Medicine, Faculty of
Obstetrics and Gynaecology, Department of
DSpace
UBCV
Toor, Kirandeep
Master of Science - MSc
University of British Columbia
Pediatric-onset anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare, systemic disease involving inflammation and damage to small and medium sized blood vessels, primarily affecting the lungs and kidneys. The rarity of AAV in childhood precludes pediatric-specific clinical trials, thus treatment strategies have been adopted from trials in adult-onset AAV. Although these âadultâ treatment approaches have substantially decreased mortality in children with AAV, significant concerns persist around the toxicity risks specific to children and the appropriateness of applying adult-based recommendations to pediatric-onset disease. Our previous research demonstrated that, compared to adult-onset AAV, pediatric-onset AAV is more likely to be severe and have major organ dysfunction, such as significantly reduced renal function and severe lung disease. The intent of this thesis is to investigate the course of renal and pulmonary disease in children with AAV in the first 12-months, and to evaluate any predictors of these outcomes. This thesis research used both retrospectively and prospectively collected clinical data from the largest multi-center, international registry of children with vasculitis hosted at the University of British Columbia and the BC Childrenâs Hospital Research Institute. This thesis reports that despite the majority of patients receiving aggressive treatment, two-thirds of patients have reduced kidney function at 12 - and 24âmonth follow-up and more than one-third of patients have evidence of permanent kidney damage at 12-months. Kidney function at diagnosis (eGFR) is a strong predictor of kidney function at 12-months. Additionally, >50% of children with AAV present with pulmonary disease; however, the majority achieve inactive disease by 12-months, and few are left with pulmonary damage. This research characterized pulmonary and renal disease course, described early outcomes, and demonstrated the utility of using eGFR as a biomarker in childhood-onset AAV. Our research identified a cutpoint eGFR value (âthresholdâ) at diagnosis, below which children have a higher likelihood of having significant renal dysfunction by 12-months. Identification of a clinical âthresholdâ is appealing as a simple and easy-to-use clinical tool and warrants further study. Improved understanding of disease course, outcomes and predictors of outcomes will contribute to better prognostication and management of childhood-onset AAV.
EVALUATING RENAL AND PULMONARY DISEASE IN PEDIATRIC-ONSET ANCA-ASSOCIATED VASCULITIS: DISEASE COURSE, OUTCOMES, AND PREDICTORS OF OUTCOME by Kirandeep Toor Honours B.Sc., Life Sciences, McMaster University, 2021 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Women+ and Childrenâs Health Sciences) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) December 2024 © Kirandeep Toor, 2024 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the thesis entitled: Evaluating renal and pulmonary disease in pediatric-onset ANCA-associated vasculitis: disease course, outcomes, and predictors of outcome submitted by Kirandeep Toor in partial fulfilment of the requirements for the degree of Master of Science in Women+ and Childrenâs Health Sciences Examining Committee: Dr. Kimberly Morishita, Clinical Associate Professor, Dept. of Pediatrics, Division of Rheumatology, UBC Co-supervisor Dr. Kelly Brown, Associate Professor, Dept. of Pediatrics, Division of Rheumatology, UBC Co-supervisor Dr. Diane Lacaille, Professor, Dept. of Medicine, Division of Rheumatology, UBC Supervisory Committee Member Dr. Jonathan Rayment, Clinical Assistant Professor, Faculty of Medicine, Dept. of Pediatrics, UBC Additional Examiner iii Abstract Pediatric-onset anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare, systemic disease involving inflammation and damage to small and medium sized blood vessels, primarily affecting the lungs and kidneys. The rarity of AAV in childhood precludes pediatric-specific clinical trials, thus treatment strategies have been adopted from trials in adult-onset AAV. Although these âadultâ treatment approaches have substantially decreased mortality in children with AAV, significant concerns persist around the toxicity risks specific to children and the appropriateness of applying adult-based recommendations to pediatric-onset disease. Our previous research demonstrated that, compared to adult-onset AAV, pediatric-onset AAV is more likely to be severe and have major organ dysfunction, such as significantly reduced renal function and severe lung disease. The intent of this thesis is to investigate the course of renal and pulmonary disease in children with AAV in the first 12-months, and to evaluate any predictors of these outcomes. This thesis research used both retrospectively and prospectively collected clinical data from the largest multi-center, international registry of children with vasculitis hosted at the University of British Columbia and the BC Childrenâs Hospital Research Institute. This thesis reports that despite the majority of patients receiving aggressive treatment, two-thirds of patients have reduced kidney function at 12 - and 24âmonth follow-up and more than one-third of patients have evidence of permanent kidney damage at 12-months. Kidney function at diagnosis (eGFR) is a strong predictor of kidney function at 12-months. Additionally, >50% of children with AAV present with pulmonary disease; however, the majority achieve inactive disease by 12-months, and few are left with pulmonary damage. iv This research characterized pulmonary and renal disease course, described early outcomes, and demonstrated the utility of using eGFR as a biomarker in childhood-onset AAV. Our research identified a cutpoint eGFR value (âthresholdâ) at diagnosis, below which children have a higher likelihood of having significant renal dysfunction by 12-months. Identification of a clinical âthresholdâ is appealing as a simple and easy-to-use clinical tool and warrants further study. Improved understanding of disease course, outcomes and predictors of outcomes will contribute to better prognostication and management of childhood-onset AAV. v Lay Summary Vasculitis is a group of rare diseases that damage blood vessels in organs like kidneys and lungs. While immune-suppressing medications have improved outcomes for children, they pose risks like infections, cancer, and infertility. Consequently, only children with severe or aggressive disease should receive these treatments over extended periods. Due to disease rarity in children, disease course and predictors of severity remain unclear. This study examined the progression of vasculitis (âdisease courseâ), lung and kidney function one year after diagnosis (âdisease outcomeâ), and early signs that indicate outcomes (âdisease predictorsâ). Results showed that many children present with severe kidney or lung involvement at diagnosis. While some experience disease improvements, many still develop permanent damage to these organs. For kidney disease, level of kidney function at diagnosis can be helpful at predicting function after one year. This information will assist doctors in counselling children and families about anticipated disease course and prognosis. vi Preface This thesis contains both published and unpublished data, described below. The research presented in this thesis was conducted at the BC Childrenâs Hospital Research Institute, which is located on an affiliated campus of the University of British Columbia, under the supervision of Dr. Kimberly A. Morishita and Dr. Kelly L. Brown. The clinical data used for this research was collected through a web-based international registry on pediatric-onset vasculitis led by investigators at UBC and BC Childrenâs Hospital (co-lead principal investigators: Dr. D.A. Cabral, Dr. K.L. Brown; and co-investigator: Dr. K.A. Morishita). ARChiVe, which was established in 2007 to collect time-of-diagnosis clinical data, became incorporated into a prospective pediatric vasculitis initiative (PedVas) in 2013 to collect both clinical and biologic follow-up data. The clinical data is hosted on the Research Electronic Data Capture (REDCap) platform which was reviewed by Dr. E. Bosman before its use in this thesis. The protocol for this study was approved by the Childrenâs and Womenâs Research Ethics Board of the University of British Columbia (H12-00894) and the respective ethics committees at participating sites Chapter 3: The results presented in Chapter 3 have been published as part of a research article (Sections 3.2-3.4): K.K. Toor, A. Chen, D.A. Cabral, C. Mammen, E.S. Bosman, Y. Shen, J.N. Bone, D. Noone, E. Al-Abadi, S. Benseler, R. Berard, M. Bohm, S. Charuvanij, K. Cook, P. Dancey, S. Deepak, C. Duffy, B. Eberhard, M. Elder, D. Foell, D. Gerstbacher, M. Heshin-Bekenstein, A. Huber, K.E. James, S. Kim, M. Klein-Gitelman, N. Martin, F. McErlane, L.N. Moorthy, C. Myrup, P. Riley, S. Shenoi, V. Sivaraman, T. Tanner, S. Tarvin, L. Wagner-Weiner, R.S. M. Yeung, K.L. Brown and K.A. Morishita. Evaluating renal disease in pediatric-onset anti- vii neutrophil cytoplasmic antibody-associated vasculitis: disease course, outcomes, and predictors of outcomes, Arthritis & Rheumatology, accepted. An online version of this manuscript can be accessed using the following link: https://doi.org/10.1002/art.43071 For this manuscript, I was responsible for 75% of the work including data extraction, data cleaning, acquisition and analysis of the data, preparation of figures and tables, as well as the writing and review of the manuscript. Drs A. Chen, C. Mammen, and K.A. Morishita were responsible for the initial pilot study design, conceptualization of pilot data and review of the manuscript. Dr. E.S. Bosman provided database assistance concerning the ARCHiVe/PedVas database in REDCap. J.N. Bone and Y. Shen provided statistical support for analyses and contributed to the preparation of figures and tables. Drs. D.A. Cabral, K.A. Morishita, and K.L. Brown provided oversight on all aspects of the manuscript and contributed to the conceptualization of the project. All other authors were involved with patient recruitment, site data management and review of the manuscript. Chapter 4: The results of this chapter have been published as an abstract (Toor KK, Chen A, Cabral DA, Shen Y, Bone JN, Brown KL, Morishita KA (2024). Pulmonary manifestation of pediatric ANCA-associated vasculitis: disease course and outcomes. Canadian Rheumatology Association (CRA) - Annual Scientific Meeting. Feb 28 â Mar 2, 2024. Winnipeg, Canada. Abstract #84 The Journal of Rheumatology 2024, ahead of print). The abstract was presented at the CRA annual viii scientific conference (2024, Winnipeg, MB). A manuscript is currently being prepared and will be submitted for publication. For this section of the thesis, I was responsible for data extraction, data cleaning, acquisition and analysis of the data, as well as the preparation of the figures and tables. A. Chen assisted with the conceptualization of pilot data. J.N. Bone and Y. Shen provided statistical support for analyses and contributed to the preparation of figures and tables. Drs. K.A. Morishita, K.L. Brown and D.A. Cabral provided oversight on all aspects of this study. ix Table of Contents Abstract ......................................................................................................................................... iii Lay Summary ................................................................................................................................ v Preface ........................................................................................................................................... vi Table of Contents ......................................................................................................................... ix List of Tables ............................................................................................................................... xiii List of Figures .............................................................................................................................. xv List of Abbreviations .................................................................................................................. xvi Acknowledgements .................................................................................................................. xviii Dedication ................................................................................................................................... xxi Chapter 1: Introduction ............................................................................................................... 1 1.1 Chronic primary systemic vasculitis (PSV) .......................................................................... 1 1.2 Pediatric-onset ANCA-associated vasculitis (AAV) ............................................................. 3 1.2.1 Anti-neutrophil cytoplasmic antibodies (ANCA) .......................................................... 3 1.2.2 Subtypes of AAV ............................................................................................................ 3 1.2.3 Classification of AAV .................................................................................................... 4 1.2.3.1 Overview of clinical manifestations ........................................................................... 6 1.2.4 Renal and pulmonary involvement in AAV ................................................................... 7 1.2.4.1 Renal involvement ...................................................................................................... 7 1.2.4.2 Pulmonary involvement .............................................................................................. 9 1.2.5 Management of AAV ................................................................................................... 10 x 1.3 Differences between pediatric and adult-onset AAV ...........................................................11 1.4 Disease course and outcomes of AAV .................................................................................11 1.4.1 Measures of disease activity and damage ........................................................................ 12 1.4.2 Predictors of renal and pulmonary disease outcomes .................................................. 13 1.5 Rationale ............................................................................................................................. 13 Chapter 2: Materials and Methods ........................................................................................... 16 2.1 Study Participants ............................................................................................................... 16 2.1.1 Pediatric-onset AAV patients with renal disease .......................................................... 16 2.1.2 Pediatric-onset AAV patients with pulmonary disease ................................................ 17 2.2 Outcome measures .............................................................................................................. 19 2.2.1 Overall disease activity (PVAS) ................................................................................... 19 2.2.2 Overall damage (pVDI) ............................................................................................... 20 2.3 Kidney-specific outcomes measures ................................................................................... 20 2.3.1 Kidney-specific disease activity and damage .............................................................. 20 2.3.2 Kidney function ........................................................................................................... 21 2.3.3 Kidney outcome assessments ....................................................................................... 22 2.4 Pulmonary-specific outcome measures............................................................................... 22 2.4.1 Pulmonary disease activity and damage scoring ......................................................... 22 2.4.2 Pulmonary function and lung imaging ......................................................................... 23 2.4.3 Pulmonary outcome assessments ................................................................................. 23 2.5 Statistical Analysis .............................................................................................................. 24 xi Chapter 3: Evaluating renal disease in pediatric-onset anti-neutrophil cytoplasmic antibody-associated vasculitis: disease course, outcomes, and utility of eGFR as a predictor of renal outcomes ........................................................................................................................ 26 3.1 Rationale and Introduction .................................................................................................. 26 3.2 Study Cohort ....................................................................................................................... 27 3.3 Results ................................................................................................................................. 31 3.3.1 Despite high renal disease activity at diagnosis, most AAV patients attain inactive renal disease within two years of diagnosis.......................................................................... 31 3.3.2 A significant proportion of AAV patients have evidence of permanent renal damage by 12-months .............................................................................................................................. 