Granulomatosis with Polyangiitis

Epidemiology and Etiology

Epidemiology

• Prevalence: 3 per 100,000 in the United States
• Peak incidence: 65–74 years of age
  • Predominantly affects individuals of Northern European descent
  • Male-to-female ratio: 1.5:1
  • Women more likely to have limited disease

Etiology

• Idiopathic
  • Tends to occur more after infections, especially of the respiratory tract
• Genetic predisposition (positive family history)
• Autoimmune reaction

Pathophysiology

• Inflammation of small to medium-sized blood vessels, primarily affecting the lungs and kidneys 
• Autoimmune trigger usually due to bacterial colonization with Staphylococcus aureus
• Antineutrophil cytoplasmic antibodies (ANCAs) are responsible for the inflammation in granulomatosis with polyangiitis (GPA).
  • ANCAs in GPA are those that react with proteinase 3, an enzyme in neutrophil granulocytes. Referred to as c-ANCA (cytoplasmic ANCA; characteristic staining pattern shown in image below)
  • ANCAs form due to an aberrant epigenetic expression of proteinase 3 on all neutrophil membranes.
• ANCAs can activate neutrophils, increase their adherence to endothelium, and induce their degranulation, which leads to damage to the vessel wall.

Clinical Presentation

• Early stage symptoms include constitutional symptoms, chronic upper respiratory tract infections, nosebleed, ear pain, hemoptysis, and hematuria.
• Late stage symptoms include bronchial stenosis, renal failure, saddle nose deformity, and sensory neuropathies.
• General symptoms:
  • Loss of appetite
  • Weight loss
  • Fever
  • Fatigue
• Mainly involves the kidney and the lungs: hematuria and hemoptysis
  • Rarely affects the heart, gastrointestinal tract, brain, and other organs
• Renal symptoms:
  • Rapidly progressive glomerulonephritis
  • Chronic kidney disease (can progress to renal failure)
  • Hematuria (most commonly seen renal symptom)
  • Hypertension
• Ear, nose, and throat symptoms:
  • Nose: nosebleeds, runny nose, and saddle-nose deformity due to destruction of nasal cartilage
  • Ears: otitis media, conductive hearing loss due to auditory tube dysfunction, sensorineural hearing loss (unclear mechanism)
  • Oral cavity: strawberry gingivitis, bone destruction with the loosening of teeth, non-specific ulceration
• Tracheal symptoms:
  • Wheezing
  • Subglottic stenosis
• Lung symptoms:
  • Cough
  • Hemoptysis (most commonly seen lung symptom)
  • Pulmonary nodules (sometimes referred to as “coin lesions”)
  • Infiltrates (often interpreted as pneumonia; represent intraparenchymal hemorrhage)
  • Cavitary lesions
  • Bronchial stenosis
• Other symptoms:
  • Arthritis
  • Subcutaneous nodules (granulomas) on the elbow, purpura
  • Sensory neuropathy and, rarely, mono-neuritis multiplex

Diagnosis

• Laboratory studies:
  • CBC shows a normocytic anemia 
  • Erythrocyte sedimentation rate (ESR) is elevated
  • C-reactive protein (CRP) is elevated
  • Complete metabolic panel will show a low serum albumin level, elevated creatinine, and highly elevated blood urea nitrogen
  • c-ANCA positivity: shows a uniform granular cytoplasmic pattern on staining; present in over 80% of patients with GPA 
• Urinalysis:
  • Proteinuria
  • Microscopic hematuria
  • RBC casts and dysmorphic RBCs (nephritic sediment)
• Imaging
  • Chest X-ray: cavitary nodules, diffuse opacities, atelectasis, and consolidation
  • Computed tomography of the chest: consolidation, ground-glass opacities, stenosis of larynx or tracheobronchial tree, thickening of bronchus, bronchiectasis, pleural thickening or effusion, and lymphadenopathy
• Biopsy (confirmation of diagnosis)
  • Biopsy of affected tissue should be performed ultimately in any patient suspected to have GPA.
  • Biopsy confirms a diagnosis of granulomatosis with polyangiitis.
  • Poorly formed granulomas, necrosis, and many giant cells are seen.

