Granulomatosis with Polyangiitis (Wegener’s Granulomatosis)

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):

• Vasculitis
• Granulomatous inflammation
• Tissue necrosis

It classically affects:

• Upper respiratory system: tracheobronchial necrotic lesions
• Lower respiratory system: cavitary lung lesions
• Kidneys
• Glomerulonephritis
• 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
• Uveitis
• Retinal vascular occlusion

Epidemiology

• 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).

History

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)
• Rhinitis
• Chronic sinusitis
• Sensorineural hearing loss
• Gingivitis
• Oral lesions
• Otitis media
• Epistaxis
• Ulcerations of nasal mucosa
• Tinnitus
• Voice changes

Respiratory symptoms are very common:

• 85% develop some type of respiratory symptom.
• Cough
• Hemoptysis
• Dyspnea
• 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)
• Pleurisy
• Cavitary pneumonitis

Musculoskeletal symptoms are also common:

• 66% of patients develop symptoms (Tarabishy 2010).
• Arthralgias
• Fever
• Malaise
• Weight loss

Ophthalmic symptoms:

• 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.
• Diplopia

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).

Skin:

• 50% of patients develop some kind of skin finding (Carlson 2006).
• Purpura
• Ulcerations
• Nail bed and digital infarctions

Neurologic:

• 20% of patients develop symptoms (Tarabishy 2010).
• Cranial nerve abnormalities
• CNS mass lesion affects
• Mononeuritis multiplex
• Pachymeningitis

Hematologic:

• Hypercoagable state
• Increased risk of deep vein thrombosis and pulmonary embolism (Merkel 2005)

Clinical features

Nonophthalmic:

• Chronic sinusitis
• Mucosal ulcerations of nasopharynx
• Saddle nose deformity and fistula formation
• Lower respiratory cough and hemoptysis
• Glomerulonephritis:
• 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
• Arthralgia
• Rash
• Less common organ system manifestations include:
• Gastrointestinal
• Cardiac
• Nervous

Limited form — upper and lower respiratory tract, no kidney involvement

Ophthalmic:

• 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)
• Inflammation
• Chemosis
• Limitation of motility
• Orbital congestion
• Visual loss
• Dacryoadenitis, nasolacrimal obstruction, nasocutaneous fistula formation
• Eyelid — periorbital edema, ptosis, lid retraction, or lid nodules

Testing

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.

Imaging:

• CT: Improved sinus characterization, bony infiltration
• MRI:
• 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).

• Fifth decade
• White
• Renal failure from glomerular sclerosis is a major cause of death.
• Increase risk of relapse with chronic S. Aureus nasal infestation

• Idiopathic orbital inflammation
• Specific causes of orbital inflammation
• Sarcoid
• Thyroid eye disease (thyroid orbitopathy)
• Other vasculitides: microscopic polyangiitis — no serious ENT issues
• Fungal infection
• Destructive lesions of the midface

Natural history

Orbital disease natural history includes:

• Variable involvement
• Can arise in sinuses and invade orbit
• Can develop intraconal initially
• Majority of patients have contiguous disease affecting orbit, nose, and sinuses.
• Typically unilateral
• Bone destruction is common.
• Progression of orbital disease is common despite systemic therapy (Belden 1993).
• 50% lose vision with infiltrative optic nerve disease (Hoffman 1992).
• Proptosis is most common, but orbit contraction can occur
• 33% of patients develop enophthalmos of 2–3 mm (Talar-Williams 2005).
• Usually unresponsive to treatment with systemic immunosuppression (Talar-Williams 2005)
• Orbital fistulas and abscesses can occur (de Silva 2007).

Adnexal disease natural history includes:

• Dacryoadenitis: GPA can present as unilateral and/or bilateral lacrimal gland enlargement (Kopstein 1999).
• Nasolacrimal duct obstruction or dacryocystitis secondary to sinonasal or direct inflammation

Eyelid disease natural history includes:

• Ptosis
• Chalazion
• Trichiasis
• Ulceration and fistula

Conjunctival disease natural history includes ulcerative and necrotic as a result of cicatricial changes in 16% of patients (Robinson 2003).

Scleral disease natural history includes:

• Scleritis is common finding
• Can become necrotizing
• Most common ocular condition reported at time of diagnosis 10% of cases (Hoffman 1992)

Corneal disease natural history includes:

• PUK or interstitial keratitis
• PUK is associated with antibody against cytokeratin 3 (Reynolds 1983).

Uveitis natural history includes:

• About 3% of GPA patients
• Most uncommon finding (Bullen 1983)

Retinal/choroidal disease natural history includes (Trocme 1991):

• Very rare (Bullen 1983)
• Variable forms of vasculitis
• Granulomas
• Choroidal folds, effusions, exudative retinal detachments
• Acute posterior multifocal placoid pigmented epitheliopathy (APMPPE) has been associated with GPA (Chiquet 1999).

