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, [[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

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

  • CBC
    • Anemia (iron deficiency): usually present
    • Leukocytosis
  • ESR: usually markedly elevated
  • Urinalysis: abnormal
  • ABG: 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
  • PFT’s
    • DLCO: increased during DAH/decreased at other times
    • Restriction (due to fibrosis) may be seen late
    • Increased VD/VT ratio
  • FOB
    • BAL with Diffuse Alveolar Hemorrhage: RBC’s, hemosiderin-laden macrophages (hemosiderin-laden macrophages indicate prior or recurrent alveolar hemorrhage)
  • OLB (best diagnostic yield of any tissue for Wegener’s Granulomatosis)
    • Tissue Ab staining: granular pattern or negative
  • Upper Airway Biopsy: diagnostic
  • Skin Biopsy: may be diagnostic
  • Renal Biopsy: 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 CXR
  • Abnormal Urinary Sediment
  • Granulomatous Inflammation on Biopsy
  • Hemoptysis

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: symptoms usually present for only days-weeks before presentation

Cardiovascular Manifestations

  • General Comments: occur in 5-30% of cases
  • Arrhythmias
  • Arteritis
  • Endocarditis (see Endocarditis, [[Endocarditis]])
  • Myocarditis (see Myocarditis, [[Myocarditis]])
  • Pericarditis (see Pericarditis, [[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, [[xxxx]])
  • Vesicles (see xxxx, [[xxxx]])

Gastrointestinal Manifestations

  • General Comments: gastrointestinal manifestations occur in <10% of cases
  • Intestinal Ischemia/Infarction
  • Gastrointestinal Perforation
  • Ulcerative Lesions
  • Weight Loss (see Weight Loss, [[Weight Loss]])

Neurologic Manifestations (22%)

  • Peripheral Neuropathy (see xxxx, [[xxxx]])
  • Mononeuritis Multiplex
  • Cranial Neuropathies
  • External Ophthalmoplegia
  • Seizures
  • Cerebritis
  • CVA
  • Posterior Reversible Encephalopathy Syndrome (PRES) (see Posterior Reversible Encephalopathy Syndrome, [[Posterior Reversible Encephalopathy Syndrome]])

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, [[Bronchiolitis]])

  • Epidemiology: less common presentation

Bronchiolitis Obliterans (BO) (see Bronchiolitis Obliterans, [[Bronchiolitis Obliterans]])

  • Epidemiology: less common presentation

Diffuse Alveolar Hemorrhage (DAH) (see Diffuse Alveolar Hemorrhage, [[Diffuse Alveolar Hemorrhage]])): recurrent DAH appears to be more common in ANCA-associated vasculitis than with other etiologies of DAH

  • Diagnosis
    • CXR/Chest CT
      • Alveolar infiltrates: during acute diffuse alveolar hemorrhage
      • Intersitital infiltrates: after chronic or recurrent diffuse alveolar hemorrhage
  • Clinical
    • Chest Pain: may occur
    • Cough
    • Dyspnea
    • Hemoptysis (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 bleed

Endobronchial Ulcerating Lesions or Stenosis

  • Epidemiology: tracheobronchial or endobronchial disease occurs in 10-50% of cases
  • Diagnosis
    • CXR/Chest CT: post-obstructive atelectasis (see [[Obstructive Lung Disease]])

Interstitial Lung Disease (see Interstitial Lung Disease, [[Interstitial Lung Disease]]): less common presentation

  • Epidemiology: may occur after chronic or recurrent diffuse alveolar hemorrhage

Lipoid Pneumonia (see Lipoid Pneumonia, [[Lipoid Pneumonia]])

  • Epidemiology: less common presentation

Lung Nodules (see Lung Nodule or Mass, [[Lung Nodule or Mass]])

  • Epidemiology: occur in 31% of cases
  • Diagnosis
    • CXR/Chest CT: 80% of cases have <10 nodules
      • Cavitary in 10% of cases
      • Absence of calcification within lung lesions

Mediastinal Lypmhadenopathy (see Mediastinal Mass, [[Mediastinal Mass]])

  • Epidemiology : occurs in only 2-15.7% of cases)
  • Clinical
    • Absence of hilar adenopathy
    • Massive adenopathy is uncommon

Pleural Effusion/Thickening (see Pleural Effusion-Exudate, [[Pleural Effusion-Exudate]])

  • Diagnosis
    • CXR/Chest CT: pleural effusion

Pneumonia-Like Picture (see Pneumonia, [[Pneumonia]]): 63% of cases

  • Diagnosis
    • CXR/Chest CT: diffuse or patchy alveolar infiltrates

Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])

  • Epidemiology: rare in Wegener’s
  • Diagnosis
    • Echocardiogram: useful to diagnose pulmonary hypertension

Renal Manifestations (50-90% of cases)

