Ophthalmology – Granulomatosis With Polyangiitis

What the Disease Represents

Granulomatosis with polyangiitis (GPA) is a systemic ANCA-associated necrotizing vasculitis that predominantly affects small- to medium-sized vessels.

The classic organ pattern is:

• Upper respiratory tract
• Lower respiratory tract
• Kidneys

Ocular and orbital disease is also common and may occasionally be the presenting manifestation.

The characteristic pathologic combination is:

Necrotizing granulomatous inflammation + vasculitis + pauci-immune glomerulonephritis.

Important Modern Terminology

The historical term:

Wegener granulomatosis

has been replaced by:

Granulomatosis with polyangiitis (GPA).

This is the preferred modern terminology in clinical practice and classification systems.

Why the Disease Develops

GPA is an autoimmune inflammatory disease involving:

• Activated neutrophils
• Vascular endothelium
• B lymphocytes
• T lymphocytes
• Complement pathways

The antibody most strongly associated with GPA is:

PR3-ANCA

which often produces a classic:

Cytoplasmic ANCA (c-ANCA) pattern.

However, ANCA status alone does not establish or exclude the diagnosis.

ANCA Patterns

The two principal ANCA antigen targets are:

• Proteinase 3 (PR3)
• Myeloperoxidase (MPO)

GPA is most strongly associated with:

PR3-ANCA

whereas microscopic polyangiitis is more frequently associated with MPO-ANCA.

Some patients with GPA are:

ANCA-negative, particularly when disease is localized to the orbit or upper respiratory tract.

Who Typically Develops GPA

GPA can occur at almost any age but most often presents in:

Middle adulthood.

There is no clinically useful strong male predominance.

Disease occurs in all ethnic groups, although incidence and ANCA subtype frequencies vary geographically and by ancestry.

Why Early Recognition Matters

Untreated systemic GPA can cause:

• Rapidly progressive glomerulonephritis
• Pulmonary hemorrhage
• Respiratory failure
• Permanent hearing loss
• Orbital destruction
• Optic neuropathy

Modern immunosuppressive therapy has transformed GPA from a frequently fatal disease into a:

Treatable but relapsing chronic systemic vasculitis.

Upper Airway Disease

ENT involvement is extremely common.

Manifestations include:

• Chronic sinusitis
• Nasal crusting
• Bloody nasal discharge
• Nasal ulceration
• Otitis media
• Conductive or sensorineural hearing loss
• Eustachian tube dysfunction
• Subglottic stenosis

Symptoms may initially resemble recurrent infection.

Saddle-Nose Deformity

Chronic destructive inflammation can damage the:

Nasal septum and supporting cartilage

producing a:

Saddle-nose deformity.

This is a classic late manifestation but should not be required for diagnosis.

Strawberry Gingivitis

A highly characteristic but uncommon oral finding is:

“Strawberry gingivitis.”

The gingiva becomes:

• Red
• Friable
• Granular
• Hyperplastic

Its presence can be a strong diagnostic clue.

Pulmonary Involvement

Pulmonary GPA may cause:

• Nodules
• Cavitary nodules
• Pulmonary infiltrates
• Cough
• Dyspnea
• Hemoptysis

A particularly severe manifestation is:

Diffuse alveolar hemorrhage.

Renal Disease

The typical renal lesion is:

Pauci-immune necrotizing crescentic glomerulonephritis.

Clinical clues include:

• Hematuria
• Dysmorphic erythrocytes
• Red-cell casts
• Proteinuria
• Rising creatinine

Renal disease may initially be:

Clinically silent.

Urinalysis and renal function testing are therefore essential even when the patient has no urinary symptoms.

Ocular Disease Can Be the First Manifestation

Eye or orbital disease may precede the systemic diagnosis.

Important ophthalmic manifestations include:

• Scleritis
• Peripheral ulcerative keratitis
• Episcleritis
• Orbital inflammatory disease
• Nasolacrimal obstruction
• Uveitis
• Retinal vasculitis
• Retinal vascular occlusion
• Optic neuropathy

Almost any ocular structure can be affected.

Scleritis

One of the most important ocular manifestations is:

Anterior or posterior scleritis.

Patients may develop:

• Deep severe ocular pain
• Violaceous scleral injection
• Tenderness
• Pain with eye movement

The most dangerous form is:

Necrotizing scleritis.

This signals potentially severe systemic vasculitis and requires urgent systemic therapy.

Peripheral Ulcerative Keratitis

Peripheral ulcerative keratitis (PUK) is another sight-threatening manifestation.

Typical findings include:

• Peripheral stromal thinning
• Epithelial defect
• Adjacent conjunctival inflammation
• Progressive corneal melt

Severe disease can progress to:

Descemetocele or perforation.

Why PUK Is a Systemic Emergency

GPA-associated PUK reflects active systemic immune-mediated vasculitis rather than simply local corneal disease.

Treatment therefore requires:

Systemic immunosuppression.

Topical treatment alone is inadequate.

Important Rule Before Treating Corneal Melt

Before escalating immunosuppression in PUK:

Exclude infectious keratitis.

Microbial infection can mimic or complicate autoimmune corneal ulceration.

