Natural History of Granulomatosis With Polyangiitis: Clinical and Genetic Biomarkers of Airway Disease NoAAC PR-03 Study

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.