32 3.3.3 Patients that present with kidney failure are unlikely to recover normal renal function............................................................................................................................................... 33 3.3.4 eGFR at diagnosis is predictive of renal function 12-months after diagnosis ............. 35 3.4 Discussion ........................................................................................................................... 38 Chapter 4: Pulmonary disease in pediatric-onset ANCA-associated vasculitis: early disease course and outcomes ................................................................................................................... 42 4.1 Rationale and Introduction .................................................................................................. 42 4.2 Study Cohort ....................................................................................................................... 43 4.3 Results ................................................................................................................................. 46 4.3.1 Chest image features .................................................................................................... 46 4.3.2 Patients present with high pulmonary disease activity at diagnosis yet achieve inactive pulmonary disease within a year of diagnosis ...................................................................... 47 xii 4.3.3 Despite high disease activity at diagnosis, the majority of patients do not develop permanent pulmonary damage ............................................................................................. 48 4.3.4 Exploratory analysis reveals no predictors of lung damage........................................ 50 4.4 Discussion ........................................................................................................................... 54 Chapter 5: Conclusion and future directions ........................................................................... 59 5.1 Summary ............................................................................................................................. 59 5.2 Clinical significance............................................................................................................ 60 5.3 Study limitations and future directions ............................................................................... 61 5.4 Conclusion .......................................................................................................................... 64 References .................................................................................................................................... 65 Appendices ................................................................................................................................... 73 Appendix A: Clinical scoring tools for disease activity (PVAS) and damage (pVDI) ............. 73 A.1 PVAS clinical scoring tool ............................................................................................. 73 A.2 pVDI clinical scoring tool .............................................................................................. 76 xiii List of Tables Table 1.1 An overview of the classification criteria for ANCA-associated vasculitis .................... 5 Table 2.1 Kidney function as defined by KDIGO stages and eGFR ............................................ 22 Table 3.1 Demographic and renal characteristic of pediatric-onset AAV patients identified with renal disease .................................................................................................................................. 28 Table 3.2 Baseline characteristics of patients with (n=79) and without (n=66) follow-up at 24-months ........................................................................................................................................... 30 Table 3.3 KDIGO category at diagnosis as a predictor of non-normal KDIGO category at 12-month follow-up............................................................................................................................ 36 Table 4.1 Demographic and clinical characteristic of pediatric-onset AAV patients with pulmonary disease at diagnosis ..................................................................................................... 45 Table 4.2 CT abnormal imaging features at diagnosis .................................................................. 47 Table 4.3 Pulmonary clinical characteristics in pediatric-onset AAV at diagnosis ....................... 48 Table 4.4 Baseline characteristics of pediatric-onset AAV patients with and without pulmonary damage at 12 months .................................................................................................................... 49 Table 4.5 Abnormal pulmonary function test manifestations at diagnosis and 12-months .......... 49 Table 4.6 Univariate logistic regression analysis of baseline factors associated with abnormal pulmonary function test at 12-months .......................................................................................... 50 Table 4.7 Univariate logistic regression analysis of baseline factors associated with pulmonary damage at 12-months .................................................................................................................... 51 Table 4.8 Baseline characteristics of pediatric-onset AAV patients on cyclophosphamide treatment versus rituximab treatment............................................................................................ 52 xiv Table 4.9 Multivariate logistic regression analysis of baseline factors associated with abnormal pulmonary function test ................................................................................................................ 53 Table 4.10 Multivariable logistic regression analysis of baseline factors associated with pulmonary damage ........................................................................................................................ 54 xv List of Figures Figure 1.1 Pediatric-onset chronic primary systemic vasculitis. .................................................... 2 Figure 1.2 Classification system for ANCA-associated glomerulonephritis .................................. 8 Figure 2.1 Inclusion and exclusion criteria for pediatric-onset AAV patients with renal disease......................................................................................................................................................... 18 Figure 2.2 Inclusion and exclusion criteria for pediatric-onset AAV patients with pulmonary disease ........................................................................................................................................... 19 Figure 3.1 Extra-renal manifestations at diagnosis and renal disease activity in the first 24 months in pediatric ANCA-associated vasculitis (AAV) .............................................................. 32 Figure 3.2 Estimated glomerular filtration rate (eGFR) at diagnosis, 12-months, and 24-months in pediatric ANCA-associated vasculitis ...................................................................................... 33 Figure 3.3 Estimated glomerular filtration rate (eGFR) in pediatric ANCA-associated vasculitis (AAV) at diagnosis, 12-month follow-up and 24-month follow-up, for patients with âextremeâ renal function (normal versus kidney failure) at diagnosis. .......................................................... 35 Figure 3.4 Predicted probability of KDIGO stage at 12-months post-diagnosis based on KDIGO stage at diagnosis. ......................................................................................................................... 36 Figure 3.5 Estimated glomerular filtration rate (eGFR) in pediatric ANCA-associated vasculitis at diagnosis and 12-months. .......................................................................................................... 38 xvi List of Abbreviations AAV ANCA-associated vasculitis ACR American College of Rheumatology ANCA anti-neutrophil cytoplasmic antibodies ANCA-GN ANCA-associated glomerulonephritis ARChiVE A Registry of Childhood Vasculitis c-ANCA cytoplasmic ANCA CHCC Chapel Hill Consensus Conference CKD chronic kidney disease CT computed tomography DAH diffuse alveolar hemorrhage eGFR estimated glomerular filtration rate EGPA eosinophilic granulomatosis with polyangiitis EMA European Medicines Agency ENT ear, nose, and throat ESKD end-stage kidney disease EULAR European Alliance of Associations for Rheumatology FEV forced expiratory volume FVC forced vital capacity GN glomerulonephritis GPA granulomatosis with polyangiitis ILD interstitial lung disease IVIG intravenous immune globulin xvii KDIGO Kidney Disease Improving Global Outcomes MPA microscopic polyangiitis MPO myeloperoxidase p-ANCA perinuclear ANCA PedVas Pediatric Vasculitis Initiative PFT pulmonary function test PR3 proteinase-3 PReS Pediatric Rheumatology European Society PRINTO Pediatric Rheumatology International Trials Organization PSV primary systemic vasculitis PVAS pediatric vasculitis activity score pVDI pediatric vasculitis damage index SVV small vessel vasculitis TLC total lung capacity VDI vasculitis damage index xviii Acknowledgements To my supervisors, Dr. Kimberly Morishita and Dr. Kelly Brown, thank you for your unwavering mentorship and support over the past two years. You created an atmosphere of positivity and encouragement that made every challenge an opportunity to learn and grow. Your belief in me gave me the confidence to work hard, push my limits and strive for excellence every step of the way. I am forever grateful to have had the opportunity to work and learn from your leadership. To my supervisory committee, Dr. Diane Lacaille, your thoughtful guidance and insightful feedback have been invaluable throughout this journey. To the past and present members of the Brown Lab, thank you for your support and for fostering such a warm and collaborative environment. Your encouragement and friendship has made this journey all the more enriching. A special thank you to Stephanie Hughes for your vibrant and infectious energy, and for always organizing unforgettable gatherings. To Sarah Bowers and Simranpreet Mann, thank you for always being there to listen through the ups and downs. I feel so incredibly lucky and grateful to have shared this journey with both of you in the lab. To the BC Childrenâs Hospital (BCCH) Biostatistics Core, specifically Jeffrey Bone and Ye Shen, thank you for your invaluable statistical support and for guiding me through the process with patience and expertise. Your knowledge has been instrumental to my project, and I am deeply grateful. To the BCCH Division of Rheumatology, especially Dr. David Cabral, I am grateful for your unwavering support and guidance. Your thoughtful feedback and encouragement have been instrumental in this journey. xix To the Centre for Blood Research (CBR), thank you for providing funding support through the Centre for Blood Research Graduate Student Fellowship. To the University of British Columbia (UBC), thank you for providing funding support through the Women+ and Childrenâs Health Sciences Supporting Diversity Award. To the Canadian Institutes for Health Research, thank you for providing funding for the Pediatric Vasculitis Initiative and for supporting my research through the Canada Graduate (Masterâs) Scholarship. To all study participants and their families, thank you for contributing to my research. This project would not have been possible without your generosity and support. To my friends in Vancouver, especially Rida Khan, Irene Chen, Eda Lee, and Mary Gan, your friendship has made this journey so much more meaningful and rewarding. I cannot express how much your support and encouragement has meant to me, and I feel incredibly fortunate to have built such wonderful friendships during my time here. Though our time together in Vancouver was far too short, the memories we created and the experiences we shared will stay with me forever. To my friends back home, thank you for believing in me and supporting me throughout this journey. Your encouragement has made all the difference and reminded me how fortunate I am to have you in my life. A special thank you to Nikhila Butani for the countless phone calls that filled my days with laughter, comfort and joy. Iâm truly grateful for your friendship. xx To my family, your endless support, encouragement and love have been the foundation of my journey. You have always motivated me to strive for my best, and your belief in me has given me the strength to preserve and achieve my goals. I am so lucky to have you by my side, and I owe so much of my success to your faith in me. xxi For my mom and dad. This is for everything youâve done for me, seen and unseen. 1 Chapter 1: Introduction Pediatric-onset anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare disease that often presents with severe dysfunction in major organs, commonly the kidneys and lungs 1,2. The rarity of AAV in childhood precludes pediatric-specific clinical trials, thus treatment strategies have been adopted from trials in adult-onset AAV. Guidelines derived from such trials recommend aggressive treatment whenever major organs like the lungs and kidneys are affected. Although these âadultâ treatment approaches have substantially decreased mortality in children with AAV â without which, most would die within a year of diagnosis â significant concerns persist around the toxicity risks specific to children and the appropriateness of applying adult-based recommendations to pediatric-onset disease. To create better, individualized treatment plans and improve outcomes in children, it is important to understand renal and pulmonary disease course, disease outcomes and identify factors at baseline that can aid in predicting outcomes. The research presented in this thesis uses data from the largest international registry of children with vasculitis to investigate the course of renal and pulmonary disease in children with AAV in the first 12-months of disease and evaluates predictors of outcomes. 1.1 Chronic primary systemic vasculitis (PSV) Vasculitis refers to a group of diseases characterized by inflammation and damage in blood vessels 3. This consists of the weakening, thickening, narrowing or scarring in any type, size and location of blood vessels 4. The disease is classified based on the vessel size affected, including small vessels (arterioles, capillaries, venules and some veins), medium vessels (main visceral 2 arteries and veins) and large vessels (aorta and its major branches) 5 (Figure 1.1). It is a polygenic and multifactorial disease with genetic, environmental, autoinflammatory and autoimmune contributions 6. The clinical presentation of the disease varies greatly, ranging from single organ involvement to a multisystem disorder with diverse manifestations 3. The disease can affect adults and children. Vasculitis can present as acute and short-lived, but it can also be a chronic and recurring disease7. In children, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is the most common type of chronic PSV. AAV predominantly affects small-sized blood vessels and will be the primary focus of this thesis research. Figure 1.1 Pediatric-onset chronic primary systemic vasculitis. This flowchart shows the classification of PSV into small, medium and large vessel vasculitis. Different subtypes (listed) of AAV affect small-sized blood vessels. 3 1.2 Pediatric-onset ANCA-associated vasculitis (AAV) ANCA-associated vasculitis (AAV) is an umbrella term for a group of small vessel vasculitides, affecting arterioles, capillaries and venules 8. The disease typically has an onset later in adulthood (>50 years), with an estimated incidence of 17.2 cases per million annually 9. However, cases have been recognized in children, with an estimated incidence of 0.45 to 6.4 cases per million children per year 10, 9. Pediatric-onset AAV has a greater female predominance compared to adults and a median age at diagnosis of 10.7 â 14.0 years 10. The disease has been described to be severe with frequent relapses and a higher cumulative morbidity in children 11. 1.2.1 Anti-neutrophil cytoplasmic antibodies (ANCA) The presence of anti-neutrophil cytoplasmic antibodies (ANCA) are characteristic of AAV. ANCA are autoantibodies that, in AAV, are directed against one of two proteins - proteinase-3 (PR3) or myeloperoxidase (MPO). These proteins are present within neutrophils and, to a lesser extent, monocytes 12. Patient plasma or sera can be screened for ANCA against PR3 or MPO by standard enzyme linked immunosorbent assays (ELISA). Alternatively, their presence in neutrophils can be inferred from a cytoplasmic (c-ANCA) or perinuclear (p-ANCA) 3 staining pattern where PR3 and MPO are the most common targets, respectively, of c-ANCA and p-ANCA. 1.2.2 Subtypes of AAV AAV is comprised of, in order of frequency: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). Isolated pauci-immune ANCA associated GN is also often included in the spectrum of AAV. 4 There is geographical variation in the incidence of AAV with GPA commonly reported in European populations while MPA is more frequently observed in Asian regions 13. GPA, is characterized by granulomas and necrotizing vasculitis 14. In comparison, MPA consists of necrotizing vasculitis without granulomas and EGPA is described by granulomas, eosinophilic infiltration and necrotizing vasculitis 15,16. 