Episcleritis

Episcleritis can occur and is generally less dangerous than scleritis.

It typically causes:

• Mild discomfort
• Sectoral redness
• Superficial vessels

Unlike scleritis, it is usually not associated with severe deep pain.

Orbital GPA

Orbital inflammation may result from:

• Direct granulomatous orbital disease
• Extension from adjacent sinus disease

Possible manifestations include:

• Proptosis
• Orbital pain
• Diplopia
• Restricted motility
• Eyelid edema
• Orbital mass-like inflammation

Why Orbital GPA Can Threaten Vision

Inflammatory tissue may compress:

• Optic nerve
• Orbital apex
• Extraocular muscles

This can produce:

Compressive optic neuropathy.

Red flags include:

• Reduced visual acuity
• Dyschromatopsia
• RAPD
• Visual-field loss

These require urgent systemic treatment and sometimes surgical decompression.

Nasolacrimal Obstruction

Chronic sinonasal and peri-lacrimal inflammation may scar the:

Nasolacrimal drainage system.

Patients may develop:

• Epiphora
• Recurrent dacryocystitis

Definitive lacrimal surgery is generally best performed once systemic inflammation is adequately controlled.

Uveitis

Anterior, intermediate, posterior, or panuveitis may occur but is less characteristic than:

• Scleritis
• PUK
• Orbital disease

When uveitis is present, search carefully for other systemic evidence of GPA.

Retinal Vasculitis

Retinal involvement may include:

• Retinal vasculitis
• Cotton-wool spots
• Retinal hemorrhage
• Arterial occlusion
• Venous occlusion
• Retinal ischemia

Vision may be permanently reduced when the:

• Macula
• Optic nerve
• Major retinal vessels

are affected.

Optic Nerve Disease

Optic neuropathy may result from:

• Orbital compression
• Vasculitic ischemia
• Contiguous inflammation
• Rare direct granulomatous infiltration

Rapidly declining vision in a patient with orbital GPA is an:

Emergency.

Neurologic Manifestations

GPA may cause:

• Mononeuritis multiplex
• Peripheral neuropathy
• Cranial neuropathies
• Pachymeningitis
• Stroke
• Rare cerebral granulomatous disease

Headache with cranial neuropathies may warrant:

Contrast-enhanced MRI.

Skin Manifestations

Skin disease may include:

• Palpable purpura
• Petechiae
• Nodules
• Ulcers
• Vesicles
• Pustules
• Digital ischemia

Lower extremities are frequently affected.

Establishing the Diagnosis

Diagnosis integrates:

• Clinical phenotype
• ANCA testing
• Urinalysis
• Renal function
• Imaging
• Histopathology when needed

No single test should be interpreted in isolation.

ANCA Testing

Modern testing generally measures:

• PR3-ANCA
• MPO-ANCA

rather than relying solely on immunofluorescence patterns such as c-ANCA or p-ANCA.

A positive PR3-ANCA in a compatible clinical setting strongly supports GPA.

Important Limitation of ANCA

A negative ANCA result does:

Not exclude GPA.

ANCA-negative disease is particularly possible in:

• Localized orbital disease
• Limited ENT disease

Clinical suspicion and biopsy may still be necessary.

Urinalysis and Renal Testing

Initial evaluation should usually include:

• Serum creatinine
• Urinalysis
• Urine protein assessment

Look for:

• Hematuria
• Proteinuria
• Red-cell casts

These may reveal occult renal involvement that immediately changes treatment intensity.

Inflammatory Markers

Useful supportive tests include:

• CRP
• ESR
• CBC

Possible findings include:

• Anemia
• Leukocytosis
• Thrombocytosis

These are nonspecific.

Chest Imaging

CT of the chest is more sensitive than plain radiography for detecting:

• Pulmonary nodules
• Cavitation
• Ground-glass opacity
• Pulmonary hemorrhage

Chest imaging is often warranted even when respiratory symptoms are relatively mild.

Sinonasal Imaging

CT of the sinuses may reveal:

• Mucosal thickening
• Chronic opacification
• Bony erosion
• Septal destruction
• Sclerosing changes

These findings can help define:

Extent of destructive ENT disease.

Orbital Imaging

For suspected orbital involvement:

Contrast-enhanced MRI or CT of the orbits and sinuses

can identify:

• Orbital inflammatory masses
• Extraocular muscle involvement
• Optic nerve compression
• Contiguous sinus disease
• Bone destruction

MRI is particularly useful for:

Orbital apex and soft-tissue disease.

Role of Biopsy

Histopathology is useful when:

• Diagnosis is uncertain
• ANCA is negative
• Malignancy or infection remains possible
• Tissue confirmation will alter treatment

Potential biopsy sites include:

• Kidney
• Lung
• Nasal or sinus tissue
• Skin
• Orbit

Renal Biopsy

Renal biopsy classically shows:

Pauci-immune necrotizing crescentic glomerulonephritis.

“Pauci-immune” means there is little or no immunoglobulin deposition on immunofluorescence.

Histopathology of Granulomatous Disease

Characteristic findings can include:

• Necrotizing vasculitis
• Geographic necrosis
• Granulomatous inflammation
• Multinucleated giant cells

Not every biopsy contains the complete classic triad.

