Wegener Granulomatosis

10 Interesting Facts of Wegener Granulomatosis

1. Granulomatosis with polyangiitis, formerly known as Wegener granulomatosis, is characterized by necrotizing granulomatous inflammation with necrotizing vasculitis affecting predominantly small to medium vessels in adults older than 55 years
2. Primarily involves the upper and/or lower respiratory tract and kidneys; may also affect skin, eyes, central nervous system, joints, and (rarely) heart or gastrointestinal tract
3. Signs and symptoms vary with organ system(s) affected; examples are as follows:
   • Upper airway manifestations include nasal congestion and crusting, sinusitis, epistaxis, and serous otitis; cartilage damage can result in saddle nose deformity
   • Lung involvement can range from asymptomatic nodules to life-threatening diffuse alveolar hemorrhage
   • Kidney involvement may range from active urinary sediment with normal kidney function to rapidly progressive glomerulonephritis
4. Diagnosis requires a high index of suspicion for vasculitis and test for ANCA directed against PR3 antigen (although the latter is absent in a minority of cases); a tissue diagnosis showing the hallmark features of the disease is confirmatory
5. Chest radiograph abnormalities, especially the presence of cavitating nodules, are common even in asymptomatic patients; chest CT is usually necessary to further evaluate chest radiograph findings, especially in the setting of possible diffuse alveolar hemorrhage
6. Organ- or life-threatening disease is treated with a combination of high-dose glucocorticoids and either cyclophosphamide, rituximab, or both, for 3 to 6 months until remission is induced, followed by at least 24 months of maintenance therapy
7. More limited disease (eg, disease limited to the upper respiratory tract) is usually treated with a regimen of glucocorticoids and either methotrexate or mycophenolate mofetil
8. After remission is attained, maintenance therapy with low-dose glucocorticoids and an immunosuppressive agent is recommended for at least 24 months
9. Complications may result from the disease process (eg, renal dysfunction, pulmonary hemorrhage) or may result from long-term use of glucocorticoids and immunosuppressive drugs (eg, infection, cardiovascular disease, malignancy)
10. Disease is chronic, follows a relapsing-remitting course, and can be fatal if untreated

Pitfalls

• Delay in diagnosis can occur because of the wide variety and nonspecific nature of disease manifestations
• Disease may be rapidly progressive, and permanent organ damage and scarring can occur with delays in treatment

• Granulomatosis with polyangiitis, formerly known as Wegener granulomatosis, is a relapsing-remitting autoimmune vasculitis predominantly affecting small to medium vessels; it is an ANCA (antineutrophil cytoplasmic autoantibodies)–associated vasculitis 
• Respiratory tract is commonly affected (in both upper and lower zones); kidney involvement is also common, ranging from active urinary sediment with normal kidney function to rapidly progressive glomerulonephritis 
• Multisystem process may also affect skin, eyes, central nervous system, joints, and (rarely) heart or gastrointestinal tract

Classification

• Vasculitides can be categorized by size of predominantly affected vessels: large, medium, or small 
• Granulomatosis with polyangiitis is an ANCA-associated vasculitis; a form of small vessel vasculitis
  • Other ANCA-associated vasculitides include microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome) 
  • All are associated with ANCA, predominantly affect small-sized arteries, and have similar features on renal histology
  • All are characterized by necrotizing vasculitis without significant immune complex deposition
• Other small vessel vasculitides
  • Immune-complex small vessel vasculitides: characterized by significant vessel wall deposits of immunoglobulin and complement components
    • Include anti–glomerular basement membrane disease, cryoglobulinemic vasculitis, IgA vasculitis (Henoch-Schönlein purpura), and hypocomplementemic urticarial vasculitis
  • Variable vessel vasculitides: vasculitis affects any sized artery or vein
    • Include Behçet syndrome and Cogan syndrome
  • Single-organ vasculitis
  • Vasculitis associated with systemic disease or specific etiology
    • May occur in patients with systemic lupus erythematosus, rheumatoid arthritis, relapsing polychondritis, and other systemic rheumatic diseases
• Phenotypes of granulomatosis with polyangiitis
  • 2 phenotypes have been described but are without consensus definition; they probably have distinct pathophysiologic processes, and transition between the 2 forms during the disease course is possible 
    • Localized (limited): manifests primarily as upper respiratory tract involvement
    • Systemic (diffuse/severe): usually manifests as rapidly progressive renal and/or pulmonary disease (often with alveolar hemorrhage)
      • Many patients with systemic disease also have upper respiratory tract symptoms