1.2.3 Classification of AAV It is difficult to differentiate clinical features of AAV from other systemic diseases early on in the disease course. Classification criteria have been developed and revised over the years to help enable the classification of GPA, MPA and EGPA in adult patients. Due to the rarity of pediatric-onset AAV, classification criteria has been derived from adult data for pediatric patients. The first classification criteria was proposed in 1990 by the American College of Rheumatology (ACR) (the 1990 ACR criteria), followed by the 1994 International Chapel Hill Conference (1994 CHCC definitions) 17. When simultaneously applying the 1990 ACR criteria and CHCC 1994 definitions on the same cohort of patients, the two systems performed differently 13. The European Medicine Agency (EMA) created an algorithm in 2007 (EMA classification algorithm 2007), integrating the ACR and CHCC systems in a hierarchical manner 13. However, there were still many unclassifiable pediatric cases using adult criteria 13. In 2008, the European League Against Rheumatism (EULAR), Paediatric Rheumatology International Trials Organisation (PRINTO) and Paediatric Rheumatology European Society (PRES) validated and improved definitions of childhood GPA 18,19. In 2012, the previous CHCC definitions were updated (2012 5 CHCC definitions) to incorporate ANCA, emphasizing its significant role in AAV 20. A comprehensive ACR/EULAR classification system created in 2022 was derived from the largest systemic vasculitis cohort ever. An overview of the classification criteria is described in Table 1.1. Table 1.1 An overview of the classification criteria for ANCA-associated vasculitis Classification Criteria Description 1990 ACR criteria â¢ Consists of classification criteria for seven forms of vasculitis â¢ Did not include criteria for MPA or use ANCA serology 13 â¢ Dataset only included North American cases and didnât account for geographical differences 13 1994 CHCC definitions â¢ Proposed nomenclature and definitions for common forms of vasculitis 20 â¢ Included criteria for MPA â¢ Did not use ANCA serology 2007 EMA classification algorithm â¢ Algorithm begins with 1990 ACR EGPA, followed by 1990 ACR GPA and CHCC MPA â¢ Combined use of ANCA and surrogate markers 2008 EULAR/PRINTO/PRES â¢ Improved sensitivity and specificity of classification definitions of childhood GPA 19 â¢ No classification criteria developed for MPA 2012 CHCC definitions â¢ SVV is divided into AAV and immune complex SVV, highlighting the significance of ANCAâs pathogenic role in AAV 2022 ACR/EULAR classification criteria â¢ Criteria accounts for clinical, radiological, histological and laboratory findings to classify GPA, MPA and EGPA patients 17 6 1.2.3.1 Overview of clinical manifestations AAV frequently presents with constitutional symptoms of fever, weight loss, myalgias and arthralgias. More specific patterns of organ involvement characterize the different subtypes of AAV. Granulomatosis with polyangiitis (GPA) commonly involves the upper and lower respiratory tract, along with renal involvement 10. It is usually associated with the presence of c-ANCA, with specificity for PR3. The spectrum of pulmonary manifestations include chronic cough, shortness of breath, hemoptysis or alveolar hemorrhage, and sometimes respiratory failure 1,21. Renal disease affects the majority of patients and can present with wide range of manifestations from mild urinary abnormalities to severe renal impairment 1,2,22. Characteristic upper airway/ear, nose and throat (ENT) involvement includes recurrent nasal discharge/crusting, sinusitis, nasal deformities and subglottic stenosis 1. GPA tends to be more severe in childhood with more frequent and aggressive ENT involvement including features of subglottic stenosis and nasal septal perforation compared to adults 11. Microscopic polyangiitis (MPA) typically presents with significant renal involvement; however, pulmonary involvement (often pulmonary capillaritis) frequently accompanies the renal disease. Renal disease usually presents with urinary abnormalities and impaired renal function, including renal failure 1,22. Pulmonary manifestations include chronic cough, hemoptysis, and pulmonary hemorrhage 10. 7 Eosinophilic GPA (EGPA) presents with asthma, allergic rhinitis or nasal polyposis early on in the disease course, followed by an eosinophilic phase with eosinophilia and pulmonary infiltrates, and then manifestations of vasculitis later in the course of disease 10. This subtype presents with cutaneous, neurological, cardiac, pulmonary and gastrointestinal manifestations 10. Renal disease in this subtype is infrequent and often mild 23â26. 1.2.4 Renal and pulmonary involvement in AAV AAV is often characterized by multisystem involvement. The various organ systems that have been implicated in this disease include: musculoskeletal, cutaneous, mucous membranes, ENT, ocular, pulmonary, cardiovascular, gastrointestinal, renal and neuropsychiatric. The focus of my thesis is on the two major organ systems that are most commonly affected â renal and pulmonary. 1.2.4.1 Renal involvement Renal involvement is a hallmark and significant complication of AAV. In adults, renal disease is present in approximately 70% of patients with GPA and in about 80-90% of patients with MPA 16,27. Large pediatric studies report similar trends, with renal involvement described in 78-88% of children 1,2,28. Of significant concern is that many children require dialysis or are in end-stage kidney disease (ESKD) at the time of diagnosis, demonstrating the severity of renal involvement in this disease 2. Renal involvement is characterized by a pauci-immune necrotizing crescentic glomerulonephritis and commonly presents with a rapid decline of renal function 27. Other common renal presentations include hematuria, proteinuria, hypertension and elevated serum creatinine 2. 8 Hematuria and proteinuria have been described in approximately 75% of children with AAV 2. Additionally, up to 20-35% of children with AAV present in kidney failure 22 with approximately 20% of cases requiring dialysis 2,29. Renal biopsies are considered the gold-standard for diagnosing renal involvement in patients with ANCA-associated vasculitis 30. The Berden histopathological classification system, proposed in 2010, is a widely used system for classifying renal biopsies in adult AAV 31. Biopsies are classified into one of four categories including focal, crescentic, mixed and sclerotic 31. These categories are described based on the prevalence of normal glomeruli, cellular crescents and sclerotic glomeruli 31. The classification system is described in Figure 1.2. Figure 1.2 Classification system for ANCA-associated glomerulonephritis 9 Berden classification categories have been shown to have prognostic utility in adult patients, but their utility in children has only been evaluated in a few small studies 31â33 . A focal pattern on biopsy has been associated with better renal outcome, including the retention of good kidney function, whereas a sclerotic pattern significantly increases the chance of developing end-stage kidney disease 22,31â33. A limitation of using biopsy classification as a predictive tool, however, is that biopsies are subject to sampling error, and they are invasive to perform repeatedly. In addition, the less extreme classes (e.g. crescentic and mixed) have less clear predictive utility, with the crescentic pattern being most common in pediatric AAV 35, unlike in adults. 1.2.4.2 Pulmonary involvement Pulmonary involvement is one of the most prominent clinical features in AAV 36. It is an important contributing factor to the morbidity and mortality seen in this disease 37. Large pediatric studies describe involvement in 74-82% of children with GPA 1,38,39. In adults, early lung involvement has been linked with severe organ damage such as pulmonary fibrosis and alveolar hemorrhage 37. These complications lead to poor outcomes in patients with GPA including raised morbidity and mortality 37. Pulmonary involvement is observed in up to 30% of patients with MPA, often manifesting as interstitial lung disease (ILD) 41,42. The course of lung disease and outcomes in children have not been fully characterized. Pulmonary involvement can present with a wide spectrum of manifestations. In adults, the most common presentations include necrotizing granulomatous inflammation (commonly manifest as lung nodules), tracheobronchial inflammation, diffuse alveolar hemorrhage (DAH), interstitial lung disease (ILD) and asthma 36. In children, the most common presentations include chronic cough, DAH and imaging findings such as the nodules, fixed pulmonary infiltrates and cavitations 1. In a study of 105 children with AAV, 11% presented in respiratory failure 2. 10 Computed tomographic (CT) imaging often shows nodular opacities, pleural effusion, pulmonary hemorrhage, lymph node enlargement and cavitating lesions 37. In adults, certain pulmonary features like DAH and ILD have been associated with a worse prognosis compared to having nodules 36. Prognostic factors in children have not been elucidated. 1.2.5 Management of AAV Adults and children with AAV are often treated aggressively due to the involvement of major organs and severity of disease at presentation. Patients are treated using a two-phase treatment approach, starting with the induction phase (first 3 to 6 months), which involves the combination of high-dose glucocorticoids and immunosuppressive agents 43. The goal of the induction phase is to control inflammation, eliminate disease activity and minimize organ damage 43. High-dose glucocorticoids and immunosuppressant agents such as cyclophosphamide and rituximab are critical in managing AAV and inducing remission, despite their recognized toxicity risks 44,45. Following remission-induction, treatment focuses on the maintenance phase (the next 24 to 48 months) which aims to preserve remission and prevent relapses 43. This involves gradually reducing steroids and switching to milder immunosuppressants (including azathioprine, methotrexate and mycophenolate mofetil) to minimize long-term side effects. Even if the disease is not aggressive at onset, patients are treated similarly using this remission-induction/remission-maintenance approach, however it involves lower doses of glucocorticoids and milder immunosuppressive agents. Due to disease rarity in children, these described treatment strategies were adapted from adult clinical trials. There remain concerns around the toxicity risks specific to children and whether it is appropriate to apply adult-based recommendations to pediatric-onset disease. 11 1.3 Differences between pediatric and adult-onset AAV There are several key differences between pediatric-onset and adult-onset AAV in terms of disease presentation, progression and outcomes. Females are more often affected in pediatric-onset AAV, whereas there is a slight male predominance in adult AAV 11. At diagnosis, there is a greater likelihood in pediatric-onset AAV of more severe disease and multi-organ involvement 2,46. Organ-specific presentation can also differ 11 e.g., crescentic glomeruli tend to predominate in diagnostic kidney biopsy tissue from children with AAV compared to more focal (renal) disease in adult AAV 35. Estimated glomerular filtration rate (eGFR) is the main measure of kidney function, used to estimate how well the kidneys are filtering blood 47. A higher eGFR indicates better kidney function, while a lower eGFR suggests impaired kidney function. In pediatric cases of AAV with renal involvement at diagnosis, the eGFR is higher (i.e., better) compared to adult-onset AAV. However, children are more likely to experience a rapid decline in kidney function (>50% decline in kidney function in less than 3 months) 48. Additionally, pediatric patients with lung involvement tend to experience better outcomes, including the preservation of lung function, compared to adults, possibly due to lower rates of DAH and ILD 49,50. 1.4 Disease course and outcomes of AAV AAV frequently progresses rapidly and can result in irreversible organ damage and death 51. Compared to the general population, patients with AAV are at a 2.6-fold increased risk of death 52. Although the disease used to be fatal for the majority of children, the current therapeutic approach has turned AAV into a chronic disease with a relapsing course 53. AAV follows a relapsing-remitting course consisting of periods of remission, interrupted by flares in disease. 12 More than 50% of patients will experience a relapse within 5 years 53. In adults, there are certain risk factors associated with an increased risk of relapse including PR3-ANCA seropositivity, pulmonary or renal involvement, and induction/maintenance treatment type 53. In pediatric patients, the reported remission rates post-diagnosis varies from 42% to 90%, though many patients demonstrate an improvement of at least 50% in disease activity 2. However, varying definitions of relapse and the practice of reporting relapse rates as a percentage of the entire cohort, rather than only those who achieved inactive disease or remission, makes it challenging to accurately determine relapse rates. 1.4.1 Measures of disease activity and damage To assess AAV disease severity and outcome, it is essential to determine the level and extent of (i) ongoing (inflammatory) disease activity, and (ii) permanent damage associated with the disease and/or treatment, both systemically and localized in the organs. To this end, the Birmingham Vasculitis Activity Score (BVAS) and the Vasculitis Damage Index (VDI) are tools developed from adult patient data and adapted for use in children, respectively, as the pediatric vasculitis activity score (PVAS) 54 and pediatric vasculitis damage index (pVDI) 55. The PVAS is a validated clinical scoring tool that quantifies disease activity by scoring disease manifestations across nine organ systems (maximum score 63) 56. The pVDI is a systematic assessment of damage across nine organ systems (maximum score 76). These tools are detailed in Section 2.2.1 and 2.2.2. These adapted tools have inherent limitations as they were developed using adult data and may not capture the physical and psychosocial aspects of pediatric disease. 13 1.4.2 Predictors of renal and pulmonary disease outcomes As the kidneys and lungs are two of the most commonly affected organs in AAV, their involvement has significant implications for the prognosis, management and outcome of the disease. Studies predominantly on adult-onset AAV have identified certain factors that can predict disease progression or poor outcomes. In AAV, renal involvement alone is known to be associated with increased mortality and morbidity 44. Declining renal function, high serum creatinine levels and dialysis dependence at diagnosis are associated with a poor prognosis, including high rates of end stage kidney disease (ESKD) and mortality 57,58,59. Additionally, as described earlier, certain histological features on kidney biopsy have been shown to have prognostic utility. Focal classification is associated with the retention of good kidney function, while sclerotic classifications have shown to be associated with a poor outcome, such as increased chances of progressing to ESKD 60. In general, pulmonary involvement can be considered a risk factor for mortality 36. As pulmonary manifestations can range from mild to severe, the outcome can look vastly different for patients. Alveolar hemorrhage been associated with early infection and relapse, whereas patients with ILD have a poor long-term prognosis including high risk of mortality 61. In comparison, the presence of pulmonary nodules is less predictive of worse pulmonary outcomes and may not impact survival 36. 1.5 Rationale Children with AAV and major organ involvement like the kidneys and the lungs are treated aggressively, without a clear understanding of what outcome is to be expected, whether such aggressive treatment is needed, and what damage might result from both the treatment and the 14 disease. While evolving treatment strategies developed in adults with AAV have significantly improved survival and reduced morbidity for both children and adults, disease relapses and irreversible organ damage still occur in many patients. Current evidence, although limited, suggests that children may have disease that is more likely to be severe at diagnosis and involve multiple organs. Additionally, due to disease rarity and scarcity of literature on disease course, treatment side effects and outcomes in the pediatric population, many questions remain regarding what a child can expect when they are diagnosed with AAV. Although studies in adult vasculitis offer valuable insights, it is important to understand that the impact of disease and its treatments (toxicity, safety, and efficacy) may be different in children, and comorbidities in children are likely to be less than those in adults. Additionally, the impact on physical and psychosocial growth and development is unique to children. It is crucial to identify specific factors at diagnosis that can predict both short- and long-term outcomes in order to better counsel families about prognosis, select best treatments and reduce morbidity. Until now, studies on outcomes and predictors of outcome have been limited by insufficient patient numbers and have often relied on retrospective chart review conducted over many years. In addition, these predictors are derived from adult studies, highlighting a gap in understanding the factors relevant to pediatric populations. It is important to determine whether these adult predictors are equally predictive in pediatric populations or if unique predictors specific to children need to be identified. Now, through the establishment of A Registry of Childhood Vasculitis (ARChiVe)/Pediatric Vasculitis Initiative (PedVas), a web-based registry of chronic childhood vasculitis, we have the ability to conduct this much needed research. Using the ARChiVe/PedVas registry, my thesis aims to describe pediatric-onset AAV-related renal (Chapter 15 3) and pulmonary (Chapter 4) disease at diagnosis, describe renal (Chapter 3) and pulmonary (Chapter 4) disease course and outcomes, assess predictors of pulmonary outcomes (Chapter 4), and evaluate the utility of eGFR at diagnosis to predict renal outcome at 12-months (Chapter 3). 