Granulomatosis with Polyangiitis

Granulomatosis with polyangiitis (GPA) is a rare autoimmune disease of unknown etiology. It leads to a necrotizing
granulomatous inflammation of small and medium-sized blood vessels of the nose, sinuses, throat, lungs, and kidneys.
Early stages of GPA often present with localized manifestations such as infections of the upper respiratory tract, skin
lesions, and/or constitutional symptoms. Later stages can present with renal failure and severe respiratory disease.
Early diagnosis and treatment of granulomatosis with polyangiitis (which involves the administration of corticosteroids
and immunosuppressive agents such as methotrexate) may lead to a full remission but without treatment, the
condition has a high mortality rate.

Last updated: August 29, 2022

CONTENTS

Epidemiology and Etiology

Pathophysiology
Clinical Presentation
Diagnosis
Management
Differential Diagnosis

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.

Uniform granular cytoplasmic staining of c-ANCA

Image by Malittle, PD.

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.

Classification criteria

1. Nasal or oral inflammation Painful or painless oral ulcers or purulent or bloody nasal discharge

2. Abnormal chest Pulmonary nodules, fixed pulmonary infiltrates, or pulmonary cavities

radiograph

3. Abnormal urinary Microscopic haematuria with or without red cell casts

sediment (glomerulonephritis)

4. Granulomatous The biopsy of an artery or perivascular area shows granulomatous

inflammation inflammation.

The presence of 2 or more of these 4 criteria yields a sensitivity of 88% and a specificity of 92%.

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.