Clinical Presentation

History

• Range of clinical presentations is wide
  • Because of the variety and nonspecific nature of disease manifestations, delay in diagnosis can result
• Commonly is a pulmonary or pulmonary plus renal disease that is rapidly progressive (referred to as systemic disease)
  • A subset of patients have disease restricted to the upper respiratory tract and/or eye (referred to as limited disease); however, many patients with systemic disease also have upper respiratory tract symptoms
• Has a relapsing and remitting course, which can be modified by maintenance immunosuppressive therapies
• Symptoms
  • Malaise, fever, arthralgias, and weight loss may precede more specific symptoms by weeks to months
  • Other symptoms reflect necrotizing granuloma formation (primarily of upper and lower respiratory tracts, sometimes with contiguous spread) and necrotizing vasculitis of small vessels (commonly in glomeruli, but potentially in any tissue)
    • Upper respiratory tract (70%-100% of cases; naso-sinus involvement is the most common manifestation of the disease) 
      • Nasal congestion, discharge, and crusting
      • Sensation of obstructed nasal airway
      • Epistaxis
      • Development of deformity of nasal bridge (after long-standing disease)
      • Sinus pain
      • Sinus infection that does not clear after antibiotic therapy
      • Sore throat
      • Hoarseness
      • Decreased hearing due to serous otitis
    • Lower respiratory tract (50%-90% of patients)
      • May be asymptomatic even in the presence of abnormalities on chest radiograph
      • If symptoms are present, they vary by degree of lung involvement
        • Most severe presentation of pulmonary disease is diffuse alveolar hemorrhage, which typically presents subacutely (over days) and may lead to respiratory failure 
          • Cough
          • Hemoptysis
          • Dyspnea
        • Other pulmonary symptoms (independent of alveolar hemorrhage)
          • Chronic cough
          • Dyspnea due to parenchymal disease or presence of pleural effusion
          • Respiratory distress with stridor due to subglottic tracheal stenosis, bronchial stenosis, or bronchial pseudotumor formation
          • Hemoptysis from airway ulceration
          • Pleuritic chest pain if pleura is involved
          • Chest pain if pneumothorax occurs (rare)
    • Kidneys (40%-100% of cases)
      • May have indolent, asymptomatic onset
      • First symptom is usually fatigue; disease may come to attention because of active urine sediment on urinalysis or evidence of renal insufficiency on laboratory test results
      • In about 20% of cases, initial presentation is as rapidly progressive glomerulonephritis 
      • Rarely, macroscopic hematuria and edema are noted by the patient
    • Other organs outside respiratory tract and kidneys may be involved and symptomatic
      • Appearance of various vasculitic skin lesions, which may be painful
      • Eye pain and/or redness, foreign body sensation, blurred vision, and dry eyes (manifestations of conjunctivitis, scleritis, lacrimal gland destruction, or duct obstruction)
      • Loss of vision, reflecting optic nerve vasculitis or retinal artery thrombosis
      • Various neurologic symptoms, reflecting hypertrophic meningitis and cerebral vasculitis (eg, chronic headache, cranial neuropathies, cerebellar ataxia, seizures, myelopathy, stroke) or mononeuritis multiplex (ie, stepwise involvement of 2 or more named nerves, with motor and sensory deficits)
      • Rarely, anterior and/or posterior pituitary dysfunction, resulting in headache, weakness, fatigue, secondary hypogonadism, and sometimes diabetes insipidus 
      • Cardiac involvement is rare, but it can manifest with symptoms of pericarditis, myocarditis, or conduction disorders 
      • Gastrointestinal involvement is rare, but it can manifest with pain from ulcerative lesions or intestinal perforation 
• Drug history is important, because drug exposures may induce ANCA-associated vasculitis 
  • Propylthiouracil
  • Minocycline
  • Penicillamine
  • Hydralazine
  • Levamisole-adulterated cocaine

Physical examination

• Fever may be present at onset of disease, before appearance of more specific symptoms, and it may also occur during an episode of diffuse alveolar hemorrhage
• Most patients have some involvement of oral cavity, nose, and sinuses
  • Nasal discharge appears purulent or bloody
  • Bleeding or crusting of nares
  • Collapse of bridge of nose (saddle nose deformity) due to nasal septal erosion
  • Oral ulcers (which may be painless)
  • Gingival hypertrophy and ulceration
• Pulmonary findings are nonspecific
  • Examination findings may be normal, even when there are abnormal findings on chest radiograph
  • With diffuse alveolar hemorrhage: 
    • Patient appears to be in distress
    • Decreased breath sounds
    • Inspiratory crackles
    • Hemoptysis in about two-thirds of patients; it may be massive
    • May be hypoxic with fulminant respiratory failure
• Other examination findings depend on which organs (and which tissues therein) are involved
  • Eyes (any part of eye, orbit, or adnexal structures may be involved)
    • Conjunctival hyperemia due to conjunctivitis 
    • Dilated scleral blood vessels suggesting episcleritis or scleritis 
    • Peripheral ulcerative keratitis, usually found within 2 mm of corneoscleral limbus 
    • Signs of orbital disease (often from contiguous sinus disease), including proptosis due to retro-orbital mass (pseudotumor) and overflow of tears from obstruction of lacrimal duct (epiphora) 
  • Ears
    • Middle ear effusion
    • Conductive hearing loss due to middle ear disease
  • Skin
    • Skin lesions are present in about half of patients
      • Palpable purpura
      • Petechiae 
      • Subcutaneous nodules, commonly over extensor surfaces of joints, especially the elbow
      • Necrotic papules and plaques
      • Ulcers
      • Vesicles
  • Neurologic findings
    • Cranial and peripheral neuropathies

Causes

• Exact cause remains unknown; may originate from infectious, environmental, chemical, toxic, or pharmacologic triggers in people with genetic predisposition for the disease 
• An autoimmune process; may be combined effect of the following:
  • B-cell–produced ANCA directed against enzyme PR3 (proteinase 3) on cell surfaces of cytokine-primed neutrophils and monocytes
  • Imbalances in T-cell subsets with decreased T-regulatory cells and loss of immune tolerance
  • Complement (may play a role)

Risk factors and/or associations

Age

• May occur at any age from childhood through elderly adulthood 
• Peak incidence is between ages 55 and 70 years 

