Pulmonary Medicine

Pulmonary Vasculitis (Necrotizing granulomatous vasculitis, Churg-Strauss syndrome, Microscopic polyanitis)

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What every physician needs to know:

The pulmonary vasculitides are a group of diseases characterized by their destructive effects on the pulmonary vasculature with subsequent tissue necrosis. These disorders can be divided into primary (idiopathic) and secondary (associated) disorders. Primary pulmonary vasculitis is thought to be autoimmune in nature, although the pathophysiology is not clearly defined. Secondary pulmonary vasculitis can be associated