung Disease (CTD-ILD).

OBJECTIVE: The impact and natural history of connective tissue disease related interstitial lung disease (CTD-ILD) are poorly understood; and have not been previously described from the patient's perspective. This investigation sought insight into CTD-ILD from the patients' perspective to add to our knowledge of CTD-ILD, identify disease-specific areas of unmet need and gather potentially meaningful information towards development of disease-specific patient-reported outcome measures (PROMs). METHODS: A mixed methods design incorporating patient focus groups (FGs) querying disease progression and life impact followed by questionnaires with items of importance generated by >250 ILD specialists were implemented among CTD-ILD patients with rheumatoid arthritis, idiopathic inflammatory myopathies, systemic sclerosis, and other CTD subtypes. FG data were analyzed through inductive analysis with five independent analysts, including a patient research partner. Questionnaires were analyzed through Fisher's Exact tests and hierarchal cluster analysis. RESULTS: Six multicenter FGs included 45 patients. Biophysiologic themes were cough and dyspnea, both pervasively impacting health related quality of life (HRQoL). Language indicating dyspnea was unexpected, unique and contextual. Psycho-social themes were Living with Uncertainty, Struggle over Self-Identity, and Self-Efficacy - with education and clinician communication strongly emphasised. All questionnaire items were rated 'moderately' to 'extremely' important with 10 items of highest importance identified by cluster analysis. CONCLUSION: Patients with CTD-ILD informed our understanding of symptoms and impact on HRQoL. Cough and dyspnea are central to the CTD-ILD experience. Initial FGs have provided disease-specific content, context and language essential for reliable PROM development with questionnaires adding value in recognition of patients' concerns.

Connective Tissue Disease-associated Interstitial Lung Diseases (CTD-ILD) - Report from OMERACT CTD-ILD Working Group.

OBJECTIVE: Interstitial lung disease (ILD) is common in connective tissue disease (CTD) and is the leading cause of mortality. Investigators have used certain outcome measures in randomized controlled trials (RCT) in CTD-ILD, but the lack of a systematically developed, CTD-specific index that captures all measures relevant and meaningful to patients with CTD-ILD has left a large and conspicuous gap in CTD-ILD research. METHODS: The CTD-ILD working group, under the aegis of the Outcome Measures in Rheumatology (OMERACT) initiative, has completed a consensus group exercise to reach harmony on core domains and items for inclusion in RCT in CTD-ILD. During the OMERACT 12 meeting, consensus was sought on domains and core items for inclusion in RCT. In addition, consensus was pursued on a definition of response in RCT. Consensus was defined as ≥ 75% agreement among the participants. RESULTS: OMERACT 12 participants endorsed the domains with minimal modifications. Clinically meaningful progression for CTD-ILD was proposed as ≥ 10% relative decline in forced vital capacity (FVC) or ≥ 5% to < 10% relative decline in FVC and ≥ 15% relative decline in DLCO. CONCLUSION: There is consensus on domains for inclusion in RCT in CTD-ILD and on a definition of clinically meaningful progression. Data-driven approaches to validate these results in different cohorts and RCT are needed.

Diagnostic disparity of previous and revised American Thoracic Society guidelines for idiopathic pulmonary fibrosis.

BACKGROUND: A revised guideline for the diagnosis of idiopathic pulmonary fibrosis (IPF) was formulated by the American Thoracic Society (ATS) in 2011 to improve disease diagnosis and provide a simplified algorithm for clinicians. The impact of these revisions on patient classification, however, remain unclear. OBJECTIVE: To examine the concordance between diagnostic guidelines to understand how revisions impact patient classification. METHODS: A cohort of 54 patients with either suspected IPF or a working diagnosis of IPF was evaluated in a retrospective chart review, in which patient data were examined according to previous and revised ATS guidelines. Patient characteristics influencing the fulfillment of diagnostic criteria were compared using one-way ANOVA and χ(2) tests. RESULTS: Revised and previous guideline criteria for IPF were met in 78% and 83% of patients, respectively. Revised guidelines modified a classification based on previous guidelines in 28% of cases. Fifteen percent of patients meeting previous ATS guidelines failed to meet revised criteria due to a lack of honeycombing on high-resolution computed tomography and the absence of a surgical lung biopsy. Patients failing to meet previous and revised diagnostic criteria for IPF were younger. CONCLUSION: The revised guidelines for the diagnosis of IPF classify a substantial proportion of patients differently than the previous guidelines.

Survival and quality of life in rheumatoid arthritis-associated interstitial lung disease after lung transplantation.

BACKGROUND: Patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) have increased mortality with limited treatment options. We set out to examine post-transplant survival in RA-ILD patients compared with patients with idiopathic pulmonary fibrosis (IPF) and scleroderma-associated ILD (SSc-ILD). We also describe post-transplant quality of life (QoL) outcomes in RA-ILD. METHODS: A retrospective review was performed on lung transplantation (1989 to 2011) among patients with RA-ILD, IPF (group-matched for age and transplant year) and SSc-ILD. Cumulative survival after transplantation was estimated by the Kaplan-Meier method and compared between groups using the log-rank test. The 36-item Medical Outcomes Survey Short Form (SF-36) and the St. George's Respiratory Questionnaire (SGRQ) scores, before and after lung transplantation, were analyzed. RESULTS: Overall, 10 patients with RA-ILD, 53 with IPF and 17 with SSc-ILD underwent lung transplantation with ages (mean ± SD) of 59.4 ± 5.6, 61.0 ± 4.0 and 45.4 ± 12.7 years, respectively. Cumulative survival rates at 1-year post-transplant for the RA-ILD, IPF and SSc-ILD groups were 67%, 69% and 82%, respectively, and there was no significant difference among groups in age- and gender-adjusted analyses. Among the RA-ILD patients, mean SF-36 physical component summary scores improved from 22.4 ± 8.1 to 32.2 ± 12.9 (p = 0.1), SF-36 mental component summary scores improved from 44.7 ± 15.3 to 54.9 ± 4.8 (p = 0.19) and SGRQ total scores improved from 70.4 ± 16.1 to 36.0 ± 18.5 (p = 0.03). CONCLUSIONS: After lung transplantation, RA-ILD and IPF patients have similar survival rates. Further, in RA-ILD patients, lung transplantation appears to result in a significant improvement in QoL with regard to respiratory symptoms. These data suggest that lung transplantation should be considered in patients with end-stage RA-ILD.

Pulmonary manifestations of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic inflammatory disease, characterized serologically by an autoantibody response to nucleic antigens, and clinically by injury and/or malfunction in any organ system. During their disease course, up to 50% of SLE patients will develop lung disease. Pulmonary manifestations of SLE include pleuritis (with or without effusion), inflammatory and fibrotic forms of interstitial lung disease, alveolar hemorrhage, shrinking lung syndrome, pulmonary hypertension, airways disease, and thromboembolic disease. Two major themes inform our understanding of SLE-associated pulmonary manifestations: first, the presence of specific autoantibodies correlates with the presence of certain pulmonary manifestations and second, vascular injury marks a common pathophysiologic thread among the various SLE-related lung diseases. This review will focus on the clinical presentation, pathogenesis, pathology, management, and prognosis of these SLE-associated lung conditions.