Granulomatosis with polyangiitis (Wegener's) is a distinct clinicopathologic entity characterized by granulomatous vasculitis of the upper and lower respiratory tracts together with glomerulonephritis. In addition, variable degrees of disseminated vasculitis involving both small arteries and veins may occur.
Granulomatosis with polyangiitis (Wegener's) is an uncommon disease with an estimated prevalence of 3 per 100,000. It is extremely rare in blacks compared with whites; the male-to-female ratio is 1:1. The disease can be seen at any age; ∼15% of patients are <19 years of age, but only rarely does the disease occur before adolescence; the mean age of onset is ∼40 years.
Pathology and Pathogenesis
The histopathologic hallmarks of granulomatosis with polyangiitis (Wegener's) are necrotizing vasculitis of small arteries and veins together with granuloma formation, which may be either intravascular or extravascular (Fig. 326-2). Lung involvement typically appears as multiple, bilateral, nodular cavitary infiltrates (Fig. 326-3), which on biopsy almost invariably reveal the typical necrotizing granulomatous vasculitis. Upper airway lesions, particularly those in the sinuses and nasopharynx, typically reveal inflammation, necrosis, and granuloma formation, with or without vasculitis.
Lung histology in granulomatosis with polyangiitis (Wegener's). This area of geographic necrosis has a serpiginous border of histiocytes and giant cells surrounding a central necrotic zone. Vasculitis is also present with neutrophils and lymphocytes infiltrating the wall of a small arteriole (upper right). (Courtesy of William D. Travis, MD; with permission.)
Computed tomography scan of a patient with granulomatosis with polyangiitis (Wegener's). The patient developed multiple, bilateral, and cavitary infiltrates.
In its earliest form, renal involvement is characterized by a focal and segmental glomerulitis that may evolve into a rapidly progressive crescentic glomerulonephritis. Granuloma formation is only rarely seen on renal biopsy. In contrast to other forms of glomerulonephritis, evidence of immune complex deposition is not found in the renal lesion of granulomatosis with polyangiitis (Wegener's). In addition to the classic triad of disease of the upper and lower respiratory tracts and kidney, virtually any organ can be involved with vasculitis, granuloma, or both.
The immunopathogenesis of this disease is unclear, although the involvement of upper airways and lungs with granulomatous vasculitis suggests an aberrant cell-mediated immune response to an exogenous or even endogenous antigen that enters through or resides in the upper airway. Chronic nasal carriage of Staphylococcus aureus has been reported to be associated with a higher relapse rate of granulomatosis with polyangiitis (Wegener's); however, there is no evidence for a role of this organism in the pathogenesis of the disease.
Peripheral blood mononuclear cells obtained from patients with granulomatosis with polyangiitis (Wegener's) manifest increased secretion of IFN-γ but not of IL-4, IL-5, or IL-10 compared to normal controls. In addition, TNF-α production from peripheral blood mononuclear cells and CD4+ T cells is elevated. Furthermore, monocytes from patients with granulomatosis with polyangiitis (Wegener's) produce increased amounts of IL-12. These findings indicate an unbalanced TH1-type T cell cytokine pattern in this disease that may have pathogenic and perhaps ultimately therapeutic implications.
A high percentage of patients with granulomatosis with polyangiitis (Wegener's) develop ANCA, and these autoantibodies may play a role in the pathogenesis of this disease (see above).
Clinical and Laboratory Manifestations
Involvement of the upper airways occurs in 95% of patients with granulomatosis with polyangiitis (Wegener's). Patients often present with severe upper respiratory tract findings such as paranasal sinus pain and drainage and purulent or bloody nasal discharge, with or without nasal mucosal ulceration (Table 326-5). Nasal septal perforation may follow, leading to saddle nose deformity. Serous otitis media may occur as a result of eustachian tube blockage. Subglottic tracheal stenosis resulting from active disease or scarring occurs in ∼16% of patients and may result in severe airway obstruction.
Table 326-5 Granulomatosis with Polyangiitis (Wegener's): Frequency of Clinical Manifestations in 158 Patients Studied at the National Institutes of Health |Favorite Table|Download (.pdf)
Table 326-5 Granulomatosis with Polyangiitis (Wegener's): Frequency of Clinical Manifestations in 158 Patients Studied at the National Institutes of Health
Percent at Disease Onset
Percent Throughout Course of Disease
Weight loss (>10% body weight)
Central nervous system disease
Pulmonary involvement may be manifested as asymptomatic infiltrates or may be clinically expressed as cough, hemoptysis, dyspnea, and chest discomfort. It is present in 85–90% of patients. Endobronchial disease, either in its active form or as a result of fibrous scarring, may lead to obstruction with atelectasis.
