Natural History of Granulomatosis With Polyangiitis: Clinical and Genetic Biomarkers of Airway Disease NoAAC PR-03 Study
Natural History of Granulomatosis With Polyangiitis: Clinical and Genetic Biomarkers of Airway Disease NoAAC PR-03 Study
The ultimate goal of this prospective natural history study is to define the natural history
 of the obstructive airway manifestations of Granulomatosis with polyangiitis (GPA).

 Additionally this proposal seeks to develop biomarkers of disease activity and define their
 correlation with clinical outcomes in an effort to transform clinical care and shape future
 drug development for this devastating rare disease.
Granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis) is a rare
 multisystem necrotizing granulomatous vasculitis of small and medium vessels. Nearly 20% of
 GPA patients suffer life-threatening obstruction of their airways. Even when survived, airway
 involvement can render patients in this disease subset unable to communicate, struggling to
 breath, and dependent on a tracheostomy for survival. Airway disease frequently leads to
 irreversible physiologic impairment and is highly correlated with reduced quality of life in
 GPA.

 Prior to the 1970s, patients with GPA had a 1-year mortality rate of >80%, primarily due to
 renal or lung failure. The introduction of combination cyclophosphamide and glucocorticoid
 treatment 4 decades ago greatly improved patient outcomes, turning this into a more chronic
 long-term disease. However, while progress has been made in the development of successful
 treatment regimes for systemic disease, the role of current therapies in ameliorating the
 airway complications of GPA is unknown. The evolution of GPA into a chronic disease has
 brought the management of the airway manifestations of GPA to the forefront. The natural
 history of the airway disease in GPA has never been longitudinally characterized, and there
 are no reliable biomarkers of clinical outcome.

 In GPA the incidence of airway stenosis localized to the anatomic region below the vocal cord
 (subglottic stenosis) has been estimated to be 16%-50%. It may occur in isolation as the
 presenting symptom of GPA, or as a late-stage manifestation of disease. Although stenosis is
 frequently limited to the subglottis, it may extend up to involve to vocal cords, or down to
 involve the distal trachea and bronchi. Unfortunately, studies have documented a relatively
 high incidence of multilevel airway involvement (34%) in GPA. In one series of 44 patients,
 one in five had evidence of laryngeal stenosis. Studies have also found a high incidence of
 metachronous bronchial disease.

 Laryngeal and Bronchial stenosis appear to be progressive and occur after the onset of
 subglottic stenosis, but the true natural history of airway involvement in GPA is unknown.

 GPA is a member of the anti-neutrophil cytoplasmic antibody (ANCA) vasculitides. Given the
 strong association of GPA with ANCA production, much focus has been placed on understanding
 the mechanisms of ANCA production and pathogenesis. The factors by which ANCAs are initially
 generated are poorly understood. The majority of in vitro and animal model research
 implicating neutrophils and T cells as the principal inflammatory cells in GPA is surprising
 given the known impressive clinical treatment response to B cell depletion with rituximab.
 This discordance reinforces that the knowledge gap between pathogenesis and therapy is GPA is
 wide.

 The distinction between focused airway disease and severe systemic disease has important
 therapeutic implications. The course of airway stenosis in GPA has been found to run
 independently of the systemic disease course and is often refractory to standard systemic
 therapy. In one representative case series, subglottic stenosis (SGS) was diagnosed in 49% of
 patients while they were receiving systemic treatment, and 56% of the patients who required
 tracheostomies did so despite having been treated for at least 2 months with systemic
 immunosuppressive agents. Developing novel therapeutics to control airway-focused GPA and
 prevent the development and/or progression of destructive airway damage is desperately
 needed.

 Because of the small numbers of patients affected, and with clinical experience dispersed
 among a small number of clinical referral centers, the natural history of rare diseases is
 often poorly described. When knowledge about disease is insufficient to guide clinical
 development, well-designed natural history studies are critical to developing and proving the
 efficacy of novel therapeutics.
Inclusion Criteria:

 -  Greater than or equal to 18 years of age.

 -  Stenotic Airway Disease (laryngeal, subglottic, distal tracheal or bronchial)

 Exclusion Criteria:

 -  <18years of age

 -  Patients without capacity to consent for themselves

 -  History of significant laryngotracheal traumatic injury.

 -  Endotracheal intubation 2 years prior to presentation.

 -  Major anterior neck surgery.

 -  History of neck irradiation.

 -  History of caustic or thermal injury to the laryngotracheal complex.