Etiology of granulomatosis with polyangiitis (GPA)
This disease is characterized by necrotizing small to medium vessel granulomatous vasculitis of unknown etiology. Classic triad (2 of 3 often present):
- Granulomatous inflammation
- Tissue necrosis
It classically affects:
- Upper respiratory system: tracheobronchial necrotic lesions
- Lower respiratory system: cavitary lung lesions
- In what is termed "limited" GPA, there can be fairly extensive orbital involvement but no renal involvement (Knoch 2003).
- Sinus mucosal involvement with
- Friable mucosa with frequent bleeding
- Bone erosion
- Ocular involvement
- In the orbit, it may present as a mass, without upper respiratory or renal disease (Perry 1997).
- Scleritis, marginal ulcerative keratitis
- Nasolacrimal system involvement and stenosis
- Retinal vascular occlusion
- 3 per 100,000; 2,300 new cases per year (Tarabishy 2010)
- 40–55 years of age
- Males = females
- GPA is most common in Caucasians; African Americans consist of 2–8% (Hoffman 1992).
ENT disease may not be evident early, but in cases that present first in the orbit, it is almost always eventually seen (Perry1997):
- Recurrent infections — apparently due to the loss of MALT cells (Tarabishy 2010)
- Chronic sinusitis
- Sensorineural hearing loss
- Oral lesions
- Otitis media
- Ulcerations of nasal mucosa
- Voice changes
Respiratory symptoms are very common:
- 85% develop some type of respiratory symptom.
- If present and no pulmonary disease noted, dyspnea is likely secondary to subglottic stenosis.
- Asymptomatic until 50% closure
- Can develop life-threatening respiratory failure
- Can have relationship with tarsal conjunctival involvement (Robinson 2003)
- Cavitary pneumonitis
Musculoskeletal symptoms are also common:
- 66% of patients develop symptoms (Tarabishy 2010).
- Weight loss
- In a Vancouver series of 13 patients with orbital GPA, the main ocular symptoms were decreased vision and pain that localized to the face and eye (Perry 1997).
- Ocular irritation and eyelid inflammation
- Proptosis is related to the presence of inflammatory mass.
Renal symptoms are not common early:
- 80% of patients with systemic GPA develop renal disease (Tarabishy 2010).
- Often patients have no renal symptoms at diagnosis.
- Renal symptoms occur later in course of disease and can signal renal failure.
- Hematuria is usually microscopic (glomerulonephritis).
- 50% of patients develop some kind of skin finding (Carlson 2006).
- Nail bed and digital infarctions
- 20% of patients develop symptoms (Tarabishy 2010).
- Cranial nerve abnormalities
- CNS mass lesion affects
- Mononeuritis multiplex
- Hypercoagable state
- Increased risk of deep vein thrombosis and pulmonary embolism (Merkel 2005)
- Chronic sinusitis
- Mucosal ulcerations of nasopharynx
- Saddle nose deformity and fistula formation
- Lower respiratory cough and hemoptysis
- If left untreated, accounts for high percentage of mortality
- 80% of patients with systemic GPA have renal involvement.
- 20% have active glomerulonephritis (Tarabishy 2010).
- asymptomatic until renal failure develops
- Less common organ system manifestations include:
Limited form — upper and lower respiratory tract, no kidney involvement
- Occurs in 50% of patients (Tarabishy 2010)
- 8% develop visual loss.
- Scleritis is most common; seen in 10% of patients.
- Marginal ulcerative keratitis
- Retinal vasculitis
- Orbital disease:
- Occurs later in disease course.
- More advanced cases can present with:
- Proptosis (15–20% of patients) (Tan 2014)
- Limitation of motility
- Orbital congestion
- Visual loss
- Dacryoadenitis, nasolacrimal obstruction, nasocutaneous fistula formation
- Eyelid — periorbital edema, ptosis, lid retraction, or lid nodules
Antineutrophil cytoplasmic antibodies (c-ANCA) can be negative at first, but should be serially followed as it will often become positive (Perry 1997):
- Although both c-ANCA and anti-proteinase 3 (PR3) are positive in 80–90% of cases with systemic disease, with a high sensitivity and specificity, both c-ANCA and anti PR3 antibodies are often negative on presentation with orbital disease (Tan 2014).
- 20% target (MPO)
- In less severe cases, 65% positive
- Can be undetectable
Perinuclear ANCA (p-ANCA) is less sensitive.
Order a complete blood count: anemia, thrombocytosis, leukocytosis.
The erythrocyte sedimentation rate is elevated.
Blood urea nitrogen (BUN) and creatinine are elevated with hematuria and proteinuria.
Rheumatoid factor can be abnormal.
Serum globulins can be elevated.
Human Lysosomal membrane associated protein 2 (hLAMP2) is present in:
- 100% of active renal disease
- 93% GPA, MPA, or renal limited vasculitides
Chest x-ray can reveal infiltrates or cavitary lesions.
- CT: Improved sinus characterization, bony infiltration
- Improved lesion characterization
- GPA lesions are hypo-intense compared with fat on both T1 and T2.
- Enhance with gadolinium.
- Baseline imaging is important to monitor subsequent recurrence of disease.
The gold standard remains biopsy of the involved tissue.
Testing for staging, fundamental impairment
Biopsy of orbital inflammatory tissue can show dense fibrosis, but scant lymphocytic infiltration, perhaps with eosinophilic infiltration, without granulomatosis or vasculitis (Knoch 2003).
Multiple biopsies are often needed until the pathognomonic findings are discovered. Necrosis is an important indication of possible GPA, when other classic findings are not evident (Perry 1997).
In a Mayo Clinic series of 13 orbital biopsies from patients with well-documented GPA, only 7 showed the classic triad of vasculitis, necrosis, and granuloma (Kalina 1992).
There is an eosinophilic variant of GPA that can be observed in the orbit, with systemic and tissue eosinophilia, in the absence of asthma or atopy (Chan 2011).
Eosinophils are important in the pathogenesis of GPA in the orbit and eye (Trocme 1991).