16 Chapter 2: Materials and Methods 2.1 Study Participants Study participants were selected from A Registry for Childhood Vasculitis (ARChiVe), a web-based registry established in 2007 to collect time-of-diagnosis data from children and adolescents with primary chronic vasculitis 1. In January 2013, as part of the Pediatric Vasculitis Initiative (PedVas), the registry was expanded to collect clinical data beyond the time of diagnosis to include post-induction (4-6 months after diagnosis), 12-months post diagnosis, 24-months post diagnosis, and flare visit data. Thirty-seven international sites recruited patients for this study, the majority of which were located in Canada, United States, and the United Kingdom. PedVas collects data on demographics, diagnosis, clinical features, investigations, ANCA status, medications, disease activity, and damage. The protocol for this study was approved by the Childrenâs and Womenâs Research Ethics Board of the University of British Columbia (H12-00894) and the respective ethics committees at participating sites. Written informed consent was obtained from parents, and informed consent or assent was obtained from patients for participation in the study. 2.1.1 Pediatric-onset AAV patients with renal disease A flowchart detailing the inclusion and exclusion criteria is provided in Figure 2.1. Patients that were included in analyses presented in Chapter 3 were: â¤18 years of age at the time of a physician diagnosis of GPA, MPA, or ANCA-positive immune glomerulonephritis (GN); had complete clinical data at the time of diagnosis and follow-up at either 12-months, 24-months, or both; had renal disease defined as biopsy-confirmed glomerulonephritis or dialysis dependence 17 at the time of diagnosis. Patients who did not have complete data for age at diagnosis, biological sex or eGFR were excluded from the cohort. In total, 145 pediatric-onset AAV patients with renal disease were included in this cohort. 2.1.2 Pediatric-onset AAV patients with pulmonary disease A flowchart detailing the inclusion and exclusion criteria is provided in Figure 2.2. Patients that were included in analyses presented in Chapter 4 were: â¤18 years of age at the time of physician diagnosis of GPA, EGPA, or MPA; had complete clinical data at the time of diagnosis and follow-up at 12 months; had pulmonary disease attributable to AAV defined by the presence of pulmonary manifestations and/or abnormalities in lung imaging, pulmonary function test (PFT), and bronchoscopy. Pulmonary manifestations included any of the following: wheeze or expiratory dyspnea, nodules or cavities, pleural effusion/pleurisy, infiltrate, endobronchial involvement, massive haemoptysis/alveolar hemorrhage and respiratory failure. Patients who did not have complete data for the age at diagnosis or biological sex were excluded from the cohort. In total, 175 pediatric-onset AAV patients with pulmonary disease were included in this cohort. 18 Figure 2.1 Inclusion and exclusion criteria for pediatric-onset AAV patients with renal disease. A flowchart detailing the inclusion and exclusion criteria that was used to select the 145 pediatric-onset AAV patients with renal disease (results presented in Chapter 3). 19 Figure 2.2 Inclusion and exclusion criteria for pediatric-onset AAV patients with pulmonary disease. A flowchart detailing the inclusion and exclusion criteria that was used to select the 175 pediatric-onset AAV patients with pulmonary disease (results presented in Chapter 4). 2.2 Outcome measures 2.2.1 Overall disease activity (PVAS) Disease activity was assessed using the pediatric vasculitis activity score (PVAS, range 0-63) (Table A.1). PVAS is a validated clinical scoring tool used for the systematic assessment of active overall and organ-specific disease activity in pediatric vasculitis 54. The tool assesses nine different organ systems, with each item weighted according to the impact on the patient, as well if it is a new/worse item or a persistent item. It is important to note that when items in the PVAS are present for longer than three months, they are no longer counted as active disease, they are 20 counted as damage. Active disease is defined by total PVAS â¥ 2. Inactive disease is defined as total PVAS = 0 or 1. 2.2.2 Overall damage (pVDI) Disease damage was assessed using a pediatric version of the vasculitis damage index (pVDI, range 0-76) (Table A.2). The VDI is a validated clinical scoring tool for the systematic assessment of damage in individual organ systems where damage is recorded when abnormal features/function persist for â¥ 3 months 40,55. This includes damage that develops as a consequence of the disease or its treatment. Although the pediatric version of the VDI has not undergone formal validation, it is widely used and is the generally accepted tool for reporting damage in pediatric studies. The presence of damage is defined by a pVDI â¥ 1. As damage is considered to be irreversible, once scored items are captured in the pVDI, they are carried forward to all subsequent visits. 2.3 Kidney-specific outcomes measures 2.3.1 Kidney-specific disease activity and damage Kidney specific disease activity was scored using the renal subcomponent of PVAS (renal PVAS, range 0-12) and includes the following components: hypertension: systolic blood pressure >95th percentile based on age and height, proteinuria: >0.3 grams from 24 hr urine collection or spot urine protein-to-creatinine ratio >20 mg/mmol, haematuria: >5 rbc/hpf or red cell casts from urinalysis/urine microscopy, estimated (e)GFR 50-80 ml/min/1.73m2, eGFR 15-49 ml/min/1.73m2, eGFR <15 ml/min/1.73m2 and rise in creatinine >10% or eGFR reduction >25% 21 from baseline. Inactive renal disease was defined as a renal PVAS of 0 or 1, whereas active renal disease was defined as a renal PVAS â¥ 2. Kidney specific damage was defined as a renal subcomponent pVDI of 1 or more (range 0-4) and included the following components: blood pressure >95th centile (for age and height) or requiring antihypertensives, proteinuria, eGFR 15-60 ml/min/1.73m2, and end stage kidney disease (ESKD). ESKD is defined by an eGFR <15 ml/min/1.73m2 and it represents the most severe, irreversible stage. 2.3.2 Kidney function Kidney function was defined by the estimated glomerular filtration rate (eGFR; mL/min/1.73m2), calculated from serum creatinine values, individual height, and a constant (k) adjusted for age and sex according to the bedside Schwartz formula 47. Using the eGFR, kidney function was categorized according to the Kidney Disease Improving Global Outcomes (KDIGO) classification 62. KDIGO is used to classify the severity of chronic kidney disease (CKD), which is defined as abnormalities in kidney function, present for at least three months. The classification system involves the use of estimated glomerular filtration rate (eGFR) as this is considered to be more clinically useful compared to serum creatinine concentration alone 63. It is defined as: normal (eGFR >90 ml/min1.73m2, category 1), mildly reduced (MildR, eGFR 60-89 ml/min/1.73m2, category 2), mild-moderately reduced (mild-ModR, eGFR 45-59 ml/min/1.73m2, category 3a), moderately-severely reduced (Mod-SevR, eGFR 30-44 ml/min/1.73m2, category 3b), severely reduced (SevR, eGFR 15-29 ml/min/1.73m2, category 4) and kidney failure (KF, 22 eGFR <15 ml/min/1.73m2, category 5). For patients that underwent a kidney transplant, their pre-transplant eGFR values were used for analyses at subsequent follow-up time periods. Table 2.1 Kidney function as defined by KDIGO stages and eGFR KDIGO Stage eGFR (ml/min/1.73m2) Description of kidney function 1 â¥ 90 Normal kidney function 2 60-89 Mildly reduced kidney function 3 30-59 Moderately reduced kidney function 4 15-29 Severely reduced kidney function 5 <15 Kidney failure 2.3.3 Kidney outcome assessments Kidney-specific outcome assessments including active kidney disease (renal PVAS â¥ 2), kidney damage (renal pVDI â¥ 1), and kidney (dys)function as measured by the KDIGO stages and eGFR were completed at 12-months and/or 24-months. 2.4 Pulmonary-specific outcome measures 2.4.1 Pulmonary disease activity and damage scoring Pulmonary-specific disease activity was determined using the chest subcomponent of PVAS (chest PVAS, range 0-6). The following components are included: wheeze or expiratory dyspnea, nodules or cavities, pleural effusion/pleurisy, infiltrate, endobronchial involvement, massive haemoptysis/alveolar hemorrhage and respiratory failure. Inactive pulmonary disease was defined as a chest PVAS of 0 or 1, whereas active pulmonary disease was defined as a chest PVAS â¥ 2. 23 Pulmonary-specific damage was defined as a pulmonary subcomponent pVDI of 1 or more (range 0-6) and captures the following components: chronic tracheal/endobronchial stenosis, chronic lower airway obstruction (PFT obstruction), chronic breathlessness, pulmonary fibrosis, pleural fibrosis, pulmonary hypertension, pulmonary thrombo-embolic disease/infarction and chronic respiratory insufficiency. 2.4.2 Pulmonary function and lung imaging Pulmonary function was assessed using results of pulmonary function tests (PFT). PFT abnormalities included restrictive, obstructive and diffusion defects. Lung imaging findings included results from radiographs and computed tomography (CT)-scans. Abnormal findings on lung imaging included: single nodule, cavitation, pneumothorax, multiple nodules, migratory or transitory infiltrate, ill-defined fixed alveolar infiltrate, interstitial lung disease, endobronchial stenosis, pleural mass, septal thickening, fibrosis, and pleural effusion. 2.4.3 Pulmonary outcome assessments Pulmonary-specific outcome measures including active pulmonary disease (chest PVAS â¥ 2), pulmonary damage (chest pVDI â¥ 1), and abnormal PFTs were collected at 12-months. If a PFT was not completed at 12-months but available at the post-induction timepoint (4-6 months after diagnosis), then this data was used. When PFTs were completed at both post-induction and 12-months, the latest data at 12-months was used. 24 2.5 Statistical Analysis Data presented includes medians and interquartile ranges for continuous variables, and counts and frequencies for categorical variables. Analyses were conducted using R (R Core Team 2024), and figures were created using GraphPad Prism v9.0 Statistical Software (GraphPad Software, San Diego, California, USA). All estimates were presented with 95% confidence intervals with interpretation based on size of estimates and range of uncertainty. Statistical significance is indicated by *p < 0.05, **p < 0.01 and ***p<0.001. A summary of the statistical models and tests are provided below: (i) Descriptive statistics to summarize baseline characteristics and to report frequencies of eGFR across 24-months. Follow-up distributions and outcomes at 12-months and 24-months were also reported using descriptive statistics. (ii) A proportional odds logistic regression model was used to assess the association between eGFR at diagnosis and eGFR at 12-months. In this analysis, eGFR was analyzed as an ordinal categorical variable according to KDIGO categories. This model was adjusted for the following covariates: diagnosis (GPA or MPA), ANCA seropositivity and specificity for PR3 or MPO, disease activity (total and renal PVAS at diagnosis) and induction medication. These variables were selected a priori as potential factors that would associate with baseline and follow-up eGFR. (iii) A linear regression model was applied to data from a subset of patients with eGFR measures at diagnosis and 12-months. To determine a âthresholdâ value at which the 25 outcome (renal function at 12-months) is likely to be significantly reduced (Mod-SevR or worse), a cutpoint analysis was conducted using R package cutpointr 64. This analysis maximized the sum of sensitivity and specificity to determine an optimal cutpoint which was then plotted on an ROC curve to visualize the trade-off between sensitivity and specificity. (iv) A linear mixed-effects model investigated longitudinal changes in the PVAS at diagnosis, 12 months post-diagnosis, and 24 months post-diagnosis, with timepoint as the fixed effect and patient as the random effect. (v) Comparisons between groups of continuous data were analyzed using a t-test with Welch or Mann-Whitney corrections according to the normality test (Shapiro-Wilk test) of each data set. Comparisons between groups of categorical data were analyzed using a Chi-squared test of independence or Fisherâs exact test, based on sample size. (vi) A univariate and multivariable logistic regression analysis was performed to evaluate the relationship between the baseline variables and the outcomes of damage and abnormal PFT. The baseline variables included age, sex, diagnosis, ANCA seropositivity and specificity for PR3 or MPO, bronchoscopy results, chest disease activity scores, induction treatment (cyclophosphamide vs rituximab), whether renal involvement was present, and type of pulmonary presentation including interstitial lung disease, alveolar hemorrhage, nodules, respiratory failure, pulmonary fibrosis, and pleural effusion were also examined. 26 Chapter 3: Evaluating renal disease in pediatric-onset anti-neutrophil cytoplasmic antibody-associated vasculitis: disease course, outcomes, and utility of eGFR as a predictor of renal outcomes 3.1 Rationale and Introduction Due to the rarity of AAV in children, most knowledge about pediatric AAV is extrapolated from adult studies 65,66. Our previous research demonstrated that, compared to adult-onset AAV, pediatric-onset AAV is more likely to be severe and have major organ dysfunction, including high rates of renal disease (78% of children) at diagnosis 2. In a study of 105 patients with pediatric-onset AAV, 78% had renal disease, 16% were requiring dialysis and 5% had kidney failure at the time of diagnosis 2. Additionally, the study reported that 35% of children had renal damage by 12-months, with features of proteinuria, decreased estimated glomerular filtration rate (eGFR), end stage renal disease and hypertension. It is particularly concerning that many children have evidence of early renal damage, despite aggressive treatment. Previous adult AAV studies have examined predictors of renal outcomes and have found that eGFR and dialysis dependence are predictors of disease relapse, kidney failure and even death 59,67. The aims of the study were to 1) elucidate renal disease course and outcomes within the first 24-months of disease, and 2) evaluate the utility of eGFR at diagnosis to predict renal outcome at 12-months. I hypothesized that the majority (>50%) of children with AAV related renal disease would not recover normal renal function over the course of disease, and eGFR at diagnosis would be a strong predictor of renal function at 12-months. 27 3.2 Study Cohort The study cohort consisted of (n=145) pediatric-onset AAV patients with renal disease enrolled in the ARChiVe/PedVas study. Among these 145 patients, 142 had biopsy-confirmed glomerulonephritis, while three patients were dialysis dependent. These patients had complete follow-up clinical data, including eGFR information, at 12- (n=143) and 24-months (minimum n=79) post-diagnosis. In this cohort, renal involvement was defined as biopsy-confirmed glomerulonephritis or dialysis dependence at time of diagnosis. Detailed characteristics of this cohort can be found in Table 3.1. At diagnosis, patients were formally classified as GPA (78%, 113/145) or MPA (22%, 32/145) and had a median age of 13.8 years (IQR: 10.7-15.7). The majority of patients were female (68%, 98/145) and Caucasian (55%, 64/117). ANCA against proteinase-3 (PR3) only or myeloperoxidase (MPO) only were detected in 49% (71/144) and 47% (67/144) of cases, respectively. Four patients (3%) presented with ANCA against both PR3 and MPO. Patients received glucocorticoid treatment, along with cyclophosphamide (70%, 101/145), rituximab (13%, 19/145) or both (9%, 13/145) as part of their induction treatment. 28 Table 3.1 Demographic and renal characteristic of pediatric-onset AAV patients identified with renal disease eGFR; estimated glomerular filtration rate, PVAS; pediatric vasculitis activity score, IQR = interquartile range *Unless indicated otherwise, values refer to the absolute number (%) of patients in each given category. 1Two patients were classified based on immunofluorescence detection of c-ANCA (likely PR3-ANCA) Haematuria â¥ rbc/hpf or red cell casts; Proteinuria >0.3g/24hr or >20mg/mmol Cr; Hypertension >95thcentile Overall Characteristics Age at diagnosis, median (IQR) years 13.8 (10.7-15.7) Sex, Female Subjects N (%) 98 (67.6) Ethnicity, N (%) Caucasian 64 (54.7) Hispanic/Latino 13 (11.1) East Indian/South Asian 10 (8.5) Mixed 9 (7.7) Aboriginal 8 (6.8) Asian 6 (5.1) Middle Eastern 3 (2.6) Black 4 (3.4) Diagnosis, N (%) Granulomatosis with polyangiitis 113 (77.9) Microscopic polyangiitis 32 (22.1) ANCA antigen positivity, N (%) of tests done Proteinase-3 (PR3)1 71 (49.3) Myeloperoxidase (MPO) 67 (46.5) Both 4 (2.8) Negative 2 (1.4) Medications, N (%) Cyclophosphamide 101 (69.7) Rituximab 19 (13.1) Cyclophosphamide + Rituximab 13 (9.0) Renal Characteristics Hematuria 132 (91.0) Proteinuria 131 (90.3) Hypertension 41 (28.2) Glomerular filtration rate (eGFR)/KDIGO Normal (>90) 42 (28.9) Mildly Reduced (60-89) 13 (8.9) Mild-Moderately Reduced (45-59) 12 (8.3) Moderately-Severely Reduced (30-44) 33 (22.8) Severely Reduced (15-29) 21 (14.5) Kidney Failure (<15) 24 (16.6) Dialysis 36 (24.8) Disease activity (renal PVAS), median (IQR) 12 (10-12) 29 Extra-renal manifestations of disease at the time of diagnosis were indicated by the presence of one or more scored items in the organ-specific domains of PVAS: constitutional (75% of patients), ear-nose-throat (ENT, 43%), respiratory (41%), cutaneous (35%), mucous membranes/eyes (33%), abdominal (26%), nervous system (12%), cardiovascular (2%) (Figure 3.1A). At the time of data extraction, 24-month follow up data was not yet available for a proportion of patients. Patients with and without 24-month follow-up data were comparable, however, with respect to demographics and renal characteristics (Table 3.2). 