  • Glomerulonephritis (80-90% of patients will eventually develop renal manifestations, but only 40% have renal symptoms at initial presentation)

Rheumatologic Manifestations

  • General Comments: occur in 80% of cases
  • Arthralgias (see Arthralgias, [[Arthralgias]])
  • Myalgias (see Myalgias, [[Myalgias]])
  • Polyarthritis (see Arthritis, [[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, [[xxxx]])
  • Otitis (see xxxx, [[xxxx]])
  • Rhinitis (see xxxx, [[xxxx]])
  • Sinusitis (see xxxx, [[xxxx]]): most common presenting symptom
  • Subglottic Stenosis (23% of cases in one NIH series): may require tracheostomy

Other Manifestations

  • Fever (see Fever, [[Fever]])
  • Fatigue (see Fatigue, [[Fatigue]])
  • Malaise
  • Nasolacrimal Duct Involvement
  • Salivary Gland Involvement

Treatment

Induction in Mild Disease

Criteria

  • Absence of Active Glomerulonephritis: normal creatinine, no red blood cell casts, and no proteinuria
  • Absence of Organ-Threatening/Life-Threatening Manifestations: absence of pulmonary hemorrhage, cerebral vasculitis, progressive neuropathy, orbital pseudotumor, gastrointestinal bleeding, pericarditis, or myocarditis

Regimens

  • Corticosteroids + Methotrexate (see Corticosteroids, [[Corticosteroids]] and Methotrexate, [[Methotrexate]])
  • Corticosteroids + Cyclophosphamide (Cytoxan) (see Corticosteroids, [[Corticosteroids]] and Cyclophosphamide, [[Cyclophosphamide]]): alternative regimen for patients who do not respond to or progress on methotrexate
  • Corticosteroids + Rituximab (Rituxan) (see Corticosteroids, [[Corticosteroids]] and Anti-CD20 Therapy, [[Anti-CD20 Therapy]]): alternative regimen for patients who do not respond to or progress on methotrexate
    • Open-Label Rituximab Trial (2006) [MEDLINE]: rituximab was a well-tolerated and effective remission induction agent for severe refractory Wegener’s granulomatosis
    • European Vasculitis Study Group-RITUXVAS Trial (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
    • RAVE-ITN Trial (NEJM, 2013): 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, [[Pneumocystis Jirovecii]])

  • Indicated During Induction

Induction in Moderate-Severe Disease

Criteria

  • Presence of Organ-Threatening/Life-Threatening Manifestations: pulmonary hemorrhage, rapidly-deteriorating renal function, etc

Regimens

  • General Comments: lack of disagreement about which of these regimens is preferred
  • Corticosteroids + Cyclophosphamide (Cytoxan) (see Corticosteroids, [[Corticosteroids]] and Cyclophosphamide, [[Cyclophosphamide]])
    • Preferred regimen in the setting of mechanical ventilation or Cr >4 mg/dL, since rituximab has not been well-studied in these setting
    • 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
  • Corticosteroids + Rituximab (Rituxan) (see Corticosteroids, [[Corticosteroids]] and Anti-CD20 Therapy, [[Anti-CD20 Therapy]])
    • Preferred regimen in patients with concerns about the risk of malignancy or fertility
    • Open-Label Rituximab Trial (2006) [MEDLINE]: rituximab was a well-tolerated and effective remission induction agent for severe refractory Wegener’s granulomatosis
    • European Vasculitis Study Group-RITUXVAS Trial (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
    • RAVE-ITN Trial (NEJM, 2013): single course of rituximab (375 mg/m2 per week for 4 wks) was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remission over the course of 18 mo
  • Plasma Exchange (see Plasmapheresis, [[Plasmapheresis]]): also recommended for patients with severe active renal disease, concurrent anti-GBM antibody disease, Cr >5.7 mg/dL, on dialysis, or who have severe pulmonary hemorrhage
    • Rationale: plasma exchange removes ANCA
    • PEXIVAS trial is examining benefit of plasma exchange

Pneumocystis Jirovecii Prophylaxis (see Pneumocystis Jirovecii, [[Pneumocystis Jirovecii]])

  • Indicated During Induction

Maintenance Therapy

Side Effects of Therapy

  • Infection
    • 10% of cyclophosphamide-treated patients develop clinically important infection (even in the absence of cyclophosphamide-induced leukopenia)
    • Combined corticosteroids + cyclophosphamide increase the risk over cyclophosphamide alone
  • Cyclophosphamide-Specific Side Effects (see Cyclophosphamide, [[Cyclophosphamide]])
    • 12% of cyclophosphamide-treated patients develop cystitis
    • 8% of cyclophosphamide-treated patients develop myelodysplastic syndrome
    • 5% of cyclophosphamide-treated patients develop a solid malignancy

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

  • 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
  • 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]
  • 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]