Eye involvement (52% of patients) may range from a mild conjunctivitis to dacryocystitis, episcleritis, scleritis, granulomatous sclerouveitis, ciliary vessel vasculitis, and retroorbital mass lesions leading to proptosis.
Skin lesions (46% of patients) appear as papules, vesicles, palpable purpura, ulcers, or subcutaneous nodules; biopsy reveals vasculitis, granuloma, or both. Cardiac involvement (8% of patients) manifests as pericarditis, coronary vasculitis, or, rarely, cardiomyopathy. Nervous system manifestations (23% of patients) include cranial neuritis, mononeuritis multiplex, or, rarely, cerebral vasculitis and/or granuloma.
Renal disease (77% of patients) generally dominates the clinical picture and, if left untreated, accounts directly or indirectly for most of the mortality rate in this disease. Although it may smolder in some cases as a mild glomerulitis with proteinuria, hematuria, and red blood cell casts, it is clear that once clinically detectable renal functional impairment occurs, rapidly progressive renal failure usually ensues unless appropriate treatment is instituted.
While the disease is active, most patients have nonspecific symptoms and signs such as malaise, weakness, arthralgias, anorexia, and weight loss. Fever may indicate activity of the underlying disease but more often reflects secondary infection, usually of the upper airway.
Characteristic laboratory findings include a markedly elevated erythrocyte sedimentation rate (ESR), mild anemia and leukocytosis, mild hypergammaglobulinemia (particularly of the IgA class), and mildly elevated rheumatoid factor. Thrombocytosis may be seen as an acute-phase reactant. Approximately 90% of patients with active granulomatosis with polyangiitis (Wegener's) have a positive antiproteinase-3 ANCA. However, in the absence of active disease, the sensitivity drops to ∼60–70%. A small percentage of patients with granulomatosis with polyangiitis (Wegener's) may have antimyeloperoxidase rather than antiproteinase-3 antibodies, and up to 20% may lack ANCA.
Patients with granulomatosis with polyangiitis (Wegener's) have been found to have an increased incidence of venous thrombotic events. Although routine anticoagulation for all patients is not recommended, a heightened awareness for any clinical features suggestive of deep venous thrombosis or pulmonary emboli is warranted.
The diagnosis of granulomatosis with polyangiitis (Wegener's) is made by the demonstration of necrotizing granulomatous vasculitis on tissue biopsy in a patient with compatible clinical features. Pulmonary tissue offers the highest diagnostic yield, almost invariably revealing granulomatous vasculitis. Biopsy of upper airway tissue usually reveals granulomatous inflammation with necrosis but may not show vasculitis. Renal biopsy can confirm the presence of pauci-immune glomerulonephritis.
The specificity of a positive antiproteinase-3 ANCA for granulomatosis with polyangiitis (Wegener's) is very high, especially if active glomerulonephritis is present. However, the presence of ANCA should be adjunctive and, with rare exceptions, should not substitute for a tissue diagnosis. False-positive ANCA titers have been reported in certain infectious and neoplastic diseases.
In its typical presentation, the clinicopathologic complex of granulomatosis with polyangiitis (Wegener's) usually provides ready differentiation from other disorders. However, if all the typical features are not present at once, it needs to be differentiated from the other vasculitides, antiglomerular basement membrane disease (Goodpasture's syndrome) (Chap. 283), relapsing polychondritis (Chap. 328), tumors of the upper airway or lung, and infectious diseases such as histoplasmosis (Chap. 199), mucocutaneous leishmaniasis (Chap. 212), and rhinoscleroma (Chap. 31) as well as noninfectious granulomatous diseases.
Of particular note is the differentiation from midline granuloma and upper airway neoplasms, which are part of the spectrum of midline destructive diseases. These diseases lead to extreme tissue destruction and mutilation localized to the midline upper airway structures including the sinuses; erosion through the skin of the face commonly occurs, a feature that is extremely rare in granulomatosis with polyangiitis (Wegener's). Although blood vessels may be involved in the intense inflammatory reaction and necrosis, primary vasculitis is not seen. Midline granuloma is part of the spectrum of angiocentric immunoproliferative lesions that are considered to represent a spectrum of postthymic T cell proliferative lesions and should be treated as such (Chap. 110). The term idiopathic has been applied to midline granuloma when extensive diagnostic workup including multiple biopsies has failed to reveal anything other than inflammation and necrosis. Under these circumstances, it is possible that the tumor cells were masked by the intensive inflammatory response. Such cases have responded to local irradiation with 50 Gy (5000 rad). Upper airway lesions should never be irradiated in granulomatosis with polyangiitis (Wegener's). Cocaine-induced tissue injury can be another important mimic of granulomatosis with polyangiitis (Wegener's) in patients who present with isolated midline destructive disease. ANCA that target human neutrophil elastase can be found in patients with cocaine-induced midline destructive lesions and can confound the differentiation from granulomatosis with polyangiitis (Wegener's).