30 Table 3.2 Baseline characteristics of patients with (n=79) and without (n=66) follow-up at 24-months eGFR; estimated glomerular filtration rate, PVAS; pediatric vasculitis activity score, IQR = interquartile range *Unless indicated otherwise, values refer to the absolute number (%) of patients in each given category. 1 Two patients were classified based on immunofluorescence detection of c-ANCA (likely PR3-ANCA) With follow-up at 24-mo (n=79) Without follow-up at 24-mo (n=66) Age at diagnosis, median (IQR) years 14.1 (10.2-15.5) 13.6 (10.9-15.6) Sex, Female N (%) 56 (70.9) 42 (63.6) Ethnicity, Caucasian N (%) 37 (46.8) 27 (40.9) Diagnosis, N (%) Granulomatosis with polyangiitis 65 (82.3) 48 (72.7) Microscopic polyangiitis 14 (17.7) 18 (27.3) 1ANCA antigen positivity, N (%) of tests done Proteinase-3 (PR3) 38 (48.1) 33 (50.0) Myeloperoxidase (MPO) 36 (45.6) 31 (46.9) Both 2 (2.5) 2 (3.0) Negative 2 (2.5) - Medications, N (%) Cyclophosphamide 60 (75.9) 41 (62.1) Rituximab 11 (13.9) 8 (12.1) Cyclophosphamide + Rituximab 6 (7.6) 7 (10.6) Renal Characteristics Hematuria 71 (89.9) 61 (92.4) Proteinuria 70 (88.6) 61 (92.4) Hypertension 15 (18.9) 24 (36.4) Glomerular Filtration rate (eGFR)/KDIGO Normal 28 (35.4) 14 (21.2) Mildly Reduced 8 (10.1) 5 (7.6) Mild-Moderately Reduced 6 (7.6) 6 (9.1) Moderately-Severely Reduced 19 (24.1) 14 (21.2) Severely Reduced 9 (11.4) 12 (18.2) Kidney Failure 9 (11.4) 15 (22.7) Dialysis 11 (13.9) 25 (37.9) Disease activity (renal PVAS), median (IQR) 10 (10-12) 12 (10-12) 31 3.3 Results 3.3.1 Despite high renal disease activity at diagnosis, most AAV patients attain inactive renal disease within two years of diagnosis At diagnosis, 99% of patients had active renal disease (renal PVAS >2). The majority (92%; 133/145) had highly active disease as indicated by a renal PVAS of 10 (n = 53) or 12 (n = 80, the maximum allowable score for renal PVAS); the median renal PVAS was 12 (IQR 10-12). At 12-months post diagnosis, 118 of 143 patients with available data (83%) had inactive renal disease (PVAS = 0 or 1). By 24-months post diagnosis, 98% of patients (85/87 with available data) had inactive renal disease. Comparing changes in renal PVAS across 24-months using a linear mixed effects model, renal disease activity decreased by 12-months (MD= -9.75; 95% CI: -10.16, -9.34) and 24-months (MD= -10.57, 95% CI: -11.05, -10.09) (Figure 3.1B). 32 Figure 3.1 Extra-renal manifestations at diagnosis and renal disease activity in the first 24 months in pediatric ANCA-associated vasculitis (AAV). A) Percent (%) of pediatric-onset AAV cases (y-axis) with organ-specific system involvement (x-axis) at the time of diagnosis. B) Renal PVAS (y-axis) in patients at time of diagnosis (TOD, n=145), 12-month follow-up (n=143) and 24-month follow-up (n=87). Inactive renal disease indicated by renal PVAS=0 or 1, regardless of corticosteroid dosage. Active renal disease is indicated by PVAS â¥2. ***P < 0.001 3.3.2 A significant proportion of AAV patients have evidence of permanent renal damage by 12-months Renal damage within two years of diagnosis was assessed in patients with a completed index of renal damage (renal pVDI) at 12-months (n=129) and/or 24-months (n=60). Despite the attainment of inactive disease in the majority of patients, more than one third had a renal pVDI â¥1 (indicative of damage) at 12-months (42%) and 24-months (35%). The renal damage items scored at 12-months were as follows: reduced eGFR of 15-60 ml/min/1.73m2 (31%), kidney failure by eGFR <15ml/min/1.73m2 (21%) and hypertension >95th centile or taking antihypertensives (15%). There were no deaths reported during the study period. 33 3.3.3 Patients that present with kidney failure are unlikely to recover normal renal function To assess the course of renal function from diagnosis, I investigated eGFR trajectory over the first 12- to 24-months of disease. At diagnosis, renal function based on eGFR varied: 29% of patients had a normal eGFR, 9% mildly reduced (MildR), 8% mild-moderately reduced (Mild-ModR), 23% moderately-severely reduced (Mod-SevR), 14% severely reduced (SevR), and 17% were in kidney failure (KF). Twenty-five percent of patients were on dialysis at diagnosis. At 24-months post diagnosis, the proportion of patients with a normal eGFR (32%) was similar to that observed at the time of diagnosis (29%) (Figure 3.2). The percentage of patients with mildly reduced eGFR increased from 9% at the time of diagnosis to 37% at 24-months. The percentage of patients with the most compromised renal function (Mod-SevR/SevR/KF) was 54% at diagnosis versus 31% at 12-months and 24% at 24-months. Figure 3.2 Estimated glomerular filtration rate (eGFR) at diagnosis, 12-months, and 24-months in pediatric ANCA-associated vasculitis. Percent of pediatric-onset AAV cases (%, y-axis) with eGFR values corresponding to KDIGO category of renal function (see legend; eGFR values in brackets with units ml/min/1.73m2) at (x-axis) diagnosis (n=145), 12-months (n=143), and 24-months (n=79). 34 Next, I followed eGFR trajectories across 12- and 24-months for patients at the âextremesâ of renal function at diagnosis, namely, patients presenting with an eGFR indicative of normal function (n = 42; eGFR >90 ml/min1.73m2) versus kidney failure (n = 23, eGFR <15 ml/min1.73m2) (Figure 3.3). Among the 42 patients that had normal renal function at diagnosis, 33 had 12-month follow-up and 17 of these patients had 24-month follow-up. Eighteen patients (53%) retained normal renal function (normal eGFR) while 14 patients (41%) had mild worsening (mild eGFR) by the time of their last follow-up (12-months or 24-months). Renal function in only two patients deteriorated to levels indicative of moderate to severely reduced function or kidney failure (Mod-SevR or KF eGFR). Among the 23 patients that were in kidney failure at diagnosis, 74% were still in kidney failure or were transplanted (n=6) by 12-months, and none achieved a normal eGFR without a renal transplant. 35 Figure 3.3 Estimated glomerular filtration rate (eGFR) in pediatric ANCA-associated vasculitis (AAV) at diagnosis, 12-month follow-up and 24-month follow-up, for patients with âextremeâ renal function (normal versus kidney failure) at diagnosis. A-D) eGFR (y-axis; ml/min/1.73m2) with A-B) ânormalâ renal function (eGFR>90) at diagnosis followed across A) 12-months (n=33) and B) 24-months (n=17), and C-D) kidney failure (eGFR<15) at diagnosis followed across C) 12-months (n=23 including renal transplant shown by dashed line, n=6) and D) 24-months (n=9 including renal transplant shown by dashed line, n=6). Upper dotted line represents the lower limit of normal eGFR (=90); middle dotted line represents the lower limit of mildly reduced eGFR (=60); lower dotted line represents the upper limit of kidney failure (eGFR=15). 3.3.4 eGFR at diagnosis is predictive of renal function 12-months after diagnosis There was a clear linear relationship between baseline KDIGO category and 12-month KDIGO category. The odds of being in a non-normal KDIGO category at 12-months were 4.77 (OR=4.77, p=0.005, 95% CI: 1.60, 14.2), 8.62 (OR=8.62, p=0.002, 95% CI: 2.31, 32.1) and 26.3 (OR= 26.3, p <0.001, 95% CI: 6.32, 109) times higher in patients with moderate, severely reduced or kidney failure at baseline compared to those with normal baseline renal function, respectively (Table 3.3, Figure 3.4). Of note, for both the mildly reduced and mild-moderately 36 reduced KDIGO categories, there was no increased odds of having impaired renal function at 12-months. Table 3.3 KDIGO category at diagnosis as a predictor of non-normal KDIGO category at 12-month follow-up Characteristic OR1 95% CI1 P-value KDIGO Diagnosis Normal MildR Mild-ModR Mod-SevR SevR KF - - - 1.36 0.31, 5.87 0.680 1.02 0.24, 4.36 0.981 4.77 1.60, 14.2 0.005 8.62 2.31, 32.1 0.002 26.3 6.32, 109 <0.001 Figure 3.4 Predicted probability of KDIGO stage at 12-months post-diagnosis based on KDIGO stage at diagnosis. KDIGO stages at diagnosis (x-axis) against the predicted probability (y-axis) of being in a certain KDIGO stage at 12-month follow-up in individuals with childhood ANCA-associated vasculitis (n=143). The KDIGO stages are defined by eGFR measures as followed: normal (eGFR >90 ml/min/1.73m2), mildly reduced (mildR, eGFR = 60-89), mild-moderately reduced (mild-modR, eGFR =45-59), moderately-severely reduced (mod-sevR, eGFR =30-44), severely reduced (sevR, eGFR =15-29), and kidney failure (KF, eGFR <15). 37 Based on this data, we then explored an optimal cutpoint eGFR at diagnosis, or âthresholdâ value at which the outcome (renal function at 12-months) is likely to be significantly reduced (Mod-SevR or worse). The analysis showed that an eGFR = 38 ml/min/1.73m2 (95% CI: 21, 41) at diagnosis maximized the sum of sensitivity and specificity as seen on the ROC curve (Figure 3.5A). At this cut-point, the sensitivity was 74% and the specificity was 89%, placing it within the Mod-SevR range. Additionally, the area under the curve (AUC) was calculated to be 0.84 (95% CI: 0.76 to 0.92), indicating good discriminative ability. Further, 31 of 51 (61%) patients who were diagnosed below the cut point continued to have, at 12-months, renal dysfunction in the Mod-SevR range or worse while the majority of patients (95%) that were above this cut point value (Mod-SevR or more mild renal dysfunction) at diagnosis remained in the same category or showed improvement by 12-months (Figure 3.5B). A number of patients improved significantly over 12-months (reaching an eGFR > 44 ml/min/1.73m2) despite having an initial eGFR indicating poor prognosis (below the cutpoint threshold at diagnosis). To assess commonalities in the baseline variables of this group of patients with substantive and unpredictable improvement, I conducted a sub-analysis comparing patients below the cutpoint threshold at diagnosis who improved by 12-months to those who did not improve by 12-months. Improvement was defined as patients exceeding the Mod-SevR upper limit of eGFR, set at 44. Baseline variables included: age, sex, diagnosis, ANCA status and treatment choice. None of the assessed variables had statistically significant differences between the two groups thus, could not provide insight into the markedly different trajectories of these two groups of patients. 38 Figure 3.5 Estimated glomerular filtration rate (eGFR) in pediatric ANCA-associated vasculitis at diagnosis and 12-months. A) Receiver operating characteristic (ROC) curve depicting the false positive rate (x-axis; 1-specificity) and true positive rate (y-axis; sensitivity) trade-off. B) eGFR values at diagnosis (x axis; ml/min/1.73m2) against eGFR values at 12-month follow-up (y axis; ml/min/1.73 m2) in patients with pediatric ANCA-associated vasculitis (n=113). The vertical dotted line at the x-axis represents the cut-point eGFR value of 38. The horizontal line on the y-axis represents the eGFR value of 44.0, the upper limit of the moderately reduced renal function (KDIGO category). 3.4 Discussion In this study of pediatric-onset AAV with renal disease, the majority of patients had a diagnosis of GPA, were predominantly female, Caucasian and had a median age at diagnosis of 13.8 years, consistent with our previous outcome study (n = 105 patients) and other pediatric AAV studies2,38. This aligns with known geographic variation in the incidence of AAV where GPA is seen more in European populations, matching the demographics of the centers involved in our study 13. Using time of diagnosis and 12- and/or 24-month follow up data from this cohort, I described the renal disease course, outcomes, and utility of eGFR at diagnosis to predict 12-month renal outcomes. 39 Although the majority of pediatric patients presented with very high renal disease activity at diagnosis, the results show that the majority achieved inactive renal disease (PVAS = 0 or 1) 12- or 24-months after diagnosis. However, despite improvement in renal disease activity, two-thirds of patients had reduced renal function (eGFR <90 ml/min/1.73m2) at 12- and 24-months and more than one-third had evidence of permanent renal damage. A previous study of AAV in adults showed the most frequently recorded damage items at 6-months follow-up and long-term follow-up (up to 7 years) consisted of renal items including eGFR <50mL/min and hypertension66. Comparatively, the most common renal damage items in this study cohort consisted of eGFR 15-60 ml/min/1.73m2, kidney failure by eGFR <15ml/min/1.73m2 and hypertension >95th centile/antihypertensives. This highlights that similar to adults, renal damage is a common occurrence in pediatric individuals with AAV; however, is potentially more concerning given the longer life-time burden for children compared to adults who are usually diagnosed at over 50 years of age. There is evidence that adult patients with chronic kidney disease (CKD) stage 4 and 5 (equivalent to KDIGO category 4 and 5) and a lower âbaselineâ eGFR are at a higher risk for kidney failure and need for renal replacement therapy 68,69. Although a few studies on adult-onset AAV describe low baseline eGFR as a predictor of renal survival and mortality 70,71, very few studies have examined this in pediatric-onset AAV 33,72. A single-center study (n=48) by Yang et al. suggested that a baseline eGFR <60 ml/min/1.73m2 is an independent predictor of non-remission and poor long-term renal outcomes 33. Another study suggested that GFR <19.42 ml/min/1.73m2 is an independent risk factor for kidney failure in children with AAV 72. In a study involving 53 patients, several variables including baseline serum creatine and eGFR were 40 associated with an increased risk of developing kidney failure or progressing to chronic kidney disease stages 3-5; however, a multivariable analysis revealed that none of these variables were independent predictors 22.The results of this study demonstrate that eGFR at diagnosis is a strong predictor of eGFR at 12-month follow-up. Patients who have a normal eGFR at diagnosis are likely to maintain normal or mildly reduced renal function. In contrast, patients who present with kidney failure at diagnosis are unlikely to experience any substantive improvement in function and go on to need renal replacement therapy in the form of dialysis or a renal transplant. Moreover, this research identified an eGFR cutpoint threshold of 38 ml/min/1.73m2, below which patients exhibited a higher likelihood of having significant (Mod-SevR, SevR, or KF) renal dysfunction by 12-months. Patients with an eGFR above this threshold at diagnosis exhibited either stabilization or improvement in renal function by 12-months. This observed finding is of interest and deserves further prospective study. We acknowledge that a single eGFR value as a threshold value may be artificial given the limitations and accepted margins of error in reporting eGFR; however, the concept of having a âthresholdâ range or category of eGFR that has predictive utility may be of significant value as a clinical tool. Validation of such a threshold could have significant clinical implications by informing prognosis and improving the ability to counsel patients at diagnosis â for patients below this threshold the prognosis might be more guarded for renal recovery versus a more optimistic outlook for those above the threshold. Patients in this study generally received standard therapy with either cyclophosphamide or rituximab, both in combination with glucocorticoids in varied regimens. Whether patients with very mild disease or very severe (with irreversible damage) disease at diagnosis could have been treated with lower doses or a reduced duration of these aggressive immunosuppressants remains 41 unclear, but of significant interest 73. The goal remains to consider limiting corticosteroids for patients that donât require it or wonât benefit from such treatment, such as those that are on trajectory for poor renal outcomes regardless of treatment. Currently, kidney biopsies play an important role in aiding prognostication around the time of diagnosis; however, their utility is impacted by sampling limitations and challenges of conducting the procedure repeatedly or at diagnosis when the patient may be facing other critical health challenges. A previous study by Noone et al. highlighted the clinical utility of the Berden histopathological classification system, particularly for focal and sclerotic features on biopsy 31,32. The results showed that 2 years after diagnosis, patients with sclerotic features (n=5) all progressed to end stage kidney disease compared to none of the patients with focal disease (n=13). Due to small sample size, however, the âless extremeâ biopsy types (mixed and crescentic categories) had to be combined and could not be analyzed as individual groups. This system offers important prognostic information in pediatric-onset ANCA glomerulonephritis; however, its utility for discriminating outcomes in less extreme biopsy cases remains unclear32. Ultimately, the optimal predictor of longer-term renal function may need to utilize both biopsy and eGFR data. 42 Chapter 4: Pulmonary disease in pediatric-onset ANCA-associated vasculitis: early disease course and outcomes 4.1 Rationale and Introduction Pulmonary involvement is reported to impact 52 - 80% of adult AAV patients and includes manifestations of alveolar hemorrhage, nodules, and pulmonary fibrosis 61,74. Studies have demonstrated that certain types of lung disease, for example interstitial lung disease (ILD) and alveolar haemorrhage, are associated with worse morbidity and mortality 75,76,61,36. Different pulmonary features can exhibit distinct clinical characteristics and outcomes â ILD is associated with poor long-term prognosis 36, pulmonary granulomas have a greater risk of relapse while those with airway involvement have a higher risk of infection 61. Studies of adult-onset AAV have further demonstrated that between 12 - 28% of patients have evidence of pulmonary damage by 12-months as scored by the VDI, including features of impaired pulmonary function and chronic breathlessness 77,78. Although renal involvement is one of the most common manifestations of pediatric-onset AAV, pulmonary involvement is also frequently observed. Pediatric studies exploring pulmonary manifestations are limited, but the few available have demonstrated that many children affected with AAV present with lung involvement 50,79. Chronic cough and pulmonary hemorrhage are often the most commonly reported presenting features 1,79. Nodules, fixed infiltrates, and ground glass opacities are the most common features on chest imaging in children with AAV, alongside obstructive, restrictive, and diffusion abnormalities in pulmonary function tests 50,79. A previous study led by our centre showed severe lung disease in children with AAV at diagnosis, including massive pulmonary hemorrhage in 32% of all cases and, in 10% of cases, respiratory failure 2. 