Granulomatosis with polyangiitis (Wegener’s granulomatosis)
I. What every physician needs to know.
Since 2011, Wegener’s granulomatosis is now known as granulomatosis with polyangiitis (GPA) as recommended by the American College of Rheumatology and will be referred to as such in this chapter.
GPA is a disorder that affects multiple organs and is characterized by necrotizing granulomatous inflammation and pauci-immune small-vessel vasculitis.
Multiple factors contribute to the development of clinical disease through tissue injury. These contributors lead to an immune response directed against neutrophil granule proteins causing the production of anti-neutrophil cytoplasmic antibodies (ANCA). Patients may present after an infectious, environmental, chemical, toxic or pharmacological trigger in people who are genetically predisposed to the disease. S. aureus has specifically been identified as a common infectious trigger for GPA.
Several vasculitides are associated with ANCA. These include GPA, microscopic polyangiitis (MPA), Churg-Strauss, and renal-limited vasculitis. However, as discussed below, each has a variable percentage of ANCA positivity, and negative ANCA tests do not rule out the presence of the disease. Clinically, GPA and MPA have significant overlap. Distinguishing the two may be challenging as the variations in ANCA between the two are not absolute.
Early recognition and diagnosis is needed to prevent progression of disease and morbidity.
II. Diagnostic Confirmation: Are you sure your patient has granulomatosis with polyangiitis?
There are no diagnostic criteria for GPA. Diagnosis is based on a constellation of clinical manifestations with supportive lab evidence, specifically ANCA serology and histological evidence of necrotising vasculitis. Prompt diagnosis is important as early initiation of therapy can result in clinical remission and reduced morbidity and mortality.
The American College of Rheumatology Classification Criteria for GPA can be a useful tool, but is limited in that it does not distinguish GPA from MPA. The presence of 2 or more of the following criteria yields a sensitivity of 88% and specificity of 92%.
Nasal or oral inflammation – including painful or painless oral ulcers or purulent or bloody nasal discharge
Abnormal chest radiograph – pulmonary nodules, fixed pulmonary infiltrates, or pulmonary cavities
Abnormal urinary sediment – microscopic hematuria with or without red cell casts
Granulomatous inflammation – biopsy of an artery or perivascular area shows granulomatous inflammation
A. History Part I: Pattern Recognition:
Constitutional symptoms such as fever, malaise, myalgias, arthralgias, anorexia and weight loss may precede the development of end-organ damage.
Four major organ systems are commonly affected (though others can also be):
Patients may present with cough, dyspnea, and hemoptysis. Tracheobronchial disease including subglottic stenosis and inflammatory mass lesions can occur. Diffuse alveolar hemorrhage is a concerning, potentially life-threatening manifestation of GPA.
Glomerulonephritis with hematuria is common in GPA.
Eye, ear, nose, and throat
Nasal-sinus involvement is the most common manifestation of GPA.
Otitis, otalgia, and both sensorineural and conductive hearing loss have all been reported in GPA.
Rhinorrhea, nasal crusting, sinusitis and pain can occur, and nasal inflammation can become severe enough to cause nasal septal destruction or saddle nose.
Eye manifestations include orbital pseudotumors causing diplopia or proptosis, episcleritis, scleritis, uveitis, conjunctivitis, keratitis, retinal vasculitis which can lead to vision loss.
Oral ulcers can also be present in GPA.
Tender cutaneous nodules may form.
Vasculitis with palpable purpura and cutaneous ulceration and gangrene can occur.
B. History Part 2: Prevalence:
GPA is a rare disorder. It is reported much more frequently in Caucasians (>90%) with equal gender distribution. It generally affects older adults with a mean age of 55 in some series and peak incidence between the ages of 65-70.