Sex

• Occurs equally in males and females 

Genetics

• Some genetic associations have been identified
  • Association with clinically frank granulomatosis with polyangiitis
    • HLA-DPB1*04:01 allele (odds ratio of 3.91 compared with unaffected controls) (OMIM %608710)
  • Association with presence of PR3-ANCA
    • Certain alleles of HLA-DP
    • Certain alleles of SERPINA1, the gene encoding alpha₁-antitrypsin, which is the endogenous inhibitor of PR3 

Ethnicity/race

• Prevalence is higher in White populations (especially those of Northern European descent) than in Asian, African, African Caribbean, and African American populations 

Other risk factors/associations

• Exposure to certain drugs can induce symptoms of vasculitis and/or seropositivity for ANCA 
  • Levamisole-contaminated cocaine
  • Propylthiouracil
  • Minocycline
  • Penicillamine
  • Hydralazine
• Infection has been implicated as an initiator of vasculitis in general
  • Nasal carriage of Staphylococcus aureus has been associated with relapses of granulomatosis with polyangiitis 
  • Antibodies to a specific membrane protein on Escherichia coli have been noted in some patients with ANCA-associated vasculitides
• Silica exposure, which can result in granuloma formation, is associated with increased risk of ANCA-associated vasculitides

Diagnostic Procedures

Primary diagnostic tools

• Diagnosis is based on combination of history and physical examination findings suggestive of systemic vasculitis, positive results on ANCA serology, and histologic evidence of necrotizing vasculitis, necrotizing glomerulonephritis, or granulomatous inflammation from biopsy of affected organ (eg, lung, kidney, skin) 
• Persistent symptoms/signs of upper and/or lower respiratory tract disease and/or glomerulonephritis with or without persistent constitutional symptoms that are not clearly due to another identifiable disease process suggest possibility of vasculitis, including an ANCA-associated vasculitis
• To narrow the diagnostic possibilities when vasculitis is considered, obtain laboratory tests to confirm an inflammatory state, document the presence of an active urine sediment, assess renal function, and identify relevant autoantibodies
  • Routine baseline laboratory tests (ie, CBC, comprehensive metabolic panel), markers of inflammation (eg, erythrocyte sedimentation rate, C-reactive protein level), and urinalysis 
  • Serologic tests to confirm an ANCA-associated vasculitis and narrow the differential of other likely vasculitides
    • ANCA: if present, this narrows the diagnostic considerations considerably, especially with confirmatory assay identifying antibodies specific to either PR3 or MPO (myeloperoxidase)
    • Anti–glomerular basement membrane antibodies: typically obtained in initial diagnostic workup when renal disease is present 
    • Antinuclear antibodies
• Obtain imaging and other diagnostic studies as directed by clinical presentation
  • Chest radiograph as baseline assessment for pulmonary disease
  • Chest CT to further characterize abnormalities on chest radiograph
  • Sinus and/or orbital CT if the patient has symptoms in those regions
  • Bronchoalveolar lavage may be useful to confirm diffuse alveolar hemorrhage or to differentiate potential infectious causes
• Perform biopsy of affected tissue to confirm diagnosis
  • Kidney is usually best site from which to obtain tissue (ie, as long as it is clinically affected, which is usually true); diagnostic yield is up to 91.5% 
  • With pulmonary involvement, open lung biopsy has higher diagnostic yield compared with transbronchial biopsy; video-assisted thoracoscopic biopsy also provides good yield
  • Biopsy of nasopharyngeal lesions is less often diagnostic (may show only nonspecific inflammation) 
  • Skin biopsy may be suitable for diagnosis in some patients 