Granulomatosis with polyangiitis (Wegener's) must also be differentiated from lymphomatoid granulomatosis, which is an Epstein-Barr virus–positive B cell proliferation that is associated with an exuberant T cell reaction. Lymphomatoid granulomatosis is characterized by lung, skin, CNS, and kidney involvement in which atypical lymphocytoid and plasmacytoid cells infiltrate nonlymphoid tissue in an angioinvasive manner. In this regard, it clearly differs from granulomatosis with polyangiitis (Wegener's) in that it is not an inflammatory vasculitis in the classic sense but an infiltration of vessels with atypical mononuclear cells; granuloma may be present in involved tissues. Up to 50% of patients may develop a true malignant lymphoma.
Treatment: Granulomatosis with Polyangiitis (Wegener's)
Prior to the introduction of effective therapy, granulomatosis with polyangiitis (Wegener's) was universally fatal within a few months of diagnosis. Glucocorticoids alone led to some symptomatic improvement, with little effect on the ultimate course of the disease. The development of treatment with cyclophophamide dramatically changed patient outcome such that marked improvement was seen in >90% of patients, complete remission in 75% of patients, and 5-year patient survival was seen in over 80%.
Despite the ability to successfully induce remission, 50–70% of remissions are later associated with one or more relapses. The determination of relapse should be based on objective evidence of disease activity, taking care to rule out other features that may have a similar appearance such as infection, medication toxicity, or chronic disease sequelae. The ANCA titer can be misleading and should not be used to assess disease activity. Many patients who achieve remission continue to have elevated titers for years. Results from a large prospective study found that increases in ANCA were not associated with relapse and that only 43% relapsed within 1 year of an increase in ANCA levels. Thus, a rise in ANCA by itself is not a harbinger of immediate disease relapse and should not lead to reinstitution or increase in immunosuppressive therapy.
Reinduction of remission after relapse is almost always achieved; however, a high percentage of patients ultimately have some degree of damage from irreversible features of their disease, such as varying degrees of renal insufficiency, hearing loss, tracheal stenosis, saddle nose deformity, and chronically impaired sinus function. Patients who developed irreversible renal failure but who achieved subsequent remission have undergone successful renal transplantation.
Because long-term cyclophosphamide is associated with substantial toxicity, approaches have been developed that seek to minimize the duration of exposure to cyclophosphamide while still taking advantage of its efficacy for severe disease. Treatment of granulomatosis with polyangiitis (Wegener's) is currently viewed as having two phases: induction, where active disease is put into remission, followed by maintenance. The decision regarding which agents to use for induction and maintenance is based upon disease severity together with individual patient factors that include contraindication, relapse history, and comorbidities.
Cyclophosphamide Induction for Severe Disease?
For patients with severe disease, daily cyclophosphamide combined with glucocorticoids has been repeatedly proved to effectively induce remission and prolong survival. At the initiation of therapy, glucocorticoids are usually given as prednisone, 1 mg/kg per day for the first month, followed by gradual tapering on an alternate-day or daily schedule with discontinuation after ∼6–9 months. Cyclophosphamide is given in doses of 2 mg/kg per day orally, but as it is renally eliminated, dosage reduction should be considered in patients with renal insufficiency. Some reports have indicated therapeutic success with less frequent and severe toxic side effects using IV cyclophosphamide. In a recent randomized trial, IV cyclophosphamide 15 mg/kg, three infusions given every 2 weeks, then every 3 weeks thereafter, was compared to cyclophosphamide 2 mg/kg daily given for 3 months followed by 1.5 mg/kg daily. Although IV cyclophosphamide was found to have a comparable rate of remission with a lower cumulative cyclophosphamide dose and occurrence of leukopenia, the use of a consolidation phase and an insufficient frequency of blood count monitoring may have negatively influenced the results in those who received daily cyclophosphamide. Of note in this study was that relapse occurred in 19% of those who received IV cyclophosphamide as compared to 9% who received daily oral administration. We continue to strongly favor daily cyclophosphamide with utilization of blood count monitoring every 1–2 weeks (as discussed above) and limiting the duration of induction exposure to 3–6 months.
In patients with imminently life-threatening disease, such as rapidly progressive glomerulonephritis or pulmonary hemorrhage requiring mechanical ventilation, a regimen of daily cyclophosphamide and glucocorticoids is the treatment of choice to induce remission. Adjunctive plasmapheresis was found to further improve renal recovery in a study of patients with rapidly progressive glomerulonephritis who had a creatinine of greater than 5.8 mg/dL.
Remission Maintenance after Cyclophosphamide?
