Granulomatosis with Polyangiitis (GPA) (Older Terminology: Wegener’s Granulomatosis; Necrotizing Granulomatous Vasculitis = NGV)

Epidemiology

History: first described in 1936
Prevalence: 3 per 100k in US
- Most common vasculitis to involve the lungs
- Represents 10% of all systemic vasculitides diagnosed
Race: overwhelming predilection for caucasians
Sex: M = F
Mean Age of Onset: 40 y/o (15% of cases are <19 y/o)

Etiology

Alpha-1 Antitrypsin Deficiency (see Alpha-1 Antitrypsin Deficiency)
- Due to the Strong Association Between c-ANCA Positive Vasculitis and A1AT Deficiency, It Has Been Suggested that All Wegener’s Granulomatosis Patients Be Tested for A1AT (Phenotyping or Genotyping May Be Required, Since A1AT is an Acute Phase Reactant Which Increases During Active Vasculitis)

Physiology

Necrotizing Vasculitis Involving Small Arteries and Veins

Airway Involvement

xxxx

Pathologic Features

(histologic material usually obtained from OLB)

Parenchymal Necrosis or Neutrophilic Microabscesses: geographic pattern
Granulomatous Inflammation: although it is usually a mixed infiltrate of neutrophils, lymphocytes, plasma cells, eosoinophils, and histiocytes
Small-Medium Arterial Necrotizing Vasculitis (although can involve capillaries and veins): vessel obstruction, bland infarcts
- Pulmonary Capillaritis: seen in about up to 33% of cases, but is an isolated finding in <3% of cases
  - Neutrophilic Invasion of Alveolar Interstitium with Fibrinoid Necrosis: destroyed alveolar-capillary membrane (leakage of RBC and neutrophils into alveoli)
  - Leukocytoclasis: neutrophils appear fragmented (nuclear dust accumulates in parenchyma)
  - Hemosiderin-Laden Macrophages/Free hemosiderin in Interstitium: appear after acute bleed
  - Type II Pneumocyte Hyperplasia/Organizing Pneumonia (organization of intra-alveolar hemorrhage)
  - Mononuclear Cell Infiltration of Interstitium
  - Small Thrombi in Capillaries and Venules
- Note: pulmonary HTN is rare in Wegener’s
Minor Histologic Criteria
- Organizing Pneumonia (70% of cases)
- Diffuse Alveolar Hemorrhage (10% of cases)
- Eosinophilia
- Bronchocentric Granulomatosis (1% of cases)
Circulating Endothelial Cells: may be found in Wegener’s and microsocpic polyangiitis -> may serve as a marker for active ANCA-associated vasculitis

Diagnosis

Complete Blood Count (CBC) (see Complete Blood Count)

Anemia (iron deficiency): usually present
Leukocytosis

Erythrocytes Sedimentation Rate (ESR) (see procxx

Usually markedly elevated

Urinalysis (see Urinalysis)

Abnormal

Arterial Blood Gas (ABG) (see xxxxx)

hypoxemia (with elevated A-a gradient)
Serum Ig: elevated

Serology – ANA: variable – Anti-DNA: negative – RF: variable (may be mildly elevated) – C3/C4/CH50: normal – c-ANCA (cytoplasmic staining, typically directed against proteinase 3, PR3): positive (>1:20) in >90-95% of untreated active systemic Wegener’s Granulomatosis cases – However, c-ANCA is only positive in 60-65% of limited Wegener’s Granulomatosis cases – ANCA positivity declines with remission but is not sensitive enough to follow disease course – Anti-GBM: negative

Chest CT (see Chest Computed Tomography)

Findings
- xxx
Example: diffuse alveolar hemorrhage in a patient with Wegener’s granulomatosis -> note the ground glass infiltrates in the right lung and extensive alveolar filling in the left lung (alveolar hemorrhage was confirmed in the left lower lobe by bronchoscopy)

Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests)