43 As literature on pulmonary manifestations in pediatric-onset AAV is scarce, knowledge about how lung disease presents, how it responds to treatment and how it affects health outcomes has not been well studied. Additionally, there is a lack of information on imaging findings, clinical presentations and whether there are features at baseline associated with outcomes. The primary objectives of this research were to describe pediatric-onset AAV-related pulmonary disease at diagnosis, evaluate early disease course and 12-month outcomes, and to assess baseline variables at diagnosis as predictors of pulmonary outcomes. 4.2 Study Cohort The study cohort consisted of (n=175) pediatric-onset AAV patients enrolled in the ARChiVe/PedVas study with complete clinical data for age at diagnosis, biological sex and one-year outcome data. Examining 24-month outcomes was limited by the availability of imaging and PFT data at this time point. All patients had pulmonary involvement attributed to AAV at diagnosis defined by the presence of pulmonary manifestations (clinical), abnormalities in lung imaging, pulmonary function tests or bronchoscopy. Further details regarding the selection criteria of the study cohort are provided in Figure 2.2. Detailed characteristics of this cohort are shown in Table 4.1. Eighty-seven percent of patients had a diagnosis of GPA with a median age of 14.0 years (IQR: 11.3-15.8). The majority of patients were female (65%, 114/175) and Caucasian (61%, 89/145). Among these patients, 65% (113/174) were PR3-ANCA seropositive and 29% (49/174) were MPO-ANCA seropositive. At 44 induction, 97% (n=169) of patients received glucocorticoid treatment, alongside cyclophosphamide (55%, 97/175), rituximab (16%, 28/175) or both (8%, 14/175). Regarding extra-pulmonary involvement, the most frequent manifestations were renal (87%, n=153), constitutional (81%, n=142), and ear-nose-throat (ENT, 57%, n=100). The median total PVAS was 20 (IQR: 15.5-24). 45 Table 4.1 Demographic and clinical characteristic of pediatric-onset AAV patients with pulmonary disease at diagnosis Overall Characteristics Age at diagnosis, median (IQR) years 14.0 years (11.3-15.8) Sex, Female subjects, N (%) 114 (65.1) Ethnicity, N (%) Caucasian 89 (61.4) East Indian/South Asian 12 (8.3) Hispanic/Latino 12 (8.3) Mixed 9 (6.2) Asian 8 (5.5) Aboriginal 6 (4.1) Middle Eastern 5 (3.4) Black 4 (2.8) Diagnosis, N (%) Granulomatosis with polyangiitis 153 (87.4) Microscopic polyangiitis 15 (8.6) Eosinophilic granulomatosis with polyangiitis 7 (4.0) ANCA Status, N (%) of tests done PR31 113 (64.9) MPO 49 (28.2) Both 3 (1.7) Negative 9 (5.2) Medications, N (%) Cyclophosphamide 97 (55.4) Rituximab 28 (16.0) Cyclophosphamide + rituximab 14 (8.0) Plasma exchange 44 (25.1) Methotrexate 15 (8.6) Intravenous gamma globulin (IVIG) 10 (5.7) Mycophenolate mofetil 8 (4.6) Azathioprine 6 (3.4) Past Medical History (Lung Related) Asthma 23 (13.1) Tuberculosis 1 (0.57) Other lung disease (including cystic fibrosis) 8 (4.6) Extra-Pulmonary Manifestations Renal 153 (87.4) 46 *Unless indicated otherwise, values refer to the absolute number (%) of patients in each given category. 1Three patients were classified based on immunofluorescence detection of c-ANCA (likely PR3-ANCA) IQR: Interquartile range 4.3 Results 4.3.1 Chest image features Of the 175 patients in the cohort, 173 had imaging done at diagnosis, including those who had CT imaging only (n=50), x-ray imaging only (n=18) or both (n=103). Of these patients, n=163 had abnormal imaging at diagnosis. The most common imaging findings were multiple nodules (46%, n=79), ill-defined fixed alveolar infiltrate (34%, n=59) and pleural effusion (21%, n=37) Of the 173 patients that had imaging done at diagnosis, 32% (n=55) underwent follow-up imaging at 12-months. 24 patients (44%) had improvement to normal imaging by 12-months while 22 patients (40%) had persisting abnormalities. Of the 153 CT scans conducted, the most prevalent findings were multiple nodules (50%, n=77), ill-defined fixed alveolar infiltrate (34%, n=52) and ground glass opacities (26%, n=40). Less common findings included pleural effusion (22%, n=34), cavitation (18%, n=28), and septal thickening (12%, n=18) (Table 4.2). Constitutional 142 (81.1) Ear-Nose-Throat (ENT) 100 (57.1) Cutaneous 69 (39.4) Mucous Membranes/Eyes 58 (33.1) Abdominal 42 (24.0) Nervous System 27 (15.4) Cardiovascular 12 (6.9) Disease Activity (total PVAS), median (IQR) 20 (15.5-24.0) 47 Table 4.2 CT abnormal imaging features at diagnosis CT Imaging Features N (%) Multiple nodules 77 (50.3) Ill-defined fixed alveolar infiltrate 52 (33.9) Ground-glass opacities 40 (26.1) Pleural effusion 34 (22.2) Cavitation 28 (18.3) Septal thickening 18 (11.7) Migratory or transitory infiltrate 14 (9.1) Fibrosis 8 (5.2) Single nodule 6 (3.9) Endobronchial stenosis 3 (1.9) Pleural mass 3 (1.9) Pneumothorax 3 (1.9) 4.3.2 Patients present with high pulmonary disease activity at diagnosis yet achieve inactive pulmonary disease within a year of diagnosis At diagnosis, 53% (n=93) of patients had evidence of active pulmonary disease (chest PVAS â¥2). The majority of the patients (78%, n=73) had a chest PVAS of 6 at diagnosis, which is the maximum allowable score for this organ system. The pulmonary disease manifestations on chest PVAS and imaging included massive haemoptysis/alveolar hemorrhage (39%, n=69), pleural effusion/pleurisy (34%, n=59) and wheeze/expiratory dyspnea (13%, n=23) (Table 4.3). By 12-months, only six patients (3%) had evidence of active pulmonary disease. 89 of the 93 patients achieved inactive disease by 12-months or maintained inactive disease throughout their disease course (45%, n=79). Two patients had inactive disease at diagnosis which became active by 12-months. 48 Table 4.3 Pulmonary clinical characteristics in pediatric-onset AAV at diagnosis Pulmonary Clinical Characteristics N (%) Diagnosis (n = 175) Month 12 (n = 174) Massive haemoptysis/alveolar hemorrhage 69 (39.4) 2 (1.1) Pleural effusion/pleurisy 59 (33.7) 2 (1.1) Wheeze/expiratory dyspnea 23 (13.1) 5 (2.9) Respiratory failure 21 (12.0) 2 (1.1) Endobronchial/endotracheal involvement 7 (4.0) 1 (0.5) Nodules or cavities 83 (47.4) 7 (4.0) Infiltrate 66 (37.7) 4 (2.3) 4.3.3 Despite high disease activity at diagnosis, the majority of patients do not develop permanent pulmonary damage The pVDI was completed in 163 patients at 12-months. Fourteen percent (22/163) of patients had evidence of pulmonary damage (pVDI â¥1). Damage characteristics included chronic respiratory insufficiency (68%, n=15), pulmonary fibrosis (23%, n=5), chronic lower airway obstruction (23%, n=5), chronic breathlessness (14%, n=3), pulmonary hypertension (9%, n=2), and pulmonary thrombo-embolic disease/infarction (9%, n=2). There were no deaths reported during the study period. The baseline characteristics of patients with pulmonary damage and without pulmonary damage at 12-months were compared (Table 4.4), and no significant differences were found. 49 Table 4.4 Baseline characteristics of pediatric-onset AAV patients with and without pulmonary damage at 12 months Baseline Characteristics Damage (n = 22) No Damage (n = 141) Age at diagnosis, median (IQR) years 14.2 years (13.2-16.2) 13.9 years (11.3-15.7) Sex, Female Subjects, N (%) 14 (63.6) 94 (66.7) Ethnicity, Caucasian, N (%) 13 (59.0) 68 (48.2) Diagnosis, N (%) Granulomatosis with polyangiitis 15 (68.2) 123 (87.2) Microscopic polyangiitis 4 (18.2) 14 (9.9) Eosinophilic granulomatosis with polyangiitis 3 (13.6) 4 (2.8) ANCA Status, N (%) Proteinase-3 13 (59.1) 92 (65.2) Myeloperoxidase 6 (27.3) 39 (27.7) Both - 2 (1.4) Negative 3 (13.6) 7 (4.9) Pulmonary Function Test, N (%) Abnormal 9 (40.9) 46 (32.6) Lungs Imaging, N (%) Abnormal 19 (86.4) 129 (91.5) At diagnosis, 98 patients (56%) had completed a pulmonary function test (PFT) among whom, 41% (40/98) had a normal PFT compared to 59% (58/98) with an abnormal PFT. Comparatively, at 12-months, 70% (52/74) had a normal PFT whereas 30% (22/74) had an abnormal PFT. The abnormalities included restrictive (48% n=28), obstructive (45%, n=26), and diffusion defects (40%, n=23) at diagnosis; compared to 32% (n=7), 55% (n=12) and 18% (n=4), respectively at 12-months (Table 4.5). Table 4.5 Abnormal pulmonary function test manifestations at diagnosis and 12-months Abnormal Pulmonary Function Test, N (%) Diagnosis (n = 58) Month 12 (n = 22) Restrictive Defect 28 (48.2) 7 (31.8) Obstructive Defect 26 (44.8) 12 (54.5) Diffusion Defect 23 (39.7) 4 (18.2) 50 4.3.4 Exploratory analysis reveals no predictors of lung damage I questioned if any predictors of lung damage, as quantified by the pVDI and/or indicated by an abnormal pulmonary function test, could be identified. A univariate logistic regression analysis assessing baseline variables (listed in Table 4.7) as predictors of the outcomes of interest (lung damage and abnormal pulmonary functions test) did not yield any statistically significant results (Table 4.6 and Table 4.7). Rituximab treatment had a 2.7 times (CI: 0.8, 8.8) higher odds of obtaining an abnormal pulmonary function test compared to cyclophosphamide treatment. Table 4.6 Univariate logistic regression analysis of baseline factors associated with abnormal pulmonary function test at 12-months Univariate Analysis for Abnormal Pulmonary Function Test Factor Comparison Odds Ratio P-value Age in years 0.968 (0.852, 1.103) 0.614 Sex at birth Male vs. Female 0.685 (0.277, 1.612) 0.396 Diagnosis eGPA vs. GPA 1.548 (0.196, 9.833) 0.642 Diagnosis MPA vs. GPA 1.548 (0.372, 5.847) 0.523 ANCA Type MPO vs. PR3 0.664 (0.234, 1.722) 0.415 Chest Disease Activity Chest PVAS 0 to 6 1.014 (0.878, 1.172) 0.848 Treatment Both* vs. Cyclophosphamide 0.511 (0.026, 3.335) 0.549 Treatment Rituximab vs. Cyclophosphamide 2.683 (0.818, 8.761) 0.098 Renal Involvement 0.966 (0.873, 1.072) 0.499 Alveolar Hemorrhage Present vs. Not present 1.086 (0.47, 2.478) 0.845 Respiratory Failure Present vs. Not present 0.5 (0.108, 1.714) 0.309 Multiple Nodules Present vs. Not present 1.035 (0.45, 2.362) 0.934 Pulmonary Fibrosis Present vs. Not present 0.547 (0.027, 3.881) 0.596 Pleural Effusion Present vs. Not present 0.393 (0.086, 1.307) 0.164 Infiltrate Present vs. Not present 1.447 (0.582, 3.512) 0.417 *Patients receiving both cyclophosphamide and rituximab treatment 51 Table 4.7 Univariate logistic regression analysis of baseline factors associated with pulmonary damage at 12-months Univariate Analysis for Pulmonary Damage Baseline factor Comparison Odds Ratio P-value Age in years 1.068 (0.937, 1.241) 0.354 Sex at birth Male vs. Female 1.236 (0.486, 3.012) 0.645 Diagnosis eGPA vs. GPA 5.625 (1.04, 27.569) 0.032 Diagnosis MPA vs. GPA 1.154 (0.172, 4.642) 0.858 ANCA Type MPO vs. PR3 1.642 (0.604, 4.271) 0.314 Chest Disease Activity Chest PVAS 0 to 6 1.188 (1.013, 1.412) 0.039 Treatment Both* vs. Cyclophosphamide 1.762 (0.364, 6.599) 0.429 Treatment Rituximab vs. Cyclophosphamide 0.497 (0.075, 1.956) 0.377 Renal Involvement 0.921 (0.835, 1.023) 0.109 Alveolar Hemorrhage Present vs. Not present 1.528 (0.625, 3.71) 0.346 Respiratory Failure Present vs. Not present 1.117 (0.245, 3.688) 0.869 Multiple Nodules Present vs. Not present 1.955 (0.689, 5.828) 0.212 Pulmonary Fibrosis Present vs. Not present 1.344 (0.066, 9.845) 0.797 Pleural Effusion Present vs. Not present 1.67 (0.424, 5.556) 0.424 Infiltrate Present vs. Not present 1.083 (0.318, 3.254) 0.891 * Patients receiving both cyclophosphamide and rituximab treatment Following this result, I compared the baseline characteristics and pulmonary involvement between the two treatment groups (rituximab vs. cyclophosphamide) to see if there were any significant differences in clinical characteristics based on treatment choice (Table 4.8). No statistically significant differences were found. Of the 22 patients with an abnormal PFT at 12-months, eight patients were on cyclophosphamide treatment and six patients were on rituximab treatment. 52 Table 4.8 Baseline characteristics of pediatric-onset AAV patients on cyclophosphamide treatment versus rituximab treatment Baseline characteristics Cyclophosphamide (n = 97) Rituximab (n = 28) Age at diagnosis, median (IQR) years 13.9 (11.3- 15.6) 14.7 (12.3 - 16.3) Sex, Female Subjects, N (%) 64 (65.9) 14 (50.0) Ethnicity, Caucasian, N(%) 47 (48.5) 15 (53.6) Diagnosis, GPA, N (%) 87 (89.7) 25 (89.3) ANCA Status, PR3, N (%) 69 (71.1) 20 (71.4) Presence of renal disease (%) 89 (91.7) 25 (89.2) Pulmonary Presentation Alveolar Hemorrhage Respiratory Failure Multiple Nodules Pulmonary Fibrosis Pleural Effusion Infiltrate Abnormal Bronchoscopy Abnormal Pulmonary Function Test 39 (40.2) 11 (11.3) 46 (47.4) 5 (5.2) 18 (18.6) 30 (30.9) 15 (15.5) 36 (37.1) 13 (46.4) 4 (14.3) 13 (46.4) - 7 (25.0) 13 (46.4) 6 (21.4) 6 (21.4) Next, a multivariable logistic regression analysis was conducted assessing baseline variables as predictors of the outcomes of interest, but no statistically significant findings were found (Table 4.9 and Table 4.10). 53 Table 4.9 Multivariate logistic regression analysis of baseline factors associated with abnormal pulmonary function test Multivariate Analysis for Abnormal Pulmonary Function Test Characteristic OR1 95% CI P-value Treatment Cyclophosphamide Rituximab Both - 3.54 0.55 - 0.97, 13.8 0.02, 4.75 - 0.058 0.6 Diagnosis GPA eGPA MPA - 0.00 3.06 - 0.45, 20.3 - >0.9 0.2 Multiple Nodules Not Present Present - 2.28 - 0.70, 8.15 - 0.2 Alveolar Hemorrhage Not Present Present - 1.41 - 0.47, 4.29 - 0.5 Pulmonary Fibrosis Not Present Present - 1.96 - 0.08, 26.6 - 0.6 Pleural Effusion Not Present Present - 0.12 - 0.01, 0.72 - 0.056 Infiltrate Not Present Present - 1.45 - 0.42, 4.99 - 0.5 1OR= Odds Ratio, CI= Confidence Interval 54 Table 4.10 Multivariable logistic regression analysis of baseline factors associated with pulmonary damage Multivariate Analysis for Pulmonary Damage Characteristic OR1 95% CI P-value Treatment Cyclophosphamide Rituximab Both - 0.67 5.12 - 0.03, 4.70 0.68, 40.4 - 0.7 0.11 Diagnosis GPA eGPA MPA - 11.3 2.56 - 0.34, 418 0.11, 30.2 - 0.14 0.5 Multiple Nodules Not Present Present - 4.04 - 0.93, 22.8 - 0.079 Alveolar Hemorrhage Not Present Present - 2.18 - 0.56, 9.07 - 0.3 Pulmonary Fibrosis Not Present Present - 3.23 - 0.12, 47.6 - 0.4 Pleural Effusion Not Present Present - 0.41 - 0.05, 2.25 - 0.4 Infiltrate Not Present Present - 1.16 - 0.22, 5.45 - 0.8 1OR= Odds Ratio, CI= Confidence Interval 4.4 Discussion The rarity of pediatric AAV and corresponding scarcity of literature on pulmonary manifestations and outcomes in this population has resulted in uncertainty about disease course, anticipated outcomes and optimal treatment strategies. Our results describe pulmonary disease course including patient demographics, clinical presentation and early outcomes in a cohort of pediatric-onset AAV patients. The predominant 55 subtype of AAV in our cohort was GPA (153 patients with GPA and 15 with MPA). This reflects the high rates of pulmonary disease in this subtype, consistent with findings from other studies 80,81. The lungs are among the most commonly affected organs in patients diagnosed with GPA, with over 90% of patients demonstrating evidence of involvement 81. In GPA, lung involvement occurs in 45-94% of patients whereas in MPA, it occurs in 22-55% of patients 80,22. Additionally, there is known geographic variation in the incidence of AAV, with GPA more commonly seen in European populations, which aligns with the centers contributing patients to our study, while MPA is more commonly observed in Asian populations 80,82. Pulmonary involvement is a common manifestation in children but has variable severity. Larger pediatric studies have reported an incidence of pulmonary involvement in 45-80% of patients, with the most prevalent features consisting of alveolar hemorrhage, fixed infiltrates and abnormal findings on chest imaging 2,28,22. In