Management

Treatment

• Immunosuppression in different combinations is the primary method of treatment. 
• For mild disease (i.e., no glomerulonephritis or possibly life-threatening issues) → corticosteroids PLUS methotrexate
• For moderate to severe disease (i.e., with glomerulonephritis, pulmonary hemorrhage, hemoptysis, etc.) → corticosteroids PLUS one of the following immunosuppressants:
  • Cyclophosphamide: Due to its toxicity, cyclophosphamide is used only until remission of the disease (approximately 3–6 months).
    • After remission, it is replaced with another immunosuppressive agent to maintain remission.
  • Rituximab
  • Azathioprine
  • Methotrexate
  • Mycophenolate-mofetil (off-label use)
• Plasmapheresis indicated for: 
  • Severe active renal disease
  • Presence of anti-GBM autoantibodies
  • Pulmonary hemorrhage

Complications

• Hearing loss
• Renal Failure
• Risk of deep venous thrombosis

Prognosis

• If left untreated, mortality rate within 2 years is 90%.
• With optimal treatment:
  • Mortality in the first year is about 10% (due to infections following immunosuppression).
  • 5-year survival in those treated is 80%.

Differential Diagnosis

• Goodpasture syndrome (GPS): a subtype of rapidly progressive glomerulonephritis (RPGN) in which auto-antibodies are formed against the renal glomeruli and pulmonary capillaries. Symptoms may include hemoptysis and signs of nephritic syndrome (hematuria, oliguria, edema, flank pain). Labs show anti-glomerular basement membrane (GBM) antibodies. Immunosuppressive treatment with corticosteroids and cyclophosphamide is necessary to slow the progression.
• Polyarteritis nodosa: a systemic vasculitis of the small and medium vessels. The condition most commonly involves the skin, peripheral nerves, muscles, joints, gastrointestinal tract, and kidneys. It is often associated with hepatitis B or C (HPV or HPC) infection. Patients often present with nonspecific symptoms (fever, arthralgias), hypertension, increased risk of myocardial infarction, and polyneuropathy. Polyarteritis nodosa usually spares the lungs and serologies will be ANCA negative. Angiography shows the classic beading appearance of alternating aneurysms and stenosis of small and medium vessels. Treatment involves immunosuppressive regimens and possible antiviral therapy against HBV and HCV.
• Microscopic polyangiitis: a necrotizing vasculitis of small vessels (typically of the kidneys, skin, and lungs). Patients usually present with palpable purpura, pulmonary vasculitis with hemoptysis, and pauci-immune glomerulonephritis with hypertension. This pathology will show positive p-ANCA antibodies (unlike in GPA). Treatment involves an immunosuppressive regimen.
• Churg-Strauss syndrome: also known as eosinophilic granulomatosis with polyangiitis. Churg-Strauss is a multisystem disease characterized by necrotizing granulomatous vasculitis with eosinophilia which most commonly involves the lung and the skin. Patients present with severe allergic asthma attacks, allergic rhinitis, sinusitis, polyneuropathy (foot or wrist drop), and skin nodules. They will have peripheral blood eosinophilia and positive p-ANCA antibodies (unlike in GPA). Treatment involves immunosuppressive regimen.
• Giant cell arteritis: also known as temporal arteritis. Giant cell is a vasculitis that causes inflammation of medium and large-sized arteries, particularly the carotid arteries and the aorta. Patients usually present with constitutional symptoms, new-onset headache, tender and hardened temporal artery, jaw claudication, and amaurosis fugax. Laboratory studies show elevated ESR and CRP. Biopsy is needed for diagnosis, which shows mononuclear infiltration of vessel walls and formation of giant cells. Treatment involves prompt administration of glucocorticoids.
• Henoch-Schonlein purpura: an autoimmune small vessel vasculitis. The condition typically presents as a triad of abdominal pain, hematuria, and purpuric rash. Pathophysiology involves deposition of immunoglobulin A immune complexes in multiple vessels following a trigger (infection/environmental), with symptoms depending on the tissues supplied by these vessels. Henoch-Schonlein has a clinical diagnosis and is managed symptomatically. 
• Rheumatoid arthritis: an inflammatory polyarthritis that presents with pain in joints that are warm and “boggy” to touch. This pain is typically worse in the mornings and improves during the day. Joint involvement is symmetrical, with the inclusion of the proximal interphalangeal and metacarpophalangeal joints but sparing of the distal interphalangeal joints. Nonsteroidal anti-inflammatory drugs are the mainstay of pain treatment; disease-modifying treatment options include methotrexate, sulfasalazine, hydroxychloroquine, and TNFɑ-inhibitors.
• Systemic lupus erythematosus: a chronic inflammatory condition characterized by the clinical involvement of the skin, joints, kidneys, blood cells, and central nervous system. The condition is believed to be an autoimmune disorder and has been associated with the formation of autoantibodies such as antinuclear antibody, anti-Smith, and anti-dsDNA. The main clinical features of lupus include malar rash, joint pain, fever, proteinuria, hypertension, anemia, lymphopenia, seizures, and/or psychosis.