Wegener granulomatosis in childhood and adolescence

Abstract

Wegener granulomatosis (WG) is a necrotising granulomatous small vessel vasculitis with a clinical predilection for involvement of the upper airways, lungs and kidneys, which occurs at all ages. The aetiology of WG, like other primary systemic vasculitides, remains unknown. Existing evidence suggests an autoimmune inflammatory process, characterised by early lesions with neutrophils and endothelial cells as active participants and involvement of antineutrophil cytoplasmatic antibodies (ANCA) directed against proteinase-3 (PR3). However, other concomitant factors like infections and environmental factors also appear to be necessary for the development of WG. In addition, multiple genetic factors seem to be involved in disease susceptibility. Whereas the first publications on WG in childhood were based on case reports, some studies in recent years allow to compare clinical findings, disease course, morbidity and mortality rates for childhood and adult onset patients. Whereas most aspects of WG are similar at all ages, some features appear to be significantly different. WG in childhood is more frequently complicated by subglottic stenosis and nasal deformity while treatment-related morbidity and malignancies are less common compared to adults. Introduction of combined treatment with cyclophosphamide and glucocorticoids resulted in a dramatic improvement of patient outcome; however, commonly occurring disease relapses and the risk of chronic organ damage at all ages make long-term follow-up of all patients and the establishment of new therapeutic regimens necessary.

Airway manifestations in childhood granulomatosis with polyangiitis (Wegener's)

“…Due to our identity as a quaternary care center, the prevalence of airway disease may be overestimated. Despite this possible referral bias, our findings are similar to those prior published data (4,6,8,10). Additionally, our cohort is small compared to adult studies on GPA, but this is a relatively large sample given the rarity of this disease in pediatric patients and our short study duration (7 years) (4 -8).…”

“…GPA involves the respiratory epithelium, extending from the nasal mucosa to the bronchi; therefore, involvement of both the upper and lower airways is common (4,6,8,10). This inflammatory process leads to airway edema, erythema, ulceration/hemorrhage, stenosis, nodules, and polyps.…”

“…Details regarding airway manifestations in childhood GPA have been limited in prior studies (4 -9). Differences between adult and childhood GPA include statistically higher prevalences of nasal deformity and subglottic stenosis (SGS) (4,6,8,10,11). Additionally, it has been proposed that GPA may encompass 2 diseases: limited and generalized (12).…”

Proteinase 3 is an IL-32 binding protein

“…Several prohormones and cytokines are cleaved or exhibit increased activity by PR3, including IL-8 (6), TGF-␤1 (7), membranebound TNF-␣ (8), IL-1␤ (9), IL-18 (10), and angiotensinogen (11). PR3, which exists in a soluble and a membrane-bound form, is the major autoantigen in Wegener's granulomatosis, the most common autoimmune necrotizing systemic vasculitis in adults (12,13). Autoantibodies to PR3, known as anti-neutrophil cytoplasmic autoantibodies, are often associated with small vessels vasculitis (14,15).…”

Management of Vasculitic Glomerulonephritis

“…This loss of renal function is rarely completely reversible, and 80 % children will have chronic kidney disease after long-term follow-up [29,30]. In addition, disease-free remission is rare, and 80 % of children will experience one or more disease relapses [31,32]. No clinical trials have been conducted in pediatric AAV, and almost all knowledge about optimal treatment and outcomes has been extrapolated from adult studies or collected from small case series.…”