C. History Part 3: Competing diagnoses that can mimic granulomatosis with polyangiitis.
Distinguishing GPA from other ANCA-associated vasculitides such as MPA and Churg-Strauss is often difficult. It is usually done based on clinical syndrome as ANCAs are not always specific for the disease. Churg-Strauss is more likely to be associated with eosinophilia and asthma. Many times, granulomatosis may not be seen on pathology, making GPA and MPA difficult to distinguish.
Other forms of small and medium vasculitis (polyarteritis nodosa, for example) and pulmonary-renal diseases (antiglomerular basement membrane diseases, connective tissue diseases) can mimic GPA.
Other pulmonary infections (invasive bacterial, fungal, mycobacterial) may have similar radiographic appearance. Evaluation to rule these out prior to initiation of immunosuppressive therapy is recommended.
D. Physical Examination Findings.
A complete physical exam to focus on the findings discussed in history should be performed.
A thorough HEENT exam to include extraocular movements, visual acuity, tympanic exam, nasal and oral exam to look for ulcerations should be conducted.
Pulmonary exam may show evidence of consolidation, stridor, or other airspace disease.
Skin exam to look for purpura and ulcerations should be conducted.
E. What diagnostic tests should be performed?
CBC, renal function panel, liver function tests, urinalysis, urine microscopy, ESR, CRP, Immunologic studies (including ANCA, ANA +/- extractable nuclear antigens [ENA] panel, RF, anti-GBM, cryoglobulins if clinically suspected), blood cultures, sputum culture (expectorated or BAL), hepatitis serologies
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
ANCAs are ordered in the initial evaluation of the patient with suspected GPA. ANCAs can be tested in two ways: immunofluorescence and enzyme immunoassay (ELISA).
Immunofluorescence distinguishes between cytoplasmic staining (c-ANCA) and perinuclear staining (p-ANCA).
ELISA is used to distinguish antibodies against proteinase 3 (PR3) and myeloperioxidase (MPO).
In patients with vasculitis, the c-ANCA generally correlates with PR3-ANCA, and the p-ANCA correlates with MPO-ANCA.
90% of patients with active, widespread GPA are ANCA positive. Patients with more limited disease are less likely to be positive. Thus, a negative ANCA does not rule out the diagnosis of GPA. Of those that are ANCA-positive, about 80 to 90% are PR3-positive while the remaining 10% are MPO-positive.
On the other hand, MPA has ANCA-positivity in about 70% of cases, and it is usually MPO-ANCA positive.
Because there is ANCA-negative GPA, and though GPA is usually PR3-positive but occasionally MPO-positive, ANCA results alone should not be used to make the diagnosis of GPA.
Additional testing that is important in the diagnosis of GPA is a renal function panel and urinalysis with sediment analysis to evaluate for dysmorphic red blood cells or red blood cell casts suggesting glomerulonephritis. ESR and CRP are often elevated but nonspecific. Analysis of other causes of vasculitis can also be considered with ANA, RF, ENA panel, complement levels, HIV, hepatitis panel, anti-GBM and cryoglobulins.
Blood and sputum cultures should be obtained to rule out infections prior to initiation of immunosuppression treatment. Patients should also be evaluated for latent and active TB prior to treatment.
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Because the lungs are often affected in GPA, a chest radiograph should be ordered. A chest CT is needed as well to determine distribution of disease and to find lesions that may not appear on a radiograph. Findings include lung nodules, infiltrates, cavities, consolidation, effusion, laryngeal or tracheobronchial stenosis, bronchiectasis, pleural thickening, lymphadenopathy, patchy or diffuse ground glass opacification.
Sinus CT can also be helpful in symptomatic patients, revealing sinus opacification, mucosal thickening and even bone destruction.
Tissue is needed to confirm the diagnosis. Renal biopsy in patients with renal involvement can be diagnostic with pathology showing pauci-immune segmental necrotizing glomerulonephritis. Skin biopsy can be considered but may be nonspecific. Transbronchial biopsy in patients with lung involvement is also an option but may not yield enough tissue.
III. Default Management.
In cases of presumed GPA, consultation with subspecialists to include rheumatology, nephrology, and pulmonary is helpful in management.