Laboratory

• CBC
  • Typical findings include:
    • Normocytic-normochromic anemia
    • Leukocytosis
    • Thrombocytosis
• Nonspecific inflammatory markers
  • Erythrocyte sedimentation rate and C-reactive protein level are typically elevated
• Comprehensive metabolic panel
  • Creatinine level rises rapidly during episode of glomerulonephritis, with rapidly declining GFR over days or weeks 
    • Initial GFR is major prognostic factor in determining both functional renal prognosis and life-threatening potential of disease 
  • Other biochemical indices may be normal, even with renal disease
• Urine tests
  • Urinalysis
    • Sensitive marker of renal involvement
    • Active urinary sediment with dysmorphic RBCs and RBC casts and/or WBC casts indicates glomerular disease 
    • Dipstick result is usually positive for protein
  • 24-hour urine specimen can be collected to quantify degree of proteinuria
    • Proteinuria is usually in moderate, non-nephrotic range (1-3 g/day) 
• ANCA serology
  • Done as 2-step testing in most laboratories, although 2017 consensus statement found that dual testing is not necessary for maximal diagnostic accuracy
    • Screening laboratory test (first step) is an indirect immunofluorescence test 
      • Fluorescence identified on microscopy is categorized by staining pattern, either C-ANCA (staining diffusely throughout cytoplasm) or P-ANCA (staining only in perinuclear area)
      • Test is positive when either pattern is detected
    • Second step is an antigen-specific immunoassay performed on samples that are positive by indirect immunofluorescence
      • There are 2 antigenic subsets of ANCA:
        • PR3-ANCA (ANCA directed against PR3)
          • In systemic disease, most patients have positive PR3-ANCA serology 
          • In localized disease, up to 40% may be negative for PR3-ANCA 
          • PR3-ANCA typically has a C-ANCA staining pattern (ie, diffuse) on screening indirect immunofluorescence assay 
        • MPO-ANCA (ANCA directed against MPO)
          • A minority of patients with clinical and pathologic characteristics of the disease may have MPO-ANCA in the absence of PR3-ANCA 
          • MPO-ANCA result is positive in most patients with microscopic polyangiitis form of small vessel vasculitis
          • MPO-ANCA typically has a P-ANCA staining pattern (ie, perinuclear) on screening indirect immunofluorescence assay 
      • 2017 consensus statement proposed that immunoassay alone, without preliminary immunofluorescence screening test, has good diagnostic performance
        • Diagnostic performance data
          • Based on multicenter study of the value of ANCA detection methods (using relevant control groups, such as patients in whom clinicians considered the possibility of an ANCA-associated vasculitis but eventually excluded it, as well as patients with systemic rheumatic diseases)
          • Sensitivity 
            • With C-ANCA by immunofluorescence: 65% to 77%
            • With PR3-ANCA by immunoassay: 77% to 81%
          • Specificity
            • With C-ANCA by immunofluorescence: 97% to 98%
            • With PR3-ANCA by immunoassay: 98% to 99%
      • Caveats
        • Positive ANCA serologic result is not mandatory in diagnosis of granulomatosis with polyangiitis, provided that clinical and histologic findings support the diagnosis and steps have been taken to exclude other systemic vasculitides or vasculitis mimics 
        • Use caution in interpretation of positive results in patients lacking clinical manifestations of ANCA-associated vasculitis or without histologic evidence of systemic vasculitis 
          • Positive results may also occur with infections (especially subacute bacterial endocarditis) and inflammatory bowel disease 
• To assist in rapid differential diagnosis, the following additional serologic tests should be obtained in all patients with pulmonary hemorrhage or a pulmonary-renal syndrome (to rule out anti–glomerular basement membrane disease and as a rapid screen for lupus vasculitis):
  • Anti–glomerular basement membrane antibodies test
    • Autoantibodies directed against noncollagen domain of α₃ chain of type IV collagen; highly specific and sensitive for anti–glomerular basement membrane disease (ie, Goodpasture syndrome) 
    • Rapid screening assays are available that test for these antibodies plus PR3-ANCA and MPO-ANCA in the same assay
  • Antinuclear antibodies test
    • Positive result, especially in combination with other clinical symptoms/signs of lupus, should lead to additional evaluation for systemic lupus

Imaging

• Chest radiograph 
  • Pulmonary nodules, often cavitary, are the most common finding
  • Other radiographic features include:
    • Pleural involvement with effusions
    • Rarely, pneumothorax
  • Diffuse alveolar hemorrhage appears as patchy, bilateral pulmonary infiltrates, but it requires further evaluation to be confirmed as the cause (eg, chest CT, bronchoalveolar lavage)
    • Chest radiograph findings may be normal in some cases of diffuse alveolar hemorrhage
• Chest CT
  • Important to evaluate suspected diffuse alveolar hemorrhage
    • Ground-glass opacities are common in diffuse alveolar hemorrhage; they may be diffuse or limited to dependent portions of lung
    • Imaging may not immediately reflect clinical improvement after alveolar bleeding stops
    • Septal thickening (crazy paving pattern) can occur after resolution of diffuse alveolar hemorrhage
    • Recurrent diffuse alveolar hemorrhage can result in development of pulmonary fibrosis

Procedures

• Kidney is usually best site from which to obtain tissue (ie, as long as it is clinically affected, which is usually true)
• With pulmonary involvement, open lung biopsy has higher diagnostic yield compared with transbronchial biopsy; video-assisted thoracoscopic biopsy also provides good yield
• Nasopharyngeal or transbronchial biopsy is more likely to show only nonspecific inflammatory changes
• In some patients, a skin lesion may be the most appropriate site for biopsy
• All suspected cases of granulomatosis with polyangiitis
• Pathologic hallmarks of granulomatosis with polyangiitis
  • Granulomatous inflammation in upper or lower respiratory tract
  • Necrotizing vasculitis affecting small vessels
  • Segmental glomerulonephritis associated with necrosis and thrombosis of capillary loops, with or without granulomatous lesions, and pauci-immune crescent formation (necrotizing and crescentic glomerulonephritis) 