our cohort, the most common presenting manifestations were massive haemoptysis/alveolar hemorrhage, pleural effusion/pleurisy and wheeze/expiratory dyspnea. With respect to imaging findings, the most frequent chest CT abnormalities were nodules, ill-defined fixed alveolar infiltrate and ground-glass opacities, consistent with previous pediatric reports 77,83,84. Alveolar hemorrhage is one of the most common manifestations of lung involvement, occurring in approximately 30% of patients with adult-onset AAV 83,85. The observed frequency of alveolar hemorrhage in our study (39%) falls within the ranges described in smaller series (30% to 57%) and large pediatric studies (21% to 34%) 79,86,2,28. A small study involving five children with pulmonary involvement showed that children that presented with 56 pulmonary hemorrhage had a favorable outcome 83. In our study, despite 39% of patients presenting with pulmonary hemorrhage, pulmonary outcomes were overall favorable. Pulmonary involvement is recognized as a predictor of poor prognosis in AAV, dependent on the type of lung manifestations 87,88. Manifestations can vary from being mildly symptomatic (including nodules, shortness of breath, pulmonary infiltrate) to being life-threatening, such as having diffuse alveolar hemorrhage or respiratory failure which leads to poor outcomes 87,88. In adults, interstitial lung disease and alveolar hemorrhage tend to have a worse prognosis. Pulmonary involvement is considered a risk factor for relapse, particularly in patients with pulmonary granulomas and alveolar hemorrhage 87,88. Long-term follow-up in adult AAV patients identified several independent factors of all-cause mortality including age â¥ 65 years, interstitial lung disease and respiratory involvement 61. Our study investigated pulmonary manifestations such as multiple nodules, alveolar hemorrhage, pulmonary fibrosis, pleural effusion and infiltrate as potential predictors of pulmonary damage but did not find any significant associations; however, our analysis was exploratory and limited by the low number of patients with the outcome of interest (damage or abnormal PFT). In our study, more than half of children had active pulmonary disease at diagnosis, and the majority of those patients had the maximal chest PVAS. Despite this, almost all patients achieved inactive pulmonary disease by 12-months. Comparatively, an adult study (n=151 patients) demonstrated that patients with lung involvement at diagnosis were more likely to develop pulmonary fibrosis and impaired lung function at two-year follow-up, and had higher initial disease activity scores as measured by the Birmingham Vasculitis Activity Score (BVAS) 89. At 57 6-months, 12-months and 24-months, patients continued to have active disease with no meaningful improvements being made 89. Our study cohort demonstrated better outcomes compared to previous reports in adult AAV patients 61 89. The reason for this difference is unclear. This could be attributed to early detection and aggressive treatment, as well as fewer comorbidities and underlying health issues in children compared to adults. Over time, with increased disease relapses, the likelihood of pulmonary infection increases as well as irreversible structural damage, potentially contributing to worse outcomes with age and longer follow-up 89. It is also possible that adult outcomes are worse due to higher rates of interstitial lung disease in adult patients. Additionally, as diffuse alveolar hemorrhage is more commonly reported in adults than in children, this may further contribute to a poorer prognosis 50. The majority of patients (87%) in our study cohort do not develop pulmonary damage. Similarly, of the patients that presented with an abnormal pulmonary function tests at diagnosis, many (55.5%) had a normal PFT by 12-months. Comparable rates of pulmonary damage have been reported in adult studies 74,77,78. One study found that 15.1% (42 of 192 patients) had evidence of pulmonary damage at 12-months, while another study described features of chronic breathlessness (12.3%) and impaired pulmonary function (22.7%) 77,78. Although damage rates are low in adult studies, the severity of damage appears to be worse and is associated with certain features that lead to worse outcomes 87,88. In summary, findings presented in this chapter demonstrate the clinical presentation of pediatric-onset AAV related pulmonary disease at diagnosis and 12-months. The majority of the patients achieved inactive disease by 12-months and few patients had evidence of pulmonary damage, 58 consistent with the frequency seen in adult-onset AAV. In addition, no baseline factors were identified as predictors of outcome in the multivariable analysis; however, this analysis was exploratory and was limited by the low frequency of the outcomes of interest, such as damage and abnormal pulmonary function tests. To my knowledge, this is the largest study of pediatric vasculitis-related pulmonary disease to date, and has, for the first time, allowed for the reporting of pulmonary disease course and early outcomes. 59 Chapter 5: Conclusion and future directions 5.1 Summary Pediatric-onset ANCA-associated vasculitis is more severe with greater major organ involvement, compared to adult-onset AAV 2,46. While mortality rates have dramatically improved due to treatment advancements, there remain concerns regarding the appropriateness of applying adult based treatment approaches to children. Since most children present with involvement of major organs like the kidneys and lungs 1,2, they receive aggressive treatment without a clear understanding of whether such treatment is warranted and what the pediatric-specific risks and anticipated outcomes are. Many clinical tools used for guiding management of AAV in adults, have not been studied in children and their utility in pediatric AAV is unclear 90. Given that the disease manifests differently in children compared to adult patients, there is an important need for pediatric focused research. The research presented in this thesis aimed to deepen the understanding of renal and pulmonary disease presentation in children, assess disease course and outcomes, and identify markers at diagnosis that could predict outcomes. Ultimately, this work seeks to address the gaps in pediatric-specific literature and contribute to improving outcomes for children with renal and pulmonary vasculitis. Results presented in Chapter 3 of this thesis demonstrated that the majority of pediatric patients achieved inactive renal disease at follow-up despite having high renal disease activity at diagnosis. Two-thirds of patients had reduced renal function at follow-up, and one-third of patients had evidence of permanent renal damage. The findings of this study showed that eGFR is a strong predictor of eGFR at 12-month follow-up, and the identified cutpoint threshold of 38 ml/min/1.73m2 has potential as a predictive clinical tool that warrants further prospective 60 evaluation. As renal involvement is not the only major organ involved in this disease, results from Chapter 4 of this thesis describe pulmonary disease course and outcomes. Although more than half of pediatric patients presented with highly active pulmonary disease at diagnosis, nearly all patients achieved inactive disease by 12-months. Relative to renal disease, few patients experienced permanent pulmonary damage. 5.2 Clinical significance The results of this study highlight the high rate of significant renal disease in pediatric AAV and demonstrate that renal function at diagnosis is a strong predictor of renal function at 12-months. In addition, the elucidation of AAV-associated renal disease trajectories builds upon our understanding of renal disease course. Early identification of patients at highest risk for poor renal outcomes is a step towards individualizing treatment and improving counseling of patients about expected disease course and prognosis. In addition, earlier intervention with renoprotective measures such as controlling hypertension, treating proteinuria, managing weight, and minimizing other potential insults to the kidney can be prioritized in such patients. The findings of this study contribute valuable insights into the underexplored area of pulmonary disease in pediatric AAV. The study highlights the high rates of pulmonary disease at diagnosis and expands our knowledge of the spectrum of clinical manifestations and imaging features at presentation. Importantly, this study also provides valuable knowledge about early disease course and outcomes in children with pulmonary AAV. Ultimately, this research addresses an important knowledge gap in the understanding of renal and pulmonary specific disease course and outcomes that will contribute to improved management and prognostication of children diagnosed with AAV. Further, providing evidence-based, individualized insights into anticipated 61 outcomes will ultimately allow patients and their families to be more involved in shaping and participating in their own care. 5.3 Study limitations and future directions Cohort characteristics: In this study, the majority of patients were diagnosed with GPA, making the results less informative of MPA outcomes. In the PedVas registry, a large proportion of centres enrolling patients (88%) are in North America and Europe. This is important given the geographic variation in the incidence of AAV, with GPA more prevalent in North American and European populations, while MPA is diagnosed more frequently in Asian populations and is often associated with renal disease . Clinical measures and scoring tools: This study used eGFR instead of measured GFR as this was the only feasible method for estimating renal function in the context of real-world registry data collection. While this is a well-accepted method for estimating GFR, there are instances when it may be less representative of actual renal function. In addition, eGFR at diagnosis was calculated based on the serum creatinine value entered at or near the time of diagnosis. Creatinine values at the time of diagnosis are constantly changing, and it is possible that the most representative value was not necessarily entered. The registry data on pulmonary function test results were recorded broadly as normal or abnormal. For abnormal results, description was limited to, restrictive, obstructive or diffusion defects. Detailed test metrics, such as forced vital capacity (FVC), forced expiratory volume (FEV), total lung capacity (TLC), and others, were not recorded. Additionally, for imaging 62 abnormalities, we cannot exclude the possibility that the reported findings were unrelated to the patientâs vasculitis diagnosis, as these judgements are made at the discretion of the site investigator. Formal training in scoring the PVAS or pVDI was not required of the multiple site investigators, but they were provided a comprehensive instruction manual for applying the PVAS and pVDI. Within the registry, there are multiple check points and prompts that assist the investigator in determining whether a sign or symptom should be scored as active vasculitis (PVAS) versus damage (pVDI). Some items within the PVAS and pVDI are challenging to attribute solely to active vasculitis or damage, respectively. For example, when hypertension is scored as part of PVAS or pVDI, it should not be due to corticosteroids, other medications, fluid overload or white coat hypertension; however, this may be difficult to differentiate clinically, and it is up to the investigator to make those judgments. These challenges are inherent to the scoring tools themselves and are not limitations to this study specifically. Site investigators are responsible for scoring using the PVAS, however, imaging findings may not have been fully reflected in the PVAS score. Modifications are being implemented to address this limitation. Follow-up information: Long-term data is important to understand the persistence of disease, progression of damage and relapse rates. This study only evaluated follow-up to 24-months, so it does not inform on longer term outcomes. In addition, a proportion of patients did not have completed 24-month visit data, preventing a comprehensive analysis from being conducted at this time point for some outcomes. There was variability in follow-up time points, with the 12-month follow-up ranging from 11 months to 15 months, which is the result of pragmatic registry 63 data collection timing that coincided with the timing of routine clinical care closest to 12- (or 24) months. Additionally, for the pulmonary study, not all patients underwent baseline or follow-up CT imaging or pulmonary functions tests, however, this simply reflects the nature of registry data and real-life clinical practice. Equity, diversity and inclusion considerations: At the time of establishment of the clinical registry in 2007, gender assessment from patients was not included. Although the registry has recently been modified to prospectively include gender information, this is currently available for very few patients. Sex is an important variable that has been considered in this project when describing demographic characteristics, and this consideration is important given that in children, vasculitis affects females more often than males, with the opposite seen in adult-onset disease. Despite our diverse cohort, our sample may not be representative of all populations. Moreover, PedVas centers tend to be larger tertiary or quarternary centers resulting in a cohort that is potentially more severe; however, patients with renal and pulmonary disease would generally require care at such centers so it is felt that very few patients with renal and pulmonary vasculitis would be followed solely at a small center. Future research that compares the predictive utility of eGFR versus other predictors such as biopsy classification, or the combination of such predictors would be informative. Two recent retrospective studies from China with predominantly MPA patients, looked at the predictive utility of risk scores that combined eGFR and biopsy features and found that such risk scores performed better than eGFR or histopathology findings alone in predicting ESKD 72,91. Prospective evaluation of an eGFR cutpoint or eGFR range that is predictive of renal outcome 64 may result in an easy-to-use tool for clinicians and families in the future. Identifying additional novel biomarkers, such as urinary or other blood markers, may also hold value for prognostication and may further contribute to a reliable and sensitive predictive tool that ultimately enables tailoring of treatment that maximizes disease control while minimizing treatment toxicity. 5.4 Conclusion The overarching aim of the research presented in this thesis was to characterize pediatric-onset AAV related renal and pulmonary disease at diagnosis, elucidate renal and pulmonary disease course and outcomes, assess predictors of pulmonary outcomes, and evaluate the utility of eGFR as a biomarker to predict renal outcome at 12-months. In this cohort of pediatric AAV, our results provide new insights into renal and pulmonary disease trajectory and prognosis, improving our understanding of anticipated outcomes. It is also the first study to evaluate the predictive value of eGFR in a multi-center, international cohort with systematically collected prospective data in such patients. Knowledge of pediatric-specific disease course and outcomes is essential to being able to appropriately counsel patients and their families about what they can expect after being diagnosed with renal or pulmonary vasculitis. Identification of predictors that can distinguish between children with an outcome of severe or mild vasculitis, especially in the kidneys and lungs, is an important first step towards deciding which children need more (or less) aggressive therapy. Ultimately this will lead to personalized treatment, better disease control, less unnecessary drug-induced side effects and improved outcomes for children and their families. 65 References 1. Cabral DA, Canter DL, Muscal E, et al. Comparing Presenting Clinical Features in 48 Children With Microscopic Polyangiitis to 183 Children Who Have Granulomatosis With Polyangiitis (Wegenerâs): An ARChiVe Cohort Study. Arthritis Rheumatol. 2016;68(10):2514-2526. doi:10.1002/art.39729 2. Morishita KA, Moorthy LN, Lubieniecka JM, et al. Early Outcomes in Children With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Rheumatol. 2017;69(7):1470-1479. doi:10.1002/art.40112 3. Sharma P, Sharma S, Baltaro R, Hurley J. Systemic Vasculitis. afp. 2011;83(5):556-565. 4. Wu X, Liu Y, Wei W, Liu ML. Extracellular vesicles in autoimmune vasculitis - Little dirts light the fire in blood vessels. Autoimmunity Reviews. 2019;18(6):593-606. doi:10.1016/j.autrev.2018.12.007 5. Saadoun D, Vautier M, Cacoub P. Medium- and Large-Vessel Vasculitis. Circulation. 2021;143(3):267-282. doi:10.1161/CIRCULATIONAHA.120.046657 6. Watts R, Lane S, Hanslik T, et al. Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies. Ann Rheum Dis. 2007;66(2):222-227. doi:10.1136/ard.2006.054593 7. Martín-Suñé N, Ríos-Blanco JJ. Pulmonary Affectation of Vasculitis. Archivos de Bronconeumología (English Edition). 2012;48(11):410-418. doi:10.1016/j.arbr.2012.08.005 8. Hunter RW, Welsh N, Farrah TE, Gallacher PJ, Dhaun N. ANCA associated vasculitis. BMJ. 2020;369:m1070. doi:10.1136/bmj.m1070 9. Bloom JL, Pickett-Nairn K, Silveira L, et al. The Association Between Age at Diagnosis and Disease Characteristics and Damage in Patients With ANCA-Associated Vasculitis. Arthritis & Rheumatology. 2023;75(12):2216-2227. doi:10.1002/art.42651 10. Jariwala M, Laxer RM. Childhood GPA, EGPA, and MPA. Clinical Immunology. 