DLCO: increased during DAH/decreased at other times
Restriction (due to fibrosis) may be seen late
Increased VD/VT ratio

Bronchoscopy (see Bronchoscopy)

BAL with Diffuse Alveolar Hemorrhage: RBC’s, hemosiderin-laden macrophages (hemosiderin-laden macrophages indicate prior or recurrent alveolar hemorrhage)

Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) (see Fluorodeoxyglucose-Positron Emission Tomography)

xxx

Video-Assisted Thoracoscopic Surgery (VATS) with Lung Biopsy (see xxxx)

xxxx
OLB (best diagnostic yield of any tissue for Wegener’s Granulomatosis)
- Tissue Ab staining: granular pattern or negative

Upper Airway Biopsy

Diagnostic

Skin Biopsy (see xxxx)

May be diagnostic

Renal Biopsy (see xxxx)

Focal segmental necrotizing glomerulonephritis and crescents
- Usually not helpful in diagnosing this condition due to non-specific changes

Clinical Diagnostic Criteria (with >2 of these criteria, sensitivity is 88% and specificity is 92%)

Nasal or Oral Inflammation
Abnormal Chest X-Ray (CXR)
Abnormal Urinary Sediment
Granulomatous Inflammation on Biopsy
Hemoptysis (see xxxx)

Limited Wegener’s Granulomatosis

Systemic Disease without Glomerulonephritis
Unclear if This is an Earlier Form of Disease or a Clinical Variant

Clinical Features

General Comments
- Disease Course: symptoms are usually present for only days-weeks before presentation

Cardiovascular Manifestations

General Comments: occur in 5-30% of cases
Arrhythmias
Arteritis
Endocarditis (see Endocarditis)
Myocarditis (see Myocarditis)
Pericarditis (see Pericarditis)

Dermatologic Manifestations

General Comments: occur in 45% of cases
Leukocytoclastic Vasculitic Rash (splinter hemorrhages/palpable purpura): may be present
Skin Nodules
Ulcers (see xxxx)
Vesicles (see xxxx)

Gastrointestinal Manifestations

General Comments

Gastrointestinal Manifestations Occur in <10% of Cases

Intestinal Ischemia/Infarction (see Acute Mesenteric Ischemia)

Epidemiology
- XXXX

Gastrointestinal Perforation

Epidemiology
- XXXX

Ulcerative Lesions

Epidemiology
- XXXX

Weight Loss (see Weight Loss)

Epidemiology
- XXXX

Neurologic Manifestations (22%)

Fatigue (see Fatigue)

Epidemiology
- XXXX

Peripheral Neuropathy (see xxxx)

Epidemiology
- XXXX

Mononeuritis Multiplex (see xxxx)

Epidemiology
- XXXX

Cranial Neuropathies

Epidemiology
- XXXX

External Ophthalmoplegia

Epidemiology
XXXX

Seizures (see xxxx)

Epidemiology
- XXXX

Cerebritis

Epidemiology
- XXXX

Cerebrovascular Accident (CVA) (see xxxx)

Epidemiology
- XXXX

Posterior Reversible Encephalopathy Syndrome (PRES) (see Posterior Reversible Encephalopathy Syndrome)

Epidemiology
- XXXX

Ophthamlogic Manifestations (25-60%)

Proptosis
Uveitis
Ocular Ulcers
Conjunctivitis
Scleritis
Retinal and Optic Nerve Vasculitis

Pulmonary Manifestations

General Comments

Parenchymal Abnormalities Occur in 45% of Cases on Initial Presentation
- Eventually, 85% of Cases Develop Parenchymal Abnormalities

Acute/Chronic Bronchiolitis (see Bronchiolitis)

Epidemiology
- Less Common Clinical Presentation

Bronchiolitis Obliterans (BO) (see Bronchiolitis Obliterans)

Epidemiology
- Less Common Clinical Presentation

Diffuse Alveolar Hemorrhage (DAH) (see Diffuse Alveolar Hemorrhage)