Major Diagnostic Alternatives

Important mimics include:

• Microscopic polyangiitis
• Eosinophilic granulomatosis with polyangiitis
• Anti-GBM disease
• Sarcoidosis
• IgG4-related disease
• Relapsing polychondritis
• Systemic lupus erythematosus
• Tuberculosis
• Fungal infection
• Lymphoma

Cocaine-Associated Midline Destruction

Intranasal cocaine, especially when contaminated with levamisole, can cause:

• Destructive sinonasal lesions
• ANCA positivity
• Vasculitic findings

This can closely resemble GPA.

A careful substance-use history may therefore be diagnostically important.

GPA vs Microscopic Polyangiitis

Both are ANCA-associated vasculitides.

GPA

Characteristically has:

• Granulomatous inflammation
• Destructive ENT disease
• Pulmonary nodules
• PR3-ANCA more commonly

Microscopic Polyangiitis

Typically lacks:

• Granulomatous inflammation
• Destructive upper-airway disease

and is more often associated with:

MPO-ANCA.

GPA vs Eosinophilic Granulomatosis With Polyangiitis

EGPA is suggested by:

• Asthma
• Marked eosinophilia
• Chronic eosinophilic airway disease

These are not typical dominant features of GPA.

The Modern Treatment Framework

Treatment is divided into:

1. Induction of remission
2. Maintenance of remission

Choice depends on whether disease is:

• Organ-threatening
• Life-threatening
• Non–organ-threatening

Organ- or Life-Threatening Disease

Examples include:

• Rapidly progressive glomerulonephritis
• Diffuse alveolar hemorrhage
• Necrotizing scleritis
• Severe PUK
• Orbital compression threatening the optic nerve
• CNS vasculitis

These generally require:

Rapid systemic induction therapy.

First-Line Induction Therapy

Modern induction usually combines:

Glucocorticoids + rituximab or cyclophosphamide.

For many patients:

Rituximab is preferred, particularly in relapsing disease or when avoidance of cyclophosphamide toxicity is desirable.

Rituximab

Rituximab is an anti-CD20 monoclonal antibody that depletes B cells.

It is effective for:

• Newly diagnosed severe GPA
• Relapsing GPA
• Maintenance therapy

It has largely replaced prolonged oral cyclophosphamide in many treatment strategies.

Cyclophosphamide

Cyclophosphamide remains highly effective for severe disease.

Potential toxicities include:

• Myelosuppression
• Serious infection
• Hemorrhagic cystitis
• Infertility
• Bladder cancer
• Other malignancies

Modern treatment generally limits cumulative exposure whenever possible.

Glucocorticoid Strategy

High-dose systemic corticosteroids are commonly used during induction.

Depending on disease severity, treatment may begin with:

• Oral prednisone/prednisolone
• IV methylprednisolone pulses for immediately threatening disease

Modern protocols increasingly favor:

Reduced cumulative glucocorticoid exposure

because prolonged high-dose therapy causes substantial toxicity.

Avacopan

A major modern development is:

Avacopan, an oral complement C5a receptor inhibitor.

It can be used in selected patients with severe ANCA-associated vasculitis as part of a regimen with:

• Rituximab

or:

• Cyclophosphamide-based therapy

Its principal role is to reduce dependence on prolonged high-dose glucocorticoids.

Non–Organ-Threatening Disease

Selected milder disease may be treated with:

• Glucocorticoids
• Methotrexate

depending on:

• Renal function
• Extent of disease
• Systemic involvement

Methotrexate is not appropriate for severe renal failure or immediately life-threatening disease.

Maintenance of Remission

Once remission is induced, maintenance options include:

• Rituximab
• Azathioprine
• Methotrexate
• Mycophenolate mofetil in selected patients

Rituximab has become a particularly important maintenance agent because it reduces relapse risk in many patients.

Why Cyclophosphamide Is Not Used Long Term

Older protocols often continued cyclophosphamide for many months.

Modern practice attempts to transition away from it once remission is achieved because cumulative toxicity rises with:

Duration and total dose.

Pneumocystis Prophylaxis

Patients receiving substantial immunosuppression, especially:

• Rituximab
• Cyclophosphamide
• High-dose corticosteroids

often require prophylaxis against:

Pneumocystis jirovecii pneumonia (PJP).

A common agent is:

Trimethoprim-sulfamethoxazole.

Important Correction About TMP-SMX

TMP-SMX should not be viewed as routine primary treatment for systemic GPA.

Its major modern role is:

PJP prophylaxis

although older studies suggested possible reduction of ENT relapse in selected patients.

It does not replace disease-modifying immunosuppression.

Plasma Exchange – Important Modern Correction

Older teaching frequently recommended plasmapheresis for:

• Severe renal disease
• Pulmonary hemorrhage

Modern evidence has substantially narrowed its routine use.

Plasma exchange is not automatically indicated for all patients with pulmonary hemorrhage or severe ANCA vasculitis.

It may still be considered in selected situations such as:

• Very severe rapidly progressive renal failure
• High risk of dialysis dependence
• Concomitant anti-GBM antibodies
• Exceptional life-threatening circumstances

Decisions are individualized with nephrology/rheumatology.