2020;211:108325. doi:10.1016/j.clim.2019.108325 11. Iudici M, Pagnoux C, Quartier P, et al. Childhood- versus adult-onset ANCA-associated vasculitides: A nested, matched caseâcontrol study from the French Vasculitis Study Group Registry. Autoimmunity Reviews. 2018;17(2):108-114. doi:10.1016/j.autrev.2017.11.014 12. Savige J, Pollock W, Trevisin M. What do antineutrophil cytoplasmic antibodies (ANCA) tell us? Best Pract Res Clin Rheumatol. 2005;19(2):263-276. doi:10.1016/j.berh.2004.10.003 13. Rathmann J, Mohammad AJ. Classification Criteria for ANCA Associated Vasculitis â Ready for Prime Time? Curr Rheumatol Rep. 2024;26(9):332-342. doi:10.1007/s11926-024-01154-9 66 14. Garlapati P, Rout P, Qurie A. Granulomatosis With Polyangiitis. In: StatPearls. StatPearls Publishing; 2024. Accessed October 3, 2024. http://www.ncbi.nlm.nih.gov/books/NBK557827/ 15. Fijolek J, Radzikowska E. Eosinophilic granulomatosis with polyangiitis â Advances in pathogenesis, diagnosis, and treatment. Front Med (Lausanne). 2023;10:1145257. doi:10.3389/fmed.2023.1145257 16. Hashmi MF, Jain V, Rout P. Microscopic Polyangiitis. In: StatPearls. StatPearls Publishing; 2024. Accessed October 6, 2024. http://www.ncbi.nlm.nih.gov/books/NBK531484/ 17. Pyo JY, Lee LE, Park YB, Lee SW. Comparison of the 2022 ACR/EULAR Classification Criteria for Antineutrophil Cytoplasmic Antibody-Associated Vasculitis with Previous Criteria. Yonsei Med J. 2023;64(1):11-17. doi:10.3349/ymj.2022.0435 18. Ozen S, Pistorio A, Iusan SM, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Annals of the rheumatic diseases. 2010;69(5):798-806. doi:10.1136/ard.2009.116657 19. Uribe AG, Huber AM, Kim S, et al. Increased Sensitivity of the European Medicines Agency Algorithm for Classification of Childhood Granulomatosis with Polyangiitis. The Journal of Rheumatology. 2012;39(8):1687-1697. doi:10.3899/jrheum.111352 20. Jennette JC. Overview of the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Clin Exp Nephrol. 2013;17(5):603-606. doi:10.1007/s10157-013-0869-6 21. Iudici M, Quartier P, Terrier B, Mouthon L, Guillevin L, Puéchal X. Childhood-onset granulomatosis with polyangiitis and microscopic polyangiitis: Systematic review and meta-analysis. Orphanet Journal of Rare Diseases. 2016;11(1). doi:10.1186/s13023-016-0523-y 22. Calatroni M, Consonni F, Allinovi M, et al. Prognostic Factors and Long-Term Outcome with ANCA-Associated Kidney Vasculitis in Childhood. Clin J Am Soc Nephrol. 2021;16(7):1043-1051. doi:10.2215/CJN.19181220 23. Eleftheriou D, Gale H, Pilkington C, Fenton M, Sebire NJ, Brogan PA. Eosinophilic granulomatosis with polyangiitis in childhood: Retrospective experience from a tertiary referral centre in the UK. Rheumatology (United Kingdom). 2016;55(7):1263-1272. doi:10.1093/rheumatology/kew029 24. Fina A, Dubus JC, Tran A, et al. Eosinophilic granulomatosis with polyangiitis in children: Data from the French RespiRare® cohort. Pediatric Pulmonology. 2018;53(12):1640-1650. doi:10.1002/ppul.24089 25. Gendelman S, Zeft A, Spalding SJ. Childhood-onset eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss Syndrome): A contemporary single-center cohort. Journal of Rheumatology. 2013;40(6):929-935. doi:10.3899/jrheum.120808 67 26. Zwerina J, Eger G, Englbrecht M, Manger B, Schett G. ChurgâStrauss Syndrome in Childhood: A Systematic Literature Review and Clinical Comparison with Adult Patients. Seminars in Arthritis and Rheumatism. 2009;39(2):108-115. doi:10.1016/j.semarthrit.2008.05.004 27. Sinico RA, Di Toma L, Radice A. Renal involvement in anti-neutrophil cytoplasmic autoantibody associated vasculitis. Autoimmun Rev. 2013;12(4):477-482. doi:10.1016/j.autrev.2012.08.006 28. Sacri AS, Chambaraud T, Ranchin B, et al. Clinical characteristics and outcomes of childhood-onset ANCA-associated vasculitis: a French nationwide study. Nephrol Dial Transplant. 2015;30 Suppl 1:i104-112. doi:10.1093/ndt/gfv011 29. Moiseev S, Novikov P, Jayne D, Mukhin N. End-stage renal disease in ANCA-associated vasculitis. Nephrology Dialysis Transplantation. 2017;32(2):248-253. doi:10.1093/ndt/gfw046 30. Molnár A, Studinger P, Ledó N. Diagnostic and Therapeutic Approach in ANCA-Associated Glomerulonephritis: A Review on Management Strategies. Front Med. 2022;9. doi:10.3389/fmed.2022.884188 31. Berden AE, Ferrario F, Hagen EC, et al. Histopathologic classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol. 2010;21(10):1628-1636. doi:10.1681/ASN.2010050477 32. Noone DG, Twilt M, Hayes WN, et al. The New Histopathologic Classification of ANCA-Associated GN and Its Association with Renal Outcomes in Childhood. Clin J Am Soc Nephrol. 2014;9(10):1684-1691. doi:10.2215/CJN.01210214 33. Yang J, Yang Y, Xu Y, et al. Clinical and Renal Histology Findings and Different Responses to Induction Treatment Affecting the Long-Term Renal Outcomes of Children With ANCA-Associated Vasculitis: a Single-Center Cohort Analysis. Frontiers in Immunology. 2022;13. Accessed December 8, 2023. https://www.frontiersin.org/articles/10.3389/fimmu.2022.857813 34. Yang J, Yang Y, Xu Y, et al. Clinical and Renal Histology Findings and Different Responses to Induction Treatment Affecting the Long-Term Renal Outcomes of Children With ANCA-Associated Vasculitis: a Single-Center Cohort Analysis. Front Immunol. 2022;13:857813. doi:10.3389/fimmu.2022.857813 35. Barnini C, Oni L, Kronbichler A. Course of paediatric ANCA-associated glomerulonephritis: advocating for an age-inclusive approach. RMD Open. 2024;10(3):e004481. doi:10.1136/rmdopen-2024-004481 36. Sacoto G, Boukhlal S, Specks U, Flores-Suárez LF, Cornec D. Lung involvement in ANCA-associated vasculitis. La Presse Médicale. 2020;49(3):104039. doi:10.1016/j.lpm.2020.104039 68 37. Mohammad AJ, Mortensen KH, Babar J, et al. Pulmonary Involvement in Antineutrophil Cytoplasmic Antibodies (ANCA)-associated Vasculitis: The Influence of ANCA Subtype. The Journal of Rheumatology. 2017;44(10):1458-1467. doi:10.3899/jrheum.161224 38. Iudici M, Puéchal X, Pagnoux C, et al. Brief Report: Childhood-Onset Systemic Necrotizing Vasculitides: Long-Term Data From the French Vasculitis Study Group Registry. Arthritis Rheumatol. 2015;67(7):1959-1965. doi:10.1002/art.39122 39. James KE, Xiao R, Merkel PA, Weiss PF. Clinical course and outcomes of childhood-onset granulomatosis with polyangiitis. Clinical and experimental rheumatology. 2017;35(1):202-208. 40. Exley AR, Bacon PA, Luqmani RA, et al. Development and initial validation of the Vasculitis Damage Index for the standardized clinical assessment of damage in the systemic vasculitides. Arthritis Rheum. 1997;40(2):371-380. doi:10.1002/art.1780400222 41. Takeshi Saraya S, Ogawa Y, Nakamoto K, Fujiwara M, Ishii H. Pulmonary Involvement in Microscopic Polyangiitis: Computed Tomography Findings in 55 Patients With Analysis of Risk Factors for Recurrence. Cureus. 2022;14(1):e21285. doi:10.7759/cureus.21285 42. Zhang Y, Ding Q, Lv C, et al. Clinical significance of microscopic polyangiitis with interstitial lung disease and bronchiectasis: probability of preexisting comorbidities. Annals of Medicine. 2023;55(1):2204449. doi:10.1080/07853890.2023.2204449 43. Puéchal X, Guillevin L. How best to manage relapse and remission in ANCA-associated vasculitis. Expert Review of Clinical Immunology. 2022;18(11):1135-1143. doi:10.1080/1744666X.2022.2122954 44. Geetha D, Jefferson JA. ANCA-Associated Vasculitis: Core Curriculum 2020. American Journal of Kidney Diseases. 2020;75(1):124-137. doi:10.1053/j.ajkd.2019.04.031 45. Morishita KA, Wagner-Weiner L, Yen EY, et al. Consensus Treatment Plans for Severe Pediatric Antineutrophil Cytoplasmic AntibodyâAssociated Vasculitis. Arthritis Care & Research. 2022;74(9):1550-1558. doi:10.1002/acr.24590 46. Mahi S louisa, Bahram S, Harambat J, et al. Pediatric ANCA vasculitis: clinical presentation, treatment, and outcomes in a French retrospective study. Pediatr Nephrol. 2023;38(8):2649-2658. doi:10.1007/s00467-022-05855-0 47. Schwartz GJ, Muñoz A, Schneider MF, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20(3):629-637. doi:10.1681/ASN.2008030287 48. Arulkumaran N, Jawad S, Smith SW, et al. Long- term outcome of paediatric patients with ANCA vasculitis. Pediatric Rheumatology. 2011;9(1):12. doi:10.1186/1546-0096-9-12 49. Ring AM, Schwerk N, Kiper N, et al. Diffuse alveolar haemorrhage in children: an international multicentre study. ERJ Open Research. 2023;9(2):00733. doi:10.1183/23120541.00733-2022 69 50. Filocamo G, Torreggiani S, Agostoni C, Esposito S. Lung involvement in childhood onset granulomatosis with polyangiitis. Pediatr Rheumatol Online J. 2017;15:28. doi:10.1186/s12969-017-0150-8 51. Houben E, de Groot PF, Vegting Y, et al. Not Everything Is as It Seems: A Case Series and Overview of Diseases Mimicking Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. J Clin Med. 2023;12(19):6144. doi:10.3390/jcm12196144 52. Flossmann O, Berden A, de Groot K, et al. Long-term patient survival in ANCA-associated vasculitis. Ann Rheum Dis. 2011;70(3):488-494. doi:10.1136/ard.2010.137778 53. Zhou H, Liang W, Hu H, Liu Z, Chu F, Ding G. An update on risk factors for relapse in antineutrophil cytoplasmic antibody-associated vasculitis. Clinical and Experimental Immunology. Published online August 14, 2024:uxae068. doi:10.1093/cei/uxae068 54. Dolezalova P, Price-Kuehne FE, Ãzen S, et al. Disease activity assessment in childhood vasculitis: development and preliminary validation of the Paediatric Vasculitis Activity Score (PVAS). Ann Rheum Dis. 2013;72(10):1628-1633. doi:10.1136/annrheumdis-2012-202111 55. Dolezalova P, Wilkinson N, Brogan P, et al. SAT0286 Paediatric Vasculitis Damage Index: A New Tool for Standardised Disease Assessment. Annals of the Rheumatic Diseases. 2014;73:696-697. doi:10.1136/annrheumdis-2014-eular.5893 56. Luqmani RA, Bacon PA, Moots RJ, et al. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM. 1994;87(11):671-678. 57. Binda V, Moroni G, Messa P. ANCA-associated vasculitis with renal involvement. J Nephrol. 2018;31(2):197-208. doi:10.1007/s40620-017-0412-z 58. Sl H, Rj F, H C, et al. Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Annals of internal medicine. 2005;143(9). doi:10.7326/0003-4819-143-9-200511010-00005 59. Slot MC, Tervaert JWC, Franssen CFM, Stegeman CA. Renal survival and prognostic factors in patients with PR3-ANCA associated vasculitis with renal involvement. Kidney Int. 2003;63(2):670-677. doi:10.1046/j.1523-1755.2003.00769.x 60. Berden AE, Wester Trejo MAC, Bajema IM. Investigations in systemic vasculitis - The role of renal pathology. Best Pract Res Clin Rheumatol. 2018;32(1):83-93. doi:10.1016/j.berh.2018.10.010 61. Zhou P, Li Z, Gao L, et al. Pulmonary involvement of ANCA-associated vasculitis in adult Chinese patients. BMC Pulm Med. 2022;22:35. doi:10.1186/s12890-022-01829-y 62. Levey AS, Eckardt KU, Tsukamoto Y, et al. Definition and classification of chronic kidney disease: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney International. 2005;67(6):2089-2100. doi:10.1111/j.1523-1755.2005.00365.x 70 63. CKD Evaluation and Management â KDIGO. Accessed November 28, 2023. https://kdigo.org/guidelines/ckd-evaluation-and-management/ 64. Thiele C, Hirschfeld G. cutpointr: Improved Estimation and Validation of Optimal Cutpoints in R. Journal of Statistical Software. 2021;98:1-27. doi:10.18637/jss.v098.i11 65. Miloslavsky EM, Specks U, Merkel PA, et al. Clinical outcomes of remission induction therapy for severe antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2013;65(9):2441-2449. doi:10.1002/art.38044 66. Robson J, Doll H, Suppiah R, et al. Damage in the anca-associated vasculitides: long-term data from the European vasculitis study group (EUVAS) therapeutic trials. Ann Rheum Dis. 2015;74(1):177-184. doi:10.1136/annrheumdis-2013-203927 67. Toraman A, Gündüz ÃS. Predictors of renal and patient outcomes in anti-neutrophil cytoplasmic antibody-associated vasculitis: Our single-center, tertiary care experience. Arch Rheumatol. 2021;36(3):445-457. doi:10.46497/ArchRheumatol.2021.8687 68. Kovesdy CP, Coresh J, Ballew SH, et al. Past Decline Versus Current eGFR and Subsequent ESRD Risk. Journal of the American Society of Nephrology. 2016;27(8):2447. doi:10.1681/ASN.2015060687 69. Zsom L, Zsom M, Salim SA, Fülöp T. Estimated Glomerular Filtration Rate in Chronic Kidney Disease: A Critical Review of Estimate-Based Predictions of Individual Outcomes in Kidney Disease. Toxins. 2022;14(2):127. doi:10.3390/toxins14020127 70. Gao R, Wu Z, Xu X, et al. Predictors of poor prognosis in ANCA-associated vasculitis (AAV): a single-center prospective study of inpatients in China. Clin Exp Med. 2023;23(4):1331-1343. doi:10.1007/s10238-022-00915-z 71. Kronbichler A, Jayne DRW. ANCA Renal Risk Score: is prediction of end-stage renal disease at baseline possible? Kidney International. 2018;94(6):1045-1047. doi:10.1016/j.kint.2018.10.001 72. Tan LW, Wan JL, Zhu CH, et al. Risk factors for renal outcomes in children with antineutrophil cytoplasmic antibody-associated vasculitis: a nationwide retrospective study in China. World J Pediatr. Published online October 19, 2023. doi:10.1007/s12519-023-00753-3 73. Chen A, Mammen C, Guzman J, et al. Wide variation in glucocorticoid dosing in paediatric ANCA-associated vasculitis with renal disease: a paediatric vasculitis initiative study. Clin Exp Rheumatol. 2022;40(4):841-848. doi:10.55563/clinexprheumatol/iol4k2 74. Makhzoum JP, Grayson PC, Ponte C, et al. Pulmonary involvement in primary systemic vasculitides. Rheumatology. 2022;61(1):319-330. doi:10.1093/rheumatology/keab325 71 75. Zhou P, Ma J, Wang G. Impact of interstitial lung disease on mortality in ANCA-associated vasculitis: A systematic literature review and meta-analysis. Chron Respir Dis. 2021;18:1479973121994562. doi:10.1177/1479973121994562 76. Doliner B, Rodriguez K, Montesi SB, Fu X, Sharma A, Wallace ZS. Interstitial lung disease in ANCA-associated vasculitis: associated factors, radiographic features and mortality. Rheumatology. 2023;62(2):716-725. doi:10.1093/rheumatology/keac339 77. Robson J, Doll H, Suppiah R, et al. Damage in the anca-associated vasculitides: long-term data from the European Vasculitis Study group (EUVAS) therapeutic trials. Annals of the Rheumatic Diseases. 2015;74(1):177-184. doi:10.1136/annrheumdis-2013-203927 78. Suppiah R, Flossmann O, Mukhtyar C, et al. Measurement of damage in systemic vasculitis: a comparison of the Vasculitis Damage Index with the Combined Damage Assessment Index. Ann Rheum Dis. 2011;70(1):80-85. doi:10.1136/ard.2009.122952 79. Sayad E, Vogel TP, Guillerman RP, et al. Pulmonary manifestations and outcomes in paediatric ANCA-associated vasculitis: a single-centre experience. Rheumatology (Oxford). 2021;60(7):3199-3208. doi:10.1093/rheumatology/keaa769 80. Chevet B, Cornec D, Casal Moura M, et al. Diagnosing and treating ANCA-associated vasculitis: an updated review for clinical practice. Rheumatology (Oxford). 2023;62(5):1787-1803. doi:10.1093/rheumatology/keac623 81. Thickett DR, Richter AG, Nathani N, Perkins GD, Harper L. Pulmonary manifestations of anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis. Rheumatology (Oxford). 2006;45(3):261-268. doi:10.1093/rheumatology/kei217 82. Kadura S, Raghu G. Antineutrophil cytoplasmic antibody-associated interstitial lung disease: a review. Eur Respir Rev. 2021;30(162):210123. doi:10.1183/16000617.0123-2021 83. Ben Ameur S, Niaudet P, Baudouin V, et al. Lung manifestations in MPO-ANCA associated vasculitides in children. Pediatric Pulmonology. 2014;49(3):285-290. doi:10.1002/ppul.22793 84. Pesci A, Manganelli P. Respiratory system involvement in antineutrophil cytoplasmic-associated systemic vasculitides: clinical, pathological, radiological and therapeutic considerations. Drugs R D. 2007;8(1):25-42. doi:10.2165/00126839-200708010-00003 85. Manganelli P, Fietta P, Carotti M, Pesci A, Salaffi F. Respiratory system involvement in systemic vasculitides. Clin Exp Rheumatol. 2006;24(2 Suppl 41):S48-59. 86. Collins CE, Quismorio FPJ. Pulmonary involvement in microscopic polyangiitis. Current Opinion in Pulmonary Medicine. 2005;11(5):447. doi:10.1097/01.mcp.0000170520.63874.fb 87. Unizony S, Abril A. Chapter 7 - Lung involvement in ANCA-associated vasculitis. In: Atzeni F, Gómez-Puerta JA, Sellares J, eds. Handbook of Systemic Autoimmune Diseases. Vol 17. 72 The Lung in Autoimmune Diseases. Elsevier; 2022:153-168. doi:10.1016/B978-0-323-91083-5.00007-4 88. Fouka E, Drakopanagiotakis F, Steiropoulos P. Pathogenesis of Pulmonary Manifestations in ANCA-Associated Vasculitis and Goodpasture Syndrome. International Journal of Molecular Sciences. 2024;25(10):5278. doi:10.3390/ijms25105278 89. Hassan TM, Hassan AS, Igoe A, et al. Lung involvement at presentation predicts disease activity and permanent organ damage at 6, 12 and 24 months followâ-âup in ANCAâ-âassociated vasculitis. BMC Immunology. 2014;15(1):20. doi:10.1186/1471-2172-15-20 90. Demirkaya E, Luqmani R, Ayaz NA, Karaoglu A, Ozen S. Time to focus on outcome assessment tools for childhood vasculitis. Pediatric Rheumatology Online Journal. 2011;9:29. doi:10.1186/1546-0096-9-29 91. Zhang P, Yao J, Gao CL, Fang X, Zhang ZQ, Xia ZK. Validation of a renal risk score in a cohort of children with ANCA-associated glomerulonephritis. J Investig Med. 2023;71(8):854-864. doi:10.1177/10815589231186534 73 Appendices Appendix A: Clinical scoring tools for disease activity (PVAS) and damage (pVDI) A.1 PVAS clinical scoring tool Adapted from Dolezalova et al. (2013) 74 75 76 A.2 pVDI clinical scoring tool Adapted from Dolezalova et al. (2014) 77 78 79
Thesis/Dissertation
eng
Women+ and Childrenâs Health Sciences
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
Morishita, Kimberly
Brown, Kelly L.
Evaluating renal and pulmonary disease in pediatric-onset ANCA-associated vasculitis : disease course, outcomes, and predictors of outcomes
Text