Epidemiology
- Recurrent Diffuse Alveolar Hemorrhage Appears to Be More Common in ANCA-Associated Vasculitis than with Other Etiologies of Diffuse Alveolar Hemorrhage
Diagnosis
- Chest X-Ray (CXR)/Chest Computed Tomography (CT) (see Chest X-Ray and Chest Computed Tomography)
  - Alveolar infiltrates: during acute diffuse alveolar hemorrhage
  - Intersitital infiltrates: after chronic or recurrent diffuse alveolar hemorrhage
Clinical
- Chest Pain (see Chest Pain): may occur
- Cough (see Cough)
- Dyspnea (see Dyspnea)
- Hemoptysis (see xxxx)
  - Occurs in 95% of Cases
  - Due to Capillaritis
  - May Occur on initial Presentation or in Established Disease
  - May Be Absent on Initial Presentation in Some Cases, Even After Significant Bleeding

Endobronchial Ulcerating Lesions or Stenosis

Epidemiology
- Tracheobronchial or Endobronchial Disease Occurs in 10-50% of Cases
Diagnosis
- Chest X-Ray (CXR)/Chest Computed Tomography (CT) (see Chest X-Ray and Chest Computed Tomography)
  - Post-Obstructive Atelectasis (see Atelectasis)

Interstitial Lung Disease (see Interstitial Lung Disease): less common presentation

Epidemiology
- May occur after chronic or recurrent diffuse alveolar hemorrhage

Lipoid Pneumonia (see Lipoid Pneumonia)

Epidemiology
- Less Common Clinical Presentation

Lung Nodules (see Lung Nodule or Mass)

Epidemiology: occur in 31% of cases
Diagnosis
- Chest X-Ray (CXR)/Chest Computed Tomography (CT) (see Chest X-Ray and Chest Computed Tomography)
  - Approximately 80% of Cases Have <10 Nodules
  - Cavitary Nodules Occur in 10% of Cases
  - Absence of Calcification within Lung Lesions

Mediastinal Lypmhadenopathy (see Mediastinal Mass)

Epidemiology
- Occurs in Only 2-15.7% of Cases
Clinical
- Absence of Hilar Lymphadenopathy
- Massive Lymphadenopathy is Uncommon

Pleural Effusion/Thickening (see Pleural Effusion-Exudate)

Diagnosis
- Chest X-Ray (CXR)/Chest Computed Tomography (CT) (see Chest X-Ray and Chest Computed Tomography)
  - Pleural Effusion

Pneumonia-Like Picture (see Pneumonia)

Epidemiology
- Pneumonia-Like Presentation Occurs in 63% of Cases
Diagnosis
- Chest X-Ray (CXR)/Chest Computed Tomography (CT) (see Chest X-Ray and Chest Computed Tomography)
  - Diffuse or Patchy Alveolar Infiltrates

Pulmonary Hypertension (see Pulmonary Hypertension)

Epidemiology
- Pulmonary Hypertension is Rare
Diagnosis
- Echocardiogram (see Echocardiogram)
  - Useful to Diagnose Pulmonary Hypertension

Renal Manifestations

General Comments

Renal Manifestations Occur in 50-90% of Cases

Glomerulonephritis

Epidemiology
- Approximately 80-90% of Patients Will Eventually Develop Renal Manifestations, But Only 40% Have Renal Symptoms on Initial Presentation)

Rheumatologic Manifestations

General Comments: occur in 80% of cases
Arthralgias (see Arthralgias)
Myalgias (see Myalgias)
Polyarthritis (see Arthritis)

Upper Airway Manifestations (75-90% of cases)

Bony Destruction (may mimic Lethal Midline Granuloma, which involves only the nose and face)
Nasal or Upper Airway Ulcers (see xxxx)
Otitis (see xxxx)
Rhinitis (see xxxx)
Sinusitis (see xxxx): most common presenting symptom
Subglottic Stenosis (23% of cases in one NIH series): may require tracheostomy