Differential Diagnosis

Most common

• Other vasculitides presenting as a pulmonary, renal, or pulmonary-renal syndrome
  • Other ANCA-associated small vessel vasculitides
    • Microscopic polyangiitis
      • Characterized by glomerulonephritis; pulmonary vasculitis also occurs in most cases, and diffuse alveolar hemorrhage may occur 
      • Although nasal and upper airway symptoms can occur in microscopic polyangiitis, they are much less frequent, and granulomatous tissue destruction is not seen
      • If pulmonary disease is present, patients with microscopic polyangiitis are more likely to develop interstitial disease and pulmonary fibrosis without cavitating nodules, whereas patients with granulomatosis with polyangiitis are more likely to have pulmonary nodules and cavitations
      • MPO-ANCA is present in most cases of microscopic polyangiitis (70%) 
      • Definitive pathologic difference between granulomatosis with polyangiitis and microscopic polyangiitis is the presence of primary small vessel vasculitis without granulomatous inflammation in the latter disease 
      • Differentiated by presence of MPO-ANCA and biopsy findings
    • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
      • Characterized by asthma, allergic rhinitis, pulmonary infiltrates, and peripheral eosinophilia
      • Pulmonary symptoms and signs typically precede vasculitic symptoms involving skin and peripheral nervous system (mononeuritis multiplex) by years; diffuse alveolar hemorrhage may occur
      • About 25% of patients develop renal disease
      • Only about half of patients with this eosinophilic disease have ANCA; most of those have MPO-ANCA, which appears during vasculitis phase of disease 
      • Differentiated by antigen-specific ANCA testing and biopsy, which show eosinophilic granulomatous inflammation 
  • Immune complex vasculitides
    • Primary disease
      • Anti–glomerular basement membrane disease (Goodpasture syndrome)
        • Classically presents with rapidly progressive renal dysfunction, active urine sediment, and moderate proteinuria, although a small percentage may have normal kidney function initially 
        • Pulmonary hemorrhage is present in about half of patients 
        • Anti–glomerular basement membrane antibodies are present in serum
        • Up to 38% of patients also test positive for ANCA, which is usually MPO-ANCA 
        • Disease generally resolves within 6 to 9 months without relapses and autoantibodies disappear. If also positive for MPO-ANCA, disease is more likely to relapse
        • Differentiated by presence of serum anti–glomerular basement membrane antibodies, by absence of serum PR3-ANCA, and by biopsy showing vasculitis of glomerular capillaries or pulmonary capillaries with basement membrane deposition of anti–glomerular basement membrane antibodies
      • IgA vasculitis (Henoch-Schönlein purpura)
        • Systemic vasculitis most common in children younger than 10 years, although it can occur in any age group; it often follows an upper respiratory tract infection
        • Presents as rash, usually affecting buttocks and legs, with most patients also having arthralgias 
          • About half of patients develop glomerulonephritis, with a substantial minority also having abdominal pain and bloody diarrhea; pulmonary involvement is uncommon
        • There are no specific serologic tests
        • Differentiated by clinical factors (onset after infection, pattern of rash on lower body, presence of abdominal pain) and negative ANCA testing
        • Confirm the diagnosis with biopsy showing immune complex deposits in small dermal vessels that stain by direct immunofluorescence microscopy using antibodies specific for IgA 
    • Secondary disease
      • Cryoglobulinemia
        • Systemic vasculitis associated with deposition of circulating serum cryoglobulins that incite small vessel damage by complement activation. Commonly caused by hepatitis C, other chronic infection, or autoimmune disease (eg, systemic lupus erythematosus)
          • Cryoglobulins are immunoglobulins that reversibly precipitate in cold temperatures; they are designated as types I to IV according to whether monoclonality and rheumatoid factor activity are present. Types II and III result in vasculitis
        • Clinical manifestations include constitutional symptoms (eg, fever, fatigue, arthralgia, myalgia), palpable purpura, and peripheral neuropathy; glomerulonephritis is common
        • Laboratory test results are positive for serum cryoglobulins; complement assays find low C4 and C3 levels, with C4 level typically more depressed than C3 level
        • Differentiated by the presence of a causative comorbidity (most commonly hepatitis C), negative ANCA serologic results, positive antinuclear antibodies serologic results (sensitive for lupus although not specific), and positive results for cryoglobulins and low complement activity; confirm diagnosis with biopsy showing membranoproliferative glomerulonephritis with immune complex deposition (kidney) or leukocytoclastic vasculitis (skin)

Treatment Goals

• Control disease process and induce remission before tissue scarring occurs
• Prevent or minimize treatment-related toxicity

Disposition

Admission criteria

Organ-threatening disease requires admission for management, including initiation of immunosuppressive therapies

Criteria for ICU admission

• Pulmonary hemorrhage (absolute indication)
• Acute renal failure (relative indication)

Recommendations for specialist referral

• Granulomatosis with polyangiitis should be managed by an experienced specialist at a center with expertise in ANCA-associated vasculitides, given the rarity of the diagnosis 
  • Depending on the organ system(s) involved, consultation with specialists from a variety of disciplines may be indicated, including rheumatologists, pulmonologists, nephrologists, ophthalmologists, otolaryngologists, allergist/immunologists, dermatologists, and others

Treatment Options

Granulomatosis with polyangiitis requires glucocorticoids plus an additional immunosuppressive agent for induction of remission; treatment should be started rapidly

• For acute organ-threatening or life-threatening disease
  • Begin induction therapy with high-dose corticosteroids plus either cyclophosphamide or rituximab 
    • IV pulsing of cyclophosphamide is as effective as daily oral dosing but produces less severe leukopenia and presents lower risk of bladder complications 
    • Rituximab is noninferior to cyclophosphamide for induction of remission (and may be superior in relapsing disease) 
    • Some experts use high-dose corticosteroids in combination with both rituximab and cyclophosphamide; however, this approach is controversial 
    • Induction therapy is usually continued for 3 to 6 months 
    • Glucocorticoids should be gradually tapered after a few weeks, with a target dosage of 7.5 to 10 mg/day (prednisolone equivalent) reached after 3 months 
  • Consider plasma exchange if there is rapidly progressive renal failure (ie, creatinine level more than 5.7 mg/dL) or pulmonary hemorrhage; no longer routinely recommended for most patients with severe disease 
• For non–organ-threatening disease
  • Examples of non–organ-threatening disease include the following in the absence of renal involvement: 
    • Nasal and paranasal disease (without bone or cartilage involvement and without hearing or olfactory disturbance)
    • Noncavitating pulmonary nodules or infiltrates without hemoptysis
    • Nonulcerative skin lesions
  • Begin induction therapy with glucocorticoids plus either methotrexate or mycophenolate mofetil 
    • Higher-grade evidence exists for use of methotrexate than for use of mycophenolate mofetil 
  • Do not use methotrexate or mycophenolate mofetil for pulmonary hemorrhage, neurologic involvement (eg, meningeal symptoms, acute mononeuritis multiplex), retro-orbital disease, cardiac disease, or mesenteric disease 