After 3–6 months of induction treatment, cyclophosphamide should be stopped and switched to another agent for remission maintenance. The agents with which there has been the greatest published experience are methotrexate and azathioprine. Methotrexate is administered orally or subcutaneously starting at a dosage of 0.3 mg/kg as a single weekly dose, not to exceed 15 mg/week. If the treatment is well tolerated after 1–2 weeks, the dosage should be increased by 2.5 mg weekly up to a dosage of 20–25 mg/week and maintained at that level. Azathioprine, 2 mg/kg per day, has also proved effective in maintaining remission following induction with daily cyclophosphamide. In a randomized trial comparing methotrexate to azathioprine for remission maintenance, comparable rates of toxicity and relapse were seen. Therefore, the choice of agent is often based on toxicity profile, as methotrexate cannot be given to patients with renal insufficiency or chronic liver disease, as well as on other individual patient factors. In patients who are unable to receive methotrexate or azathioprine or who have relapsed through such treatment, mycophenolate mofetil, 1000 mg twice a day, may also sustain remission following cyclophosphamide induction.
The optimal duration of maintenance therapy is uncertain. In the absence of toxicity, maintenance therapy is usually given for a minimum of 2 years past remission, after which time consideration can be given for tapering over a 6–12 month period until discontinuation. Some patients with significant organ damage or a history of relapse may benefit from longer-term continuation of a maintenance agent.
Methotrexate Induction for Nonsevere Disease?
For selected patients whose disease is not immediately life threatening or in those patients who have experienced significant cyclophosphamide toxicity, methotrexate together with glucocorticoids given at the dosages described above may be considered as an alternative for induction therapy, which is then continued for maintenance.
Rituximab Induction for Severe Disease?
Rituximab is a chimeric monoclonal antibody directed against CD20 present on normal and malignant B lymphocytes that is FDA approved for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic lymphoma, and rheumatoid arthritis. In two recent randomized trials that enrolled ANCA positive patients with severe active granulomatosis with polyangiitis (Wegener's) or microscopic polyangiitis, rituximab 375 mg/m2 once a week for 4 weeks in combination with glucocorticoids was found to be as effective as cyclophosphamide with glucocorticoids for inducing disease remission. In the trial which also enrolled patients with relapsing disease, rituximab was found to be statistically superior to cyclophosphamide.
While the data supports that rituximab is effective for remission induction severe active granulomatosis with polyangiitis (Wegener's) or microscopic polyangiitis, there remain a number of ongoing questions regarding rituximab that must be considered in weighing its use in the individual patient. These include that there are no long-term data regarding relapse risk or long-term safety with rituximab, it is unclear how often rituximab needs to be given, and as all patients in the randomized trials were ANCA positive, its efficacy in ANCA negative patients is unknown. It is also uncertain whether the use of other maintenance agents after rituximab would provide any additional benefit in prolonging remission or increase toxicity as these were not used in either randomized trial.
While rituximab does not have the bladder toxicity or infertility concerns, as can occur with cyclophosphamide, in both of the randomized trials, the rate of adverse events was similar in the rituximab and cyclophosphamide arms. Serious side effects of rituximab include infusion reactions, severe mucocutaneous reactions, and rare reports of progressive multifocal leukoencephalopathy. As rituximab can bring about reactivation of hepatitis B, all patients should undergo hepatitis screening prior to treatment with rituximab.
Other Biologic Therapies?
Etanercept, a dimeric fusion protein containing the 75-kDa TNF receptor bound to human IgG1, was not found to sustain remission when used adjunctively to standard therapy and should not be used in the treatment of granulomatosis with polyangiitis (Wegener's).
Although certain reports have indicated that TMP-SMX may be of benefit in the treatment of granulomatosis with polyangiitis (Wegener's) isolated to the sinonasal tissues, it should never be used alone to treat active granulomatosis with polyangiitis (Wegener's) outside of the upper airway such as in patients with renal or pulmonary disease. In a study examining the effect of TMP-SMX on relapse, decreased relapses were shown only with regard to upper airway disease, and no differences in major organ relapses were observed.
Not all manifestations of granulomatosis with polyangiitis (Wegener's) require or respond to cytotoxic therapy. In managing non-major organ disease, such as that isolated to the sinus, joints, or skin, the risks of treatment should be carefully weighed against the benefits. Treatment with cyclophosphamide is rarely if ever justified for the treatment of isolated sinus disease in granulomatosis with polyangiitis (Wegener's). Although patients with non-major organ disease may be effectively treated without cytotoxic therapy, these individuals must be monitored closely for the development of disease activity affecting the lungs, kidneys, or other major organs. Subglottic tracheal stenosis and endobronchial stenosis are examples of disease manifestations that do not typically respond to systemic immunosuppressive treatment.