Other Manifestations

Fever (see Fever)
Malaise
Nasolacrimal Duct Involvement
Salivary Gland Involvement

Treatment

Induction in Mild Disease

Criteria for Mild Disease

Absence of Active Glomerulonephritis
- Normal Creatinine
- No Red Blood Cell Casts
- No Proteinuria
Absence of Organ-Threatening/Life-Threatening Manifestations
- Absence of Pulmonary Hemorrhage
- Absence of Cerebral Vasculitis
- Absence of Progressive Neuropathy
- Absence of Orbital Pseudotumor
- Absence of Gastrointestinal Bleeding
- Absence of Pericarditis
- Absence of Myocarditis

Regimens

Corticosteroids + Methotrexate (see Corticosteroids and Methotrexate)
- Initial Therapy for Patients with Mild Extrarenal Disease and Little or No Renal Involvement
Corticosteroids + Cyclophosphamide (Cytoxan) (see Corticosteroids and Cyclophosphamide)
- Alternative for Patients with Lack of Response or Progression on Methotrexate Therapy
- Adverse Effects
  - Cyclophosphamide-Specific Side Effects (see Cyclophosphamide)
    - Cystitis: occur in 12% of cyclophosphamide-treated patients
    - Myelodysplastic Syndrome: occurs in 8% of cyclophosphamide-treated patients
    - Solid Malignancy: occurs in 5% of cyclophosphamide-treated patients
  - Infection
    - Clinically-Important Infection: occurs in 10% of cyclophosphamide-treated patients (even in the absence of cyclophosphamide-induced leukopenia)
    - Combined Corticosteroids + Cyclophosphamide Increase the Risk of Infection Over that of Cyclophosphamide Alone
Corticosteroids + Rituximab (Rituxan) (see Corticosteroids and Rituximab)
- Alternative for Patients with Lack of Response or Progression on Methotrexate Therapy
Clinical Efficacy
- Open-Label Rituximab Trial in Wegener’s Granulomatosis (Am J Respir Crit Care Med, 2006) [MEDLINE]
  - Rituximab Was a Well-Tolerated and Effective Remission Induction Agent for Severe Refractory Wegener’s Granulomatosis
- RAVE-ITN Trial of Rituximab vs Cyclophosphamide for ANCA-Associated Vasculitis (Wegener’s Granulomatosis or Microscopic Polyangiitis) (NEJM, 2010) [MEDLINE]
  - Rituximab Was Not Inferior to Daily Cyclophosphamide for Induction of Remission in Severe ANCA-Associated Vasculitis and May Be Superior in Relapsing Disease
- European Vasculitis Study Group-RITUXVAS Trial in ANCA-Associated Renal Vasculitis (NEJM, 2010) [MEDLINE]
  - Rituximab Was Not Superior to Standard Intravenous Cyclophosphamide for Severe ANCA-Associated Vasculitis: sustained-remission rates were high in both groups
  - No Difference in Adverse Events: rituximab-based regimen was not associated with reductions in early severe adverse events
- Multicenter Randomized Trial of Remission-Induction Regimens for ANCA-Associated Vasculitis (NEJM, 2013) [MEDLINE]
  - Single Course of Rituximab was as Effective as Continuous Conventional Immunosuppressive Therapy for the Induction and Maintenance of Remission Over the Course of 18 mo

Pneumocystis Jirovecii Prophylaxis (see Pneumocystis Jirovecii)

Indicated During Induction, Due to Risk of Infection (Am J Respir Crit Care Med, 1995) [MEDLINE]

Induction in Moderate-Severe Disease

Criteria for Moderate-Severe Disease

Presence of Organ-Threatening/Life-Threatening Manifestations
- Pulmonary Hemorrhage
- Rapidly-Deteriorating Renal Function