Refractory disease is addressed with reevaluation of primary diagnosis, optimization of drug dosing, evaluation of role of infection or other comorbidity, and switching to rituximab if currently on cyclophosphamide 

• Adjunctive IV immunoglobulin can be considered for continued low-level PR3-ANCA activity 

If remission is attained, transition to maintenance therapy with a combination of low-dose glucocorticoids (eg, prednisolone 5-10 mg/day) and 1 of the following: azathioprine, rituximab, methotrexate, or mycophenolate mofetil (methotrexate should not be used in a patient with renal dysfunction) 

• Role of ANCA testing to predict relapse is controversial; guidelines by the European League Against Rheumatism recommend regular repeated testing but also recommend that changes in treatment should not be based on the result 
• Treatment duration should be individually determined (recommended for at least 24 months after induction of sustained remission) 
• In controlled trials evaluating relapse rate:
  • Low-dose rituximab superior to tapering dose of azathioprine at 28 months 
  • Tapering dose of azathioprine superior to tapering dose of mycophenolate mofetil at 39 months 
• Leflunomide is a second line drug to maintain remission in cases of intolerance to first line drugs 
• Trimethoprim-sulfamethoxazole is recommended for prophylaxis against Pneumocystis jirovecii infection in patients with granulomatosis with polyangiitis who are receiving immunosuppressive therapies
  • Granulomatosis with polyangiitis is considered a high-risk condition for pneumocystis pneumonia (more than 45 cases per 100,000 patient-years) 
  • Guidelines by the European League Against Rheumatism strongly recommend trimethoprim-sulfamethoxazole prophylaxis for patients on cyclophosphamide; manufacturer’s package insert also recommends such prophylaxis for patients taking rituximab
    • Though not specifically recommended, has been shown to reduce severe infections, particularly respiratory infections, in patients treated with rituximab 
  • American Thoracic Society states that prophylaxis should also be considered when prednisone dose exceeds 20 mg/day for longer than 1 month, especially if the patient is receiving additional cytotoxic drugs
  • Use of trimethoprim-sulfamethoxazole as an adjunct to immunosuppressive therapy has been considered in some patients with upper airway involvement (distinct from its role in infection prophylaxis) based on reduced incidence of relapse based on 1 small randomized controlled trial 
    • Trimethoprim-sulfamethoxazole treatment was not associated with a reduced risk of relapse of granulomatosis with polyangiitis in a meta-analysis of 7 studies (2 of which were RCTs) 
• Investigational therapies showing promising results include belimumab, abatacept, and complement component C5a inhibitor (avacopan) 

Relapses are treated with an increase in steroid dose (if relapse is minor) or with steroids plus either rituximab or cyclophosphamide (if relapse is major) 

Drug therapy

• Induction therapy
  • Immunosuppressive agents for remission induction, in combination with a glucocorticoid
    • Cyclophosphamide (for acute organ- or life-threatening disease)
      • Cyclophosphamide Solution for injection; Adults: 0.5 to 1 g/m2 IV monthly in addition to corticosteroids, especially if there is major organ system involvement.
      • For patients receiving pulse IV dosing, give oral or IV mesna (2-mercaptoethanesulfonate sodium) to decrease toxicity
    • Rituximab (for acute organ- or life-threatening disease)
      • Rituximab (Murine) Solution for injection; Adults: 375 mg/m2 IV infusion once weekly for 4 weeksas induction therapy. Administer methylprednisolone 1,000 mg/day IV for 1 to 3 days, then give prednisone 1 mg/kg/day PO (max: 80 mg/day PO and tapered per clinical need; begin steroids within 14 days prior to or with initiation of rituximab; steroids may continue during and after the 4-week induction course). Maintenance therapy consists of 500 mg IV infusion every 2 weeks for 2 doses, then give 500 mg IV infusion every 6 months per clinical evaluation. Begin maintenance within 24 weeks of, and no sooner than 16 weeks after, the last rituximab induction infusion. If induction of active disease was achieved with other immunosuppressants, initiate rituximab maintenance within 4 weeks of disease control. Premedicate with acetaminophen, methylprednisolone (100 mg IV), and an antihistamine 30 minutes prior to each infusion.
    • Methotrexate (for less severe disease with normal renal function) 
      • Oral
        • Methotrexate Sodium Oral tablet; Adults: 20 to 25 mg PO once weekly.
      • Parenteral
        • Methotrexate Sodium Solution for injection; Adults: 20 to 25 mg IV/IM given as a single weekly dose.
    • Mycophenolate mofetil (for less severe disease) 
      • Mycophenolate Mofetil Oral capsule; Adults: Doses ranging from 1 to 2 g PO daily have been used.
  • Glucocorticoids
    • Prednisolone Oral solution; Adolescents, Children, and Infants: 0.14 to 2 mg/kg/day PO or 4 to 60 mg/m2/day PO, given in 3 to 4 divided doses. Individualize dose based on the nature and severity of the disease and patient response.
    • Prednisolone Oral tablet; Adults: 5 mg/day to 60 mg/day PO as single or divided doses. Individualize dose based on the nature and severity of the disease and patient response.
• Maintenance therapy
  • If remission is attained, transition to maintenance therapy with a combination of low-dose glucocorticoids (eg, prednisolone 5-10 mg/day) and 1 of the following: azathioprine, rituximab, methotrexate, or mycophenolate mofetil (methotrexate should not be used in a patient with renal dysfunction)
• Prophylaxis against Pneumocystis jirovecii in patients receiving immunosuppressive therapy
  • Trimethoprim-sulfamethoxazole
    • Sulfamethoxazole, Trimethoprim Oral suspension; Infants, Children, and Adolescents 2 months to 17 years: 150 mg/m2/day (trimethoprim component) PO once or twice daily, 2 or 3 times weekly, or once weekly (Max: 320 mg trimethoprim/day).
    • Sulfamethoxazole, Trimethoprim Oral tablet; Adults: 160 mg trimethoprim/800 mg sulfamethoxazole PO once daily or 3 times weekly or 80 mg trimethoprim/400 mg sulfamethoxazole PO once daily.