A. Immediate management.
Life-threatening manifestations of GPA include diffuse alveolar hemorrhage and acute kidney injury. Stabilization to avoid respiratory failure and evaluation for urgent dialysis are needed.
Initial therapy and management should be directed by subspecialists. Various immunosuppressive regimens have been used for GPA.
Induction therapy in GPA
Classically, cyclophosphamide has been used for induction therapy either orally (2 mg/kg/day) or in monthly pulse intravenous dosing. Also, in 2011 the FDA approved the use of rituximab for the management of GPA and MPA ANCA associated vasculitis (375 mg/m2) weekly for 4 weeks. Rituximab has been shown in studies to be noninferior to cyclophosphamide with a suggestion of superiority in relapsing GPA.
Steroids are used in conjunction with induction therapy. Methylprednisolone 500-1000 mg intravenously daily for 3 days followed by oral prednisolone 0.5-1 mg/kg/day for at least 4 weeks followed by a taper is recommended. Steroids as monotherapy are insufficient in severe disease, but can be used in mild relapses.
Some experts recommend plasma exchange in conjunction with cyclophosphamide in patients with rapidly progressive renal failure or diffuse alveolar hemorrhage.
Maintenance therapy in GPA
Maintenance therapy is used to reduce the risk of relapse and organ failure in GPA and lasts 18-24 months after remission is achieved. Agents used for maintenance therapy include azathioprine (2 mg/kg/day) and leflunomide (20-30 mg/day). More limited GPA can be treated with other agents such as methotrexate. Rituximab (500 mg every 6 months) is also used for maintenance therapy and has been shown to be more effective than azathioprine in preventing relapse.
B. Physical Examination Tips to Guide Management.
Daily otoscopic and nasal cavity examination to see if there is a change in ulcerations.
Lung exam to evaluate for consolidation.
Skin exam to evaluate for changes in purpura if present.
C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
Creatinine should be followed to evaluate effect of therapy on renal function.
Repeat urinalysis may show change in amount of hematuria and sediment.
Repeat chest radiograph may show change in pulmonary involvement.
Cyclophosphamide can cause significant bone marrow suppression, especially neutropenia, so weekly blood counts should be monitored while on therapy.
Renal function, liver function and urinalysis should be monitored with use of cyclophosphamide given risks of renal dysfunction, hepatic dysfunction, and hemorrhagic cystitis.
D. Long-term management.
Long-term management is guided by outpatient subspecialty care. Pneumocystis carinii pneumonia prophylaxis with TMP-SMX should be started in patients who will remain on long-term steroids and immunosuppressants.
E. Common Pitfalls and Side-Effects of Management
Hemorrhagic cystitis is an adverse reaction associated with cyclophosphamide therapy. Increasing oral and intravenous fluid intake and serial monitoring of urine samples is need when initiating therapy. Mesna can be started in conjunction with cyclophosphamide to minimize the risk of hemorrhagic cystitis. Other side effects include bone marrow suppression, bladder cancer, malignancy and infertility.
Side effects of rituximab include severe immunosuppression, progressive multifocal leukoencephalopathy (PML) associated with reactivations of JC virus, hypogammaglobulinemia, opportunistic infections and allergic, anaphylactic or infusion reactions.
Methotrexate is contraindicated in pregnancy. Adverse effects of leflunomide can include severe hypertension, bone marrow suppression and immunosuppression.
IV. Management with Co-Morbidities
A. Renal Insufficiency.
Most patients who receive cyclophosphamide and high-dose steroids have some element of worsening renal function. Dose adjustment is needed in the setting of renal failure. Renal dosing should also be considered for azathioprine.
B. Liver Insufficiency.
Dose adjustment for cyclophosphamide may be needed, but specific guidelines do not exist. Leflunomide should be avoided with pre-existing hepatic disease.