Regimens

General Comments: lack of disagreement about which of these regimens is preferred
Corticosteroids + Cyclophosphamide (Cytoxan) (see Corticosteroids and Cyclophosphamide)
- Preferred Regimen in the Setting of Mechanical Ventilation or Cr >4 mg/dL, Since Rituximab Has Not Been Well-Studied in These Settings
- Cyclophosphamide: PO or IV
- Corticosteroids and Oral Cyclophosphamide Induce Remission in 85-90% of Cases, with Approximately 75% of Cases Achieving Complete Remission
  - Most Remissions Occur Between 2-6 mo
- Adverse Effects
  - Cyclophosphamide-Specific Side Effects (see Cyclophosphamide)
    - Cystitis: occur in 12% of cyclophosphamide-treated patients
    - Myelodysplastic Syndrome: occurs in 8% of cyclophosphamide-treated patients
    - Solid Malignancy: occurs in 5% of cyclophosphamide-treated patients
  - Infection
    - Clinically-Important Infection: occurs in 10% of cyclophosphamide-treated patients (even in the absence of cyclophosphamide-induced leukopenia)
    - Combined Corticosteroids + Cyclophosphamide Increase the Risk of Infection Over that of Cyclophosphamide Alone
Corticosteroids + Rituximab (Rituxan) (see Corticosteroids and Rituximab)
- Preferred Regimen in Patients with Concerns About the Risk of Malignancy or Fertility
Plasma Exchange (see Plasmapheresis and Plasma Exchange)
- Recommended as Add-On Therapy for the Following Indications
  - Concurrent Anti-GBM Antibody Disease
  - Cr >5.7 mg/dL
  - Need for Hemodialysis (see Hemodialysis)
  - Severe Active Renal Disease
  - Severe Pulmonary Hemorrhage (see Diffuse Alveolar Hemorrhage)
- Rationale: plasma exchange removes ANCA
- Clinical Efficacy
  - Retrospective Review of Plasmapheresis for Diffuse Alveolar Hemorrhage in Patients with Small Vessel Vasculitis (Am J Kidney Dis, 2003) [MEDLINE]
    - Plasmapheresis with Immunosuppression is Effective in ANCA-Associated Small Vessel Vasculitis and Diffuse Alveolar Hemorrhage
  - Randomized Trial of Plasma Exchange or High-Dose Methylprednisolone as Adjunctive Therapy in Severe Renal Vasculitis (J Am Soc Nephrol, 2007) [MEDLINE]
    - As Compared to Intravenous Methylprednisolone, Plasma Exchange was Associated with a Decreased Risk in Progression to End-Stage Renal Disease at 12 mo
    - Plasma Exchange Increased the Rate of Renal Recovery in ANCA-Associated Vasculitis with Renal Failure, as Compared to Intravenous Methylprednisolone
    - No Difference in Mortality Rate Between the Groups
  - PEXIVAS Trial is Currently in Process to Examine the Benefit of Plasma Exchange
Clinical Efficacy
- Open-Label Rituximab Trial in Wegener’s Granulomatosis (Am J Respir Crit Care Med, 2006) [MEDLINE]
  - Rituximab Was a Well-Tolerated and Effective Remission Induction Agent for Severe Refractory Wegener’s Granulomatosis
- RAVE-ITN Trial of Rituximab vs Cyclophosphamide for ANCA-Associated Vasculitis (Wegener’s Granulomatosis or Microscopic Polyangiitis) (NEJM, 2010) [MEDLINE]
  - Rituximab Was Not Inferior to Daily Cyclophosphamide for Induction of Remission in Severe ANCA-Associated Vasculitis and May Be Superior in Relapsing Disease
- European Vasculitis Study Group-RITUXVAS Trial in ANCA-Associated Renal Vasculitis (NEJM, 2010) [MEDLINE]
  - Rituximab Was Not Superior to Standard Intravenous Cyclophosphamide for Severe ANCA-Associated Vasculitis: sustained-remission rates were high in both groups
  - No Difference in Adverse Events: rituximab-based regimen was not associated with reductions in early severe adverse events
- Multicenter Randomized Trial of Remission-Induction Regimens for ANCA-Associated Vasculitis (NEJM, 2013) [MEDLINE]
  - Single Course of Rituximab was as Effective as Continuous Conventional Immunosuppressive Therapy for the Induction and Maintenance of Remission Over the Course of 18 mo