Treating GPA-Associated Scleritis

Sight-threatening scleritis requires:

Systemic control of the vasculitis.

Treatment may include:

• Systemic corticosteroid
• Rituximab
• Cyclophosphamide
• Other immunomodulatory therapy during maintenance

Topical treatment alone is inadequate for severe GPA scleritis.

Treating Peripheral Ulcerative Keratitis

Management includes:

• Urgent systemic immunosuppression
• Intensive lubrication
• Treatment of associated surface disease

For impending or actual perforation, structural measures may include:

• Cyanoacrylate glue
• Bandage contact lens
• Amniotic membrane
• Lamellar or penetrating keratoplasty in selected cases

The systemic vasculitis must still be controlled.

Orbital Disease Management

Active orbital GPA generally requires:

Systemic immunosuppression.

If progressive proptosis causes:

• Optic nerve compression
• Exposure keratopathy
• Severe structural compromise

urgent orbital decompression or biopsy may be required.

Surgery alone does not control the underlying vasculitis.

Surgical Timing in Quiescent Disease

Reconstructive procedures for:

• Nasolacrimal obstruction
• Saddle-nose deformity
• Eyelid abnormalities

are generally best performed after inflammatory disease has been:

Stably controlled.

Monitoring Treatment Safety

Depending on therapy, monitoring may include:

• CBC
• Creatinine
• Liver function
• Urinalysis
• Immunoglobulin levels with repeated rituximab
• Infection screening

Cyclophosphamide requires particular attention to:

• Cytopenia
• Hematuria
• Bladder toxicity

Fertility Considerations

Cyclophosphamide can cause:

Gonadal toxicity and infertility.

For younger patients, fertility preservation should be considered before substantial exposure when circumstances allow.

Bone Protection During Steroid Therapy

Patients receiving prolonged systemic glucocorticoids should undergo individualized:

• Fracture-risk assessment
• Calcium/vitamin D optimization
• Bone-density assessment when indicated
• Pharmacologic osteoporosis prophylaxis when risk warrants

Routine calcium alone is not sufficient management for every patient.

Why ANCA Titers Should Not Dictate Treatment Alone

Serial PR3-ANCA levels may correlate imperfectly with disease activity.

A rising ANCA level does:

Not by itself prove relapse.

Treatment decisions should be based primarily on:

• Clinical findings
• Organ involvement
• Laboratory evidence of active disease
• Imaging when appropriate

Follow-Up Strategy

Long-term follow-up generally involves:

• Rheumatology
• Nephrology when renal disease is present
• Pulmonology when lung disease is significant
• ENT
• Ophthalmology for ocular involvement

Patients remain at risk of:

Relapse even after prolonged remission.

Relapse

Relapses are relatively common, particularly in:

PR3-ANCA–positive GPA.

Recurrence may involve:

• Same organ system
• Different organ system

A patient previously treated for GPA who develops new:

• Eye pain
• Hematuria
• Sinus disease
• Pulmonary symptoms

requires prompt reassessment.

Expected Long-Term Course

Modern therapy allows many patients to achieve durable remission.

However, morbidity may result from:

• Recurrent vasculitis
• Chronic renal impairment
• Airway stenosis
• Hearing loss
• Structural ENT damage
• Ocular injury
• Immunosuppressive toxicity

Long-term management therefore balances:

Relapse prevention against treatment toxicity.

Major Causes of Ocular Visual Loss

Permanent visual impairment may result from:

• Necrotizing scleritis
• Corneal perforation from PUK
• Compressive optic neuropathy
• Retinal artery occlusion
• Retinal vasculitis
• Severe orbital inflammation
• Secondary glaucoma

Early systemic diagnosis can be vision-saving as well as life-saving.

High-Yield Takeaways

• Granulomatosis with polyangiitis is the modern name for Wegener granulomatosis.
• GPA is an ANCA-associated necrotizing granulomatous vasculitis affecting mainly the upper airway, lungs, kidneys, and eyes.
• The antibody most strongly associated with GPA is PR3-ANCA, often producing a c-ANCA pattern.
• Negative ANCA does not exclude GPA, particularly in localized orbital or ENT disease.
• Classic systemic manifestations include destructive sinus disease, pulmonary nodules or hemorrhage, and pauci-immune crescentic glomerulonephritis.
• Urinalysis is essential because significant renal vasculitis can be asymptomatic initially.
• Important ophthalmic manifestations include scleritis, peripheral ulcerative keratitis, orbital inflammation, nasolacrimal obstruction, retinal vasculitis, and optic neuropathy.
• Necrotizing scleritis and PUK are sight-threatening manifestations of systemic vasculitis and require systemic immunosuppression.
• Orbital disease can produce compressive optic neuropathy; falling acuity, dyschromatopsia, or RAPD requires urgent assessment.
• PR3-ANCA/MPO-ANCA testing is preferred over relying exclusively on c-ANCA/p-ANCA staining patterns.
• Biopsy may demonstrate necrotizing granulomatous vasculitis, while renal biopsy classically shows pauci-immune necrotizing crescentic glomerulonephritis.
• Important mimics include microscopic polyangiitis, EGPA, anti-GBM disease, sarcoidosis, IgG4-related disease, infection, lymphoma, and cocaine-associated destructive sinonasal disease.
• Modern induction of severe GPA generally uses glucocorticoids plus rituximab or cyclophosphamide.
• Rituximab is now a major first-line agent and is particularly useful in relapsing disease.
• Avacopan can reduce glucocorticoid exposure in selected patients with severe ANCA-associated vasculitis.
• Cyclophosphamide remains effective but should be limited because of infection, infertility, marrow toxicity, hemorrhagic cystitis, and malignancy risk.
• Maintenance commonly uses rituximab, azathioprine, or methotrexate, depending on the patient.
• TMP-SMX is important primarily for Pneumocystis prophylaxis during substantial immunosuppression, not as definitive treatment for systemic GPA.
• Plasma exchange is no longer routinely used for every case of pulmonary hemorrhage or severe renal GPA; it is reserved for selected high-risk situations.
• ANCA titers should not be used alone to diagnose relapse or dictate therapy.
• With early diagnosis and modern immunosuppressive treatment, long-term survival is dramatically better than in the pre-treatment era, but lifelong surveillance for relapse and treatment toxicity is essential.