Nondrug and supportive care

• Immunization
  • In patients with granulomatosis with polyangiitis on immunosuppressive therapies, the following is recommended:
    • Yearly influenza vaccination should be given. Response appears to be adequate in patients with granulomatosis with polyangiitis, without risk of precipitating relapse 
    • Vaccines should be administered before immunosuppression if feasible 
    • Live vaccines should be administered 4 or more weeks before immunosuppression and should be avoided within 2 weeks of start of immunosuppression 
    • Inactivated vaccines should be administered 2 or more weeks before immunosuppression 
• Plasma exchange by apheresis
  • One session removes 1 to 1.5 times the total plasma volume; albumin or fresh frozen plasma is infused as a replacement
  • May be considered useful for selected patients with severe alveolar hemorrhage, persistent deterioration in renal insufficiency, despite conventional treatment or rapidly deteriorating glomerulonephritis and/or alveolar hemorrhage 
    • Some studies have found short-term renal benefits 
    • However, there is a growing evidence that this has no benefit on mortality, complete remission, and adverse effects in patients with renal disease or diffuse alveolar hemorrhage 
  • Requires systemic anticoagulation with unfractionated heparin

Comorbidities

• Increased risk of cardiovascular disease has been noted in patients with granulomatosis with polyangiitis, which may be partly treatment related 
  • Traditional risk factors should be addressed and optimally managed

Special populations

• Pregnant patients
  • Complications include:
    • Preterm delivery (up to 35%), most likely when disease is active during pregnancy 
    • Preeclampsia, premature rupture of membranes, spontaneous abortion, prepartum hemorrhage, and retroplacental hematoma have all been reported 
    • Pregnancy outcomes are generally worse for women who conceived during an active phase of disease or who had initial onset of disease during pregnancy 
  • Management during pregnancy
    • Granulomatosis with polyangiitis tends to remain active throughout pregnancy if conception occurs during an active phase of disease. If conception occurs during a remission, only 40% of women will experience a disease flare 
    • Cyclophosphamide, methotrexate, and mycophenolate are teratogens and should be stopped before conception 
      • Exposure to cyclophosphamide or mycophenolate results in about 25% risk for any birth defect; methotrexate doubles the risk (but risk remains less than 10%) 
      • These drugs also double the risk of pregnancy loss 
      • If conception occurs while the patient is receiving these drugs, discontinue the drugs immediately and switch to nonteratogenic immunosuppressant medication
        • Of the available options, azathioprine has the most safety data 
          • Some transplacental transfer; may cause mild temporary immunosuppression in neonate
    • Rituximab should not be infused in the second half of pregnancy (associated with the absence of B cells in the offspring, persisting for months), but infusion in early pregnancy may be acceptable for a flare of disease at that time 
    • Glucocorticoids
      • Should be used only as necessary to control active inflammation 
      • First-trimester exposure has been reported to increase risk of cleft palate, but newer data suggest no increased risk 
• Men and women who wish to preserve future fertility
  • Cyclophosphamide is associated with reduced male and female fertility
  • Counseling and gamete storage should be offered
  • Rituximab may be preferable to cyclophosphamide in these patients (no studies of rituximab’s effects on fertility, but no concerns have been reported) 
• Children
  • Granulomatosis with polyangiitis is rare in children; it occurs more frequently in females and during adolescence 
  • Data on childhood cases are very limited
  • Presentation is most commonly with ear, nose, and throat disease (82%), constitutional symptoms (73%), renal disease (65%), and lower respiratory tract disease (62%) 
  • Ischemic abdominal pain is reported more frequently in children than in adults (but is rare in both)
  • Relapses are more likely in children 
  • Principal adverse treatment-related effect in children is infection. Infertility, hemorrhagic cystitis, cataracts, glaucoma, Cushing syndrome, and depression have been reported. Growth restriction has been reported but has not been confirmed in all studies 
  • Consensus treatment plans for severe ANCA-associated vasculitis in children have been developed 

Monitoring

• Provide follow-up at 1- to 3-month intervals
  • Obtain history and perform structured physical examination; relapse may be at same site as original presentation or may occur elsewhere
    • Specialist performing examination can use clinical tools to aid it (eg, Birmingham Vasculitis Activity Score or Vasculitis Damage Index)
  • Obtain laboratory tests and compare results with previous values; the following suggest relapse: 
    • Rising erythrocyte sedimentation rate or C-reactive protein level
    • Persistence of ANCA or rising of ANCA titer
      • However, rising ANCA titer is not specific enough to be used as therapeutic management tool 
      • Absence of PR3-ANCA strongly predicts a relapse-free status after remission induction 
    • Microscopic hematuria and/or casts
    • Increasing serum creatinine level
  • Evaluate the patient for treatment-related adverse effects that may require dosage adjustment or drug discontinuation 
    • Obtain CBC to evaluate for progressive leukopenia
    • Obtain liver function tests to evaluate for drug toxicity
    • Obtain serum immunoglobulin levels to evaluate for hypogammaglobulinemia before each course of rituximab and if the patient has recurrent infections
    • Obtain periodic evaluation of blood glucose control while the patient is taking glucocorticoids
    • Rising creatinine level may indicate drug toxicity
    • Persistent unexplained hematuria necessitates further urologic evaluation in a patient with prior exposure to cyclophosphamide (increased risk of bladder cancer)
• Periodically assess cardiovascular risk factor status, because the risk of cardiovascular disease appears to be greater than can be explained through traditional cardiovascular risk factors alone 
• In any patient taking cyclophosphamide, periodically perform urinalysis to evaluate for hematuria, because cyclophosphamide is strongly associated with increased risk of bladder cancer, even years after its discontinuation
• Screen periodically for cervical cancer and skin cancers 

Complications

• Complications of disease process
  • Chronic kidney disease leading to end-stage renal disease
    • End-stage renal disease develops in 14% of patients after 5 years 
    • Kidney transplant should be delayed until patients are in complete extrarenal remission for 12 months 
  • Pulmonary hemorrhage
    • Diffuse alveolar hemorrhage occurs owing to destruction of capillary-alveolar basement membrane, which leads to extravasation of RBCs into alveolar spaces
    • Recurrent diffuse alveolar hemorrhage may result in pulmonary fibrosis
  • Other types of organ damage due to localized necrotizing vasculitis and/or necrotizing granulomatous inflammation include the following, but damage may result to any anatomic area affected by the disease process:
    • Sinonasal structural damage and deformity
    • Hearing loss
    • Vision loss
    • Peripheral neuropathy
• Complications of treatment
  • Due to long-term use of glucocorticoids and immunosuppressive drugs
  • At long-term follow-up, the following diagnoses in patients with granulomatosis with polyangiitis are thought to be at least partially attributable to treatment-related organ damage: 
    • Hypertension
    • Osteoporosis (about 14%)
    • Diabetes (about 10%)
    • Malignancy (about 13%)
      • Increased risk of nonmelanoma skin carcinomas, hematological malignancies, bladder, breast, lung, prostate, and colorectal cancer 
      • Incidence of malignancy increases significantly after 5 years of immunosuppressant therapy, though risk may also be increased with shorter duration of exposure 
    • Cardiovascular event: 14% of patients have such an event within 5 years of diagnosis 
      • Includes cardiovascular-related death, stroke, myocardial infarction, coronary artery bypass graft, percutaneous coronary intervention
    • Infectious complications
      • Hypogammaglobulinemia is associated with rituximab and repeated use of cyclophosphamide, and it may (but does not always) predispose to infections 
      • High risk for Pneumocystis jirovecii infection with immunosuppressive treatments, including glucocorticoid use more than 20 mg/day of prednisone (or equivalent) for more than 1 month (antibiotic prophylaxis is recommended)
      • Lower respiratory tract, urinary tract infections, and bacteremia are the most common 

Prognosis

• Clinical course is marked by frequent relapses; 50% of patients relapse within 5 years after the disease onset 
• Relapsing-remitting course results in accumulation of organ and tissue damage over time 
  • In a 2008 systematic review (published before use of rituximab combination therapy), the following were found:
    • Remission is more likely with more severe initial disease presentation (most likely owing to greater response to immunosuppressive therapies) 
    • Relapse is common in first 24 months, but rate varies widely depending on definitions used and type of maintenance therapy 
  • Localized forms (with upper respiratory presentation and/or granulomatous manifestations) relapse more frequently than systemic forms with renal involvement 
• Fatal if untreated
  • Use of corticosteroids and immunosuppressants and/or immunomodulators has greatly improved prognosis 
  • 5-year survival rate is 74% to 91% 
  • 10-year survival rate is 75% in latest studies 
  • Primary causes of mortality
    • In first year after diagnosis, causes include infection (32%), active vasculitis (18%), and renal failure (18%) 
      • Risk of mortality is increased (to about 10%) in first 6 months after diagnosis, primarily owing to infection as a consequence of treatment (rather than to vasculitis itself) 
    • Long-term causes of mortality are multifactorial; they include infection, organ damage, cardiovascular disease, and malignancy 
      • Factors most strongly influencing long-term mortality are increasing age and renal dysfunction
      • Cardiovascular disease and major infections are significant causes of death 

References

1: Geetha D et al: ANCA-associated vasculitis: core curriculum 2020. Am J Kidney Dis. 75(1):124-37, 2020 Reference