Pneumocystis Jirovecii Prophylaxis (see Pneumocystis Jirovecii)

Indicated During Induction, Due to Risk of Infection (Am J Respir Crit Care Med, 1995) [MEDLINE]

Maintenance Therapy

Azathioprine (Imuran) (see Azathioprine)
Methotrexate (see Methotrexate)
Mycophenolate Mofetil (Cellcept) (see Mycophenolate Mofetil)
Rituximab (Rituxan) (see Anti-CD20 Therapy)

Relapse

Prevalance of Relapse
- 50% of all ANCA-associated vasculitis patients have at least one relapse, despite active treatment
- Relapse occurs in 40-65% of Wegener’s Granulomatosis cases (in contrast, relapse occurs in 25-33% of Microscopic Polyangiitis cases and 15-25% of Churg-Strauss cases)
Site of Relapse: may be in an initially affected organ or in a new organ
Treatment of Relapse: repeat induction

Disease Markers to Follow

Erythrocyte Sedimentation Rate (ESR)
ANCA
DLCO
Urinalysis

Prognosis

5-Year Survival: 75%
- Survival: months-years without treatment
Causes of Death: cardiac disease, infection, renal failure, malignancy
Predictors of Poor Outcome: advanced age, lack of otolaryngology clinician involvement, more severe renal disease, pulmonary involvement (especially with diffuse alveolar hemorrhage), hypoalbuminemia, high level of anti-PR3 (c-ANCA) positivity
Better prognosis with limited Wegener’s

References

General

Cardiac involvement in Wegener’s granulomatosis. Br Heart J. 1995 February; 73(2): 110–115
Neurological involvement in Wegener’s granulomatosis: an analysis of 324 consecutive patients at the Mayo Clinic. Ann Neurol. Jan 1993;33(1):4-9
An unusual presentation of relapsing Wegener’s granulomatosis. Nephrol. Dial. Transplant. (2001) 16 (7): 1511-1512
Severe Intestinal Involvement in Wegener’s Granulomatosis: Report of Two cases and Review of the Literature. British Journal of Rheumatology 1998;37:387–390
Pulmonary renal syndrome: a 4-year, single-center experience. Am J Kidney Dis. 2002 Jan;39(1):42-7 [MEDLINE]

Classification

Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 1994;37(2):187 [MEDLINE]
2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1 [MEDLINE]

Treatment

Pneumocystis carinii pneumonia: a major complication of immunosuppressive therapy in patients with Wegener’s granulomatosis. Am J Respir Crit Care Med. 1995 Mar;151(3 Pt 1):795-9 [MEDLINE]
Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small-vessel vasculitis. Am J Kidney Dis. 2003 Dec;42(6):1149-53 [MEDLINE]
Rituximab for refractory Wegener’s granulomatosis: report of a prospective open-label pilot trial. Am J Respir Crit Care Med 2006;173:180-187 [MEDLINE]
Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol. 2007 Jul;18(7):2180-8. Epub 2007 Jun 20 [MEDLINE]
RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221-32. doi: 10.1056/NEJMoa0909905 [MEDLINE]
European Vasculitis Study Group. Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis. N Engl J Med 2010; 363:221-232 [MEDLINE]
RAVE-ITN Research Group. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med 2013;369(36):417-427 [MEDLINE]
Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014;371(19):1771 [MEDLINE]
Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small-vessel vasculitis. Am J Kidney Dis. 2003 Dec;42(6):1149-53 [MEDLINE]
Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol. 2007 Jul;18(7):2180-8. Epub 2007 Jun 20 [MEDLINE]