C. Systolic and Diastolic Heart Failure
Fluid retention with high-dose steroid use is a concern. Additionally, intravenous fluids may be needed with cyclophosphamide therapy to prevent hemorrhagic cystitis.
E. Diabetes or other Endocrine issues
Monitoring of glucose and adjustment of insulin dosing is needed in the setting of high-dose steroid use.
G. Immunosuppression (HIV, chronic steroids, etc).
As above, patients will need prophylaxis against PCP while immunosuppressed.
H. Primary Lung Disease (COPD, Asthma, ILD)
Baseline lung disease with poor reserve will increase the risk of pulmonary compromise from GPA.
J. Hematologic or Coagulation Issues
Bone marrow suppression and neutropenia is a significant risk associated with many of the therapies used to treat GPA.
K. Dementia or Psychiatric Illness/Treatment
High-dose steroids may precipitate delirium or mania. There is a need for monitoring for changing in mental status with measures as needed to prevent harm.
V. Transitions of Care
A. Sign-out considerations While Hospitalized.
In patients with sudden change in respiratory status or hypoxia, consideration of diffuse alveolar hemorrhage should be made. Supportive care including transfusion and face mask oxygen with transfer to intensive care may be needed. Patients undergoing therapy or with worsening renal function may develop an acute need for hemodialysis.
B. Anticipated Length of Stay.
No predicted length of stay – depends on disease severity.
1. When should clinic follow up be arranged and with whom.
Follow-up with rheumatology will be needed for chronic disease management. Depending on organs involved, follow-up with pulmonary, renal, and otolaryngology, specialists may be needed.
2. What tests should be conducted prior to discharge to enable best clinic first visit.
3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.
Complete blood count with differential and renal function panel with urinalysis.
E. Placement Considerations.
Depending on level of pulmonary compromise, continued ventilatory support may be needed in an LTACH. Hemodialysis may also be required if renal disease progresses rapidly.
F. Prognosis and Patient Counseling.
Relapse is common in patients with GPA. One quarter of patients will relapse within the first 2 years after diagnosis. Patients who are nasal carriers of S. aureus are more prone to relapse and should be maintained on TMP-SMX. Renal involvement is a major prognostic factor, specifically the initial GFR on presentation.
VI. Patient Safety and Quality Measures
A. Core Indicator Standards and Documentation.
B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
Patients with GPA are at increased risk for venous thrombosis. Prophylaxis must be balanced with risk of pulmonary hemorrhage. Ulcer prophylaxis in the setting of high-dose steroids should also be considered.
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- I. What every physician needs to know.
- II. Diagnostic Confirmation: Are you sure your patient has granulomatosis with polyangiitis?
- A. History Part I: Pattern Recognition:
- B. History Part 2: Prevalence:
- C. History Part 3: Competing diagnoses that can mimic granulomatosis with polyangiitis.
- D. Physical Examination Findings.
- E. What diagnostic tests should be performed?
- III. Default Management.
- A. Immediate management.
- B. Physical Examination Tips to Guide Management.
- C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
- D. Long-term management.
- E. Common Pitfalls and Side-Effects of Management
- IV. Management with Co-Morbidities
- A. Renal Insufficiency.
- B. Liver Insufficiency.
- C. Systolic and Diastolic Heart Failure
- E. Diabetes or other Endocrine issues
- G. Immunosuppression (HIV, chronic steroids, etc).
- H. Primary Lung Disease (COPD, Asthma, ILD)
- J. Hematologic or Coagulation Issues
- K. Dementia or Psychiatric Illness/Treatment
- V. Transitions of Care
- A. Sign-out considerations While Hospitalized.
- B. Anticipated Length of Stay.
- 1. When should clinic follow up be arranged and with whom.
- 2. What tests should be conducted prior to discharge to enable best clinic first visit.
- 3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.
- E. Placement Considerations.
- F. Prognosis and Patient Counseling.
- VI. Patient Safety and Quality Measures
- A. Core Indicator Standards and Documentation.
- B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.