Neuro ophthalmologic disease natural history includes:

• AION (Paul 2002)
• Compressive Optic Neuropathy
• Cranial neuropathies from inflammation
• Diplopia (Loke 1999)

Medical therapy

Severe (life-threatening):

• Cyclophosphamide and glucocorticoids
• 3–6-month treatment course for remission with cyclophosphamide (Tarabishy 2010)
• Methotrexate or azathioprine for maintenance
• Usually requires 6–9-month course of steroids including taper (Jane 1993)

Limited disease: glucocorticoids +/- Methotrexate for remission therapy

Rituximab:

• For remission induction in severe ANCA-positive disease, rituximab (375 mg per square meter of body-surface area per week for 4 weeks) can be superior to cyclophosphamide (2 mg per kilogram of body weight per day) in relapsing disease. According to a multicenter, randomized, double-blind study (Stone 2010), 67% of the rituximab group achieved remission at 6 months.
• Patients can be divided into groups with localized disease (ocular +/- ear-nose-throat/lung) versus generalized disease (ocular plus other organs). In a retrospective, long-term study in which remission was induced with cyclophosphamide and rituximab for the generalized group, and rituximab alone in the localized group, the rate of relapse was significantly higher for the localized group, suggesting that a combination of cyclophosphamide and rituximab can be superior for the induction of persistent remission (Joshi 2015).

Mycophenolate mofetil:

• Useful for both remission and maintenance
• Can improve recovery of renal function (Hu 2008)

Intravenous immunoglobulin can be beneficial in persistent disease (Jayne 1993).

Cotreatment with antibiotics can be used as prophylaxis against pneumocystis infection (Nowack 1999).

Long-term trimethoprim-sulfamethoxazole can suppress disease activity.

• Follow-up frequently until disease stabilizes.
• Ensure that nonophthalmic disease conditions are under treatment.
• Ophthalmic treatment
• Most diseases (scleritis, uveitis, orbital inflammation, etc.) respond to systemic therapy.
• Can require periocular steroids or intraocular steroids

Radiation

Can be considered in refractory cases

Nasal and sinus involvement in one instance was treated with 2 courses of 20 and 26 Gy, administered in 2-Gy fractions given a month apart (Neviani 2002).

Surgery

This is a medically treated systemic disorder, however, some complications of the disease, such as lacrimal and sinus obstructions are treated surgically.

• About 5–10% of patients with sinus and nasal involvement will require attention for nasolacrimal duct obstruction (Bullen 1983).
• Endonasal dacryocystorhinostomy can be performed, though concerns arise about secondary fibrosis, bleeding, possibly accelerating disease progression and difficulties navigating through altered anatomy (Morris 2010).
• Favorable results were reported in sixteen patients at the University of Michigan treated with external DCR surgery (Lee 2012).
• The lacrimal sac mucosa should be submitted for biopsy, particularly in cases of limited Wegner when tissue diagnosis can be hard to obtain, as it may show pathognomonic findings (Ghanem 2004).
• Delay lacrimal drainage surgery until disease is well controlled (Hardwig 1992).
• Need for drainage of chronic purulent, inflammatory tissue
• Risk of necrosis and fistula formation is high if the disease process is active.
• Following cytoplasmic ANCA is a useful way to monitor activity of the disease.

In refractory cases, consider orbital decompression.

Other management considerations

GPA requires multidisciplinary approach with ENT, rheumatology, and pulmonary.

Common treatment responses, follow-up strategies

Compressive optic neuropathy from mass effect can be profound, can respond dramatically to immunosuppressive therapy, and should be aggressively treated (Aakalu 2009).

Complications associated with medical therapies

• Glucocorticoid complications include
• GI ulcer, hemorrhage
• Osteopenia
• Cushinoid appearance
• Methotrexate
• Contraindicated in patients with impaired renal or liver dysfunction
• Myelosuppression
• Cyclophosphamide
• Hemorrhagic cystitis
• Sterility
• Rituximab
• Cough and throat irritation
• Night sweats
• Lack of energy
• Prolonged immunosuppression

Describe appropriate patient instructions

• Take medications as prescribed.
• Monitor for any signs symptoms of medication toxicity.
• Return with worsening of symptoms:
• Worsening vision
• Increase in pain
• Increasing diplopia
• New onset symptoms

• Vision loss due to:
• Diplopia
• Proptosis
• Saddle nose deformities
• Death

• Optic nerve ischemia
• CRAO
• Scleritis
• Exposure keratopathy and corneal ulceration

• Previously named after Friedrich Wegener, a pathologist in Berlin, 1937
• Prior to 1970, 50% mortality at 5 months and 80% mortality at 1 year (Tarabishy 2010)
• Treatment was only glucocorticoids.
• This has significantly improved with chemotherapy and immunosuppressives.

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