High-Yield Takeaways

Important Modern Terminology The historical term: Wegener granulomatosis has been replaced by: Granulomatosis with polyangiitis (GPA). This is the preferred modern terminology in clinical practice and classification systems.

Why the Disease Develops GPA is an autoimmune inflammatory disease involving:  Activated neutrophils Vascular endothelium B lymphocytes T lymphocytes Complement pathways  The antibody most strongly associated with GPA is: PR3-ANCA which often produces a classic: Cytoplasmic ANCA (c-ANCA) pattern. However, ANCA status alone does not establish or exclude the diagnosis.

ANCA Patterns The two principal ANCA antigen targets are:  Proteinase 3 (PR3) Myeloperoxidase (MPO)  GPA is most strongly associated with: PR3-ANCA whereas microscopic polyangiitis is more frequently associated with MPO-ANCA. Some patients with GPA are: ANCA-negative, particularly when disease is localized to the orbit or upper respiratory tract.

Who Typically Develops GPA GPA can occur at almost any age but most often presents in: Middle adulthood. There is no clinically useful strong male predominance. Disease occurs in all ethnic groups, although incidence and ANCA subtype frequencies vary geographically and by ancestry.

Why Early Recognition Matters Untreated systemic GPA can cause:  Rapidly progressive glomerulonephritis Pulmonary hemorrhage Respiratory failure Permanent hearing loss Orbital destruction Optic neuropathy  Modern immunosuppressive therapy has transformed GPA from a frequently fatal disease into a: Treatable but relapsing chronic systemic vasculitis.

Upper Airway Disease ENT involvement is extremely common. Manifestations include:  Chronic sinusitis Nasal crusting Bloody nasal discharge Nasal ulceration Otitis media Conductive or sensorineural hearing loss Eustachian tube dysfunction Subglottic stenosis  Symptoms may initially resemble recurrent infection.

Saddle-Nose Deformity Chronic destructive inflammation can damage the: Nasal septum and supporting cartilage producing a: Saddle-nose deformity. This is a classic late manifestation but should not be required for diagnosis.

Strawberry Gingivitis A highly characteristic but uncommon oral finding is: “Strawberry gingivitis.” The gingiva becomes:  Red Friable Granular Hyperplastic  Its presence can be a strong diagnostic clue.

Pulmonary Involvement Pulmonary GPA may cause:  Nodules Cavitary nodules Pulmonary infiltrates Cough Dyspnea Hemoptysis  A particularly severe manifestation is: Diffuse alveolar hemorrhage.

Renal Disease The typical renal lesion is: Pauci-immune necrotizing crescentic glomerulonephritis. Clinical clues include:  Hematuria Dysmorphic erythrocytes Red-cell casts Proteinuria Rising creatinine  Renal disease may initially be: Clinically silent. Urinalysis and renal function testing are therefore essential even when the patient has no urinary symptoms.

Ocular Disease Can Be the First Manifestation Eye or orbital disease may precede the systemic diagnosis. Important ophthalmic manifestations include:  Scleritis Peripheral ulcerative keratitis Episcleritis Orbital inflammatory disease Nasolacrimal obstruction Uveitis Retinal vasculitis Retinal vascular occlusion Optic neuropathy  Almost any ocular structure can be affected.

Scleritis One of the most important ocular manifestations is: Anterior or posterior scleritis. Patients may develop:  Deep severe ocular pain Violaceous scleral injection Tenderness Pain with eye movement  The most dangerous form is: Necrotizing scleritis. This signals potentially severe systemic vasculitis and requires urgent systemic therapy.

Peripheral Ulcerative Keratitis Peripheral ulcerative keratitis (PUK) is another sight-threatening manifestation. Typical findings include:  Peripheral stromal thinning Epithelial defect Adjacent conjunctival inflammation Progressive corneal melt  Severe disease can progress to: Descemetocele or perforation.

Why PUK Is a Systemic Emergency GPA-associated PUK reflects active systemic immune-mediated vasculitis rather than simply local corneal disease. Treatment therefore requires: Systemic immunosuppression. Topical treatment alone is inadequate.

Important Rule Before Treating Corneal Melt Before escalating immunosuppression in PUK: Exclude infectious keratitis. Microbial infection can mimic or complicate autoimmune corneal ulceration.

Episcleritis Episcleritis can occur and is generally less dangerous than scleritis. It typically causes:  Mild discomfort Sectoral redness Superficial vessels  Unlike scleritis, it is usually not associated with severe deep pain.

Orbital GPA Orbital inflammation may result from:  Direct granulomatous orbital disease Extension from adjacent sinus disease  Possible manifestations include:  Proptosis Orbital pain Diplopia Restricted motility Eyelid edema Orbital mass-like inflammation

Why Orbital GPA Can Threaten Vision Inflammatory tissue may compress:  Optic nerve Orbital apex Extraocular muscles  This can produce: Compressive optic neuropathy. Red flags include:  Reduced visual acuity Dyschromatopsia RAPD Visual-field loss  These require urgent systemic treatment and sometimes surgical decompression.

Nasolacrimal Obstruction Chronic sinonasal and peri-lacrimal inflammation may scar the: Nasolacrimal drainage system. Patients may develop:  Epiphora Recurrent dacryocystitis  Definitive lacrimal surgery is generally best performed once systemic inflammation is adequately controlled.

Uveitis Anterior, intermediate, posterior, or panuveitis may occur but is less characteristic than:  Scleritis PUK Orbital disease  When uveitis is present, search carefully for other systemic evidence of GPA.

Retinal Vasculitis Retinal involvement may include:  Retinal vasculitis Cotton-wool spots Retinal hemorrhage Arterial occlusion Venous occlusion Retinal ischemia  Vision may be permanently reduced when the:  Macula Optic nerve Major retinal vessels  are affected.

Optic Nerve Disease Optic neuropathy may result from:  Orbital compression Vasculitic ischemia Contiguous inflammation Rare direct granulomatous infiltration  Rapidly declining vision in a patient with orbital GPA is an: Emergency.

Neurologic Manifestations GPA may cause:  Mononeuritis multiplex Peripheral neuropathy Cranial neuropathies Pachymeningitis Stroke Rare cerebral granulomatous disease  Headache with cranial neuropathies may warrant: Contrast-enhanced MRI.

Skin Manifestations Skin disease may include:  Palpable purpura Petechiae Nodules Ulcers Vesicles Pustules Digital ischemia  Lower extremities are frequently affected.

Establishing the Diagnosis Diagnosis integrates:  Clinical phenotype ANCA testing Urinalysis Renal function Imaging Histopathology when needed  No single test should be interpreted in isolation.

ANCA Testing Modern testing generally measures:  PR3-ANCA MPO-ANCA  rather than relying solely on immunofluorescence patterns such as c-ANCA or p-ANCA. A positive PR3-ANCA in a compatible clinical setting strongly supports GPA.

Important Limitation of ANCA A negative ANCA result does: Not exclude GPA. ANCA-negative disease is particularly possible in:  Localized orbital disease Limited ENT disease  Clinical suspicion and biopsy may still be necessary.

Urinalysis and Renal Testing Initial evaluation should usually include:  Serum creatinine Urinalysis Urine protein assessment  Look for:  Hematuria Proteinuria Red-cell casts  These may reveal occult renal involvement that immediately changes treatment intensity.

Inflammatory Markers Useful supportive tests include:  CRP ESR CBC  Possible findings include:  Anemia Leukocytosis Thrombocytosis  These are nonspecific.

Chest Imaging CT of the chest is more sensitive than plain radiography for detecting:  Pulmonary nodules Cavitation Ground-glass opacity Pulmonary hemorrhage  Chest imaging is often warranted even when respiratory symptoms are relatively mild.

Sinonasal Imaging CT of the sinuses may reveal:  Mucosal thickening Chronic opacification Bony erosion Septal destruction Sclerosing changes  These findings can help define: Extent of destructive ENT disease.

Orbital Imaging For suspected orbital involvement: Contrast-enhanced MRI or CT of the orbits and sinuses can identify:  Orbital inflammatory masses Extraocular muscle involvement Optic nerve compression Contiguous sinus disease Bone destruction  MRI is particularly useful for: Orbital apex and soft-tissue disease.

Role of Biopsy Histopathology is useful when:  Diagnosis is uncertain ANCA is negative Malignancy or infection remains possible Tissue confirmation will alter treatment  Potential biopsy sites include:  Kidney Lung Nasal or sinus tissue Skin Orbit

Renal Biopsy Renal biopsy classically shows: Pauci-immune necrotizing crescentic glomerulonephritis. “Pauci-immune” means there is little or no immunoglobulin deposition on immunofluorescence.

Histopathology of Granulomatous Disease Characteristic findings can include:  Necrotizing vasculitis Geographic necrosis Granulomatous inflammation Multinucleated giant cells  Not every biopsy contains the complete classic triad.

Major Diagnostic Alternatives Important mimics include:  Microscopic polyangiitis Eosinophilic granulomatosis with polyangiitis Anti-GBM disease Sarcoidosis IgG4-related disease Relapsing polychondritis Systemic lupus erythematosus Tuberculosis Fungal infection Lymphoma

Cocaine-Associated Midline Destruction Intranasal cocaine, especially when contaminated with levamisole, can cause:  Destructive sinonasal lesions ANCA positivity Vasculitic findings  This can closely resemble GPA. A careful substance-use history may therefore be diagnostically important.

GPA vs Microscopic Polyangiitis Both are ANCA-associated vasculitides. GPA Characteristically has:  Granulomatous inflammation Destructive ENT disease Pulmonary nodules PR3-ANCA more commonly  Microscopic Polyangiitis Typically lacks:  Granulomatous inflammation Destructive upper-airway disease  and is more often associated with: MPO-ANCA.

GPA vs Eosinophilic Granulomatosis With Polyangiitis EGPA is suggested by:  Asthma Marked eosinophilia Chronic eosinophilic airway disease  These are not typical dominant features of GPA.

The Modern Treatment Framework Treatment is divided into:  Induction of remission Maintenance of remission  Choice depends on whether disease is:  Organ-threatening Life-threatening Non–organ-threatening

Organ- or Life-Threatening Disease Examples include:  Rapidly progressive glomerulonephritis Diffuse alveolar hemorrhage Necrotizing scleritis Severe PUK Orbital compression threatening the optic nerve CNS vasculitis  These generally require: Rapid systemic induction therapy.

First-Line Induction Therapy Modern induction usually combines: Glucocorticoids + rituximab or cyclophosphamide. For many patients: Rituximab is preferred, particularly in relapsing disease or when avoidance of cyclophosphamide toxicity is desirable.

Rituximab Rituximab is an anti-CD20 monoclonal antibody that depletes B cells. It is effective for:  Newly diagnosed severe GPA Relapsing GPA Maintenance therapy  It has largely replaced prolonged oral cyclophosphamide in many treatment strategies.

Cyclophosphamide Cyclophosphamide remains highly effective for severe disease. Potential toxicities include:  Myelosuppression Serious infection Hemorrhagic cystitis Infertility Bladder cancer Other malignancies  Modern treatment generally limits cumulative exposure whenever possible.

Glucocorticoid Strategy High-dose systemic corticosteroids are commonly used during induction. Depending on disease severity, treatment may begin with:  Oral prednisone/prednisolone IV methylprednisolone pulses for immediately threatening disease  Modern protocols increasingly favor: Reduced cumulative glucocorticoid exposure because prolonged high-dose therapy causes substantial toxicity.

Avacopan A major modern development is: Avacopan, an oral complement C5a receptor inhibitor. It can be used in selected patients with severe ANCA-associated vasculitis as part of a regimen with:  Rituximab  or:  Cyclophosphamide-based therapy  Its principal role is to reduce dependence on prolonged high-dose glucocorticoids.

Non–Organ-Threatening Disease Selected milder disease may be treated with:  Glucocorticoids Methotrexate  depending on:  Renal function Extent of disease Systemic involvement  Methotrexate is not appropriate for severe renal failure or immediately life-threatening disease.

Maintenance of Remission Once remission is induced, maintenance options include:  Rituximab Azathioprine Methotrexate Mycophenolate mofetil in selected patients  Rituximab has become a particularly important maintenance agent because it reduces relapse risk in many patients.

Why Cyclophosphamide Is Not Used Long Term Older protocols often continued cyclophosphamide for many months. Modern practice attempts to transition away from it once remission is achieved because cumulative toxicity rises with: Duration and total dose.

Pneumocystis Prophylaxis Patients receiving substantial immunosuppression, especially:  Rituximab Cyclophosphamide High-dose corticosteroids  often require prophylaxis against: Pneumocystis jirovecii pneumonia (PJP). A common agent is: Trimethoprim-sulfamethoxazole.

Important Correction About TMP-SMX TMP-SMX should not be viewed as routine primary treatment for systemic GPA. Its major modern role is: PJP prophylaxis although older studies suggested possible reduction of ENT relapse in selected patients. It does not replace disease-modifying immunosuppression.

Plasma Exchange – Important Modern Correction Older teaching frequently recommended plasmapheresis for:  Severe renal disease Pulmonary hemorrhage  Modern evidence has substantially narrowed its routine use. Plasma exchange is not automatically indicated for all patients with pulmonary hemorrhage or severe ANCA vasculitis. It may still be considered in selected situations such as:  Very severe rapidly progressive renal failure High risk of dialysis dependence Concomitant anti-GBM antibodies Exceptional life-threatening circumstances  Decisions are individualized with nephrology/rheumatology.

Treating GPA-Associated Scleritis Sight-threatening scleritis requires: Systemic control of the vasculitis. Treatment may include:  Systemic corticosteroid Rituximab Cyclophosphamide Other immunomodulatory therapy during maintenance  Topical treatment alone is inadequate for severe GPA scleritis.

Treating Peripheral Ulcerative Keratitis Management includes:  Urgent systemic immunosuppression Intensive lubrication Treatment of associated surface disease  For impending or actual perforation, structural measures may include:  Cyanoacrylate glue Bandage contact lens Amniotic membrane Lamellar or penetrating keratoplasty in selected cases  The systemic vasculitis must still be controlled.

Orbital Disease Management Active orbital GPA generally requires: Systemic immunosuppression. If progressive proptosis causes:  Optic nerve compression Exposure keratopathy Severe structural compromise  urgent orbital decompression or biopsy may be required. Surgery alone does not control the underlying vasculitis.

Surgical Timing in Quiescent Disease Reconstructive procedures for:  Nasolacrimal obstruction Saddle-nose deformity Eyelid abnormalities  are generally best performed after inflammatory disease has been: Stably controlled.

Monitoring Treatment Safety Depending on therapy, monitoring may include:  CBC Creatinine Liver function Urinalysis Immunoglobulin levels with repeated rituximab Infection screening  Cyclophosphamide requires particular attention to:  Cytopenia Hematuria Bladder toxicity

Fertility Considerations Cyclophosphamide can cause: Gonadal toxicity and infertility. For younger patients, fertility preservation should be considered before substantial exposure when circumstances allow.

Bone Protection During Steroid Therapy Patients receiving prolonged systemic glucocorticoids should undergo individualized:  Fracture-risk assessment Calcium/vitamin D optimization Bone-density assessment when indicated Pharmacologic osteoporosis prophylaxis when risk warrants  Routine calcium alone is not sufficient management for every patient.

Why ANCA Titers Should Not Dictate Treatment Alone Serial PR3-ANCA levels may correlate imperfectly with disease activity. A rising ANCA level does: Not by itself prove relapse. Treatment decisions should be based primarily on:  Clinical findings Organ involvement Laboratory evidence of active disease Imaging when appropriate

Follow-Up Strategy Long-term follow-up generally involves:  Rheumatology Nephrology when renal disease is present Pulmonology when lung disease is significant ENT Ophthalmology for ocular involvement  Patients remain at risk of: Relapse even after prolonged remission.

Relapse Relapses are relatively common, particularly in: PR3-ANCA–positive GPA. Recurrence may involve:  Same organ system Different organ system  A patient previously treated for GPA who develops new:  Eye pain Hematuria Sinus disease Pulmonary symptoms  requires prompt reassessment.

Expected Long-Term Course Modern therapy allows many patients to achieve durable remission. However, morbidity may result from:  Recurrent vasculitis Chronic renal impairment Airway stenosis Hearing loss Structural ENT damage Ocular injury Immunosuppressive toxicity  Long-term management therefore balances: Relapse prevention against treatment toxicity.

Major Causes of Ocular Visual Loss Permanent visual impairment may result from:  Necrotizing scleritis Corneal perforation from PUK Compressive optic neuropathy Retinal artery occlusion Retinal vasculitis Severe orbital inflammation Secondary glaucoma  Early systemic diagnosis can be vision-saving as well as life-saving.

High-Yield Takeaways  Granulomatosis with polyangiitis is the modern name for Wegener granulomatosis. GPA is an ANCA-associated necrotizing granulomatous vasculitis affecting mainly the upper airway, lungs, kidneys, and eyes. The antibody most strongly associated with GPA is PR3-ANCA, often producing a c-ANCA pattern. Negative ANCA does not exclude GPA, particularly in localized orbital or ENT disease. Classic systemic manifestations include destructive sinus disease, pulmonary nodules or hemorrhage, and pauci-immune crescentic glomerulonephritis. Urinalysis is essential because significant renal vasculitis can be asymptomatic initially. Important ophthalmic manifestations include scleritis, peripheral ulcerative keratitis, orbital inflammation, nasolacrimal obstruction, retinal vasculitis, and optic neuropathy. Necrotizing scleritis and PUK are sight-threatening manifestations of systemic vasculitis and require systemic immunosuppression. Orbital disease can produce compressive optic neuropathy; falling acuity, dyschromatopsia, or RAPD requires urgent assessment. PR3-ANCA/MPO-ANCA testing is preferred over relying exclusively on c-ANCA/p-ANCA staining patterns. Biopsy may demonstrate necrotizing granulomatous vasculitis, while renal biopsy classically shows pauci-immune necrotizing crescentic glomerulonephritis. Important mimics include microscopic polyangiitis, EGPA, anti-GBM disease, sarcoidosis, IgG4-related disease, infection, lymphoma, and cocaine-associated destructive sinonasal disease. Modern induction of severe GPA generally uses glucocorticoids plus rituximab or cyclophosphamide. Rituximab is now a major first-line agent and is particularly useful in relapsing disease. Avacopan can reduce glucocorticoid exposure in selected patients with severe ANCA-associated vasculitis. Cyclophosphamide remains effective but should be limited because of infection, infertility, marrow toxicity, hemorrhagic cystitis, and malignancy risk. Maintenance commonly uses rituximab, azathioprine, or methotrexate, depending on the patient. TMP-SMX is important primarily for Pneumocystis prophylaxis during substantial immunosuppression, not as definitive treatment for systemic GPA. Plasma exchange is no longer routinely used for every case of pulmonary hemorrhage or severe renal GPA; it is reserved for selected high-risk situations. ANCA titers should not be used alone to diagnose relapse or dictate therapy. With early diagnosis and modern immunosuppressive treatment, long-term survival is dramatically better than in the pre-treatment era, but lifelong surveillance for relapse and treatment toxicity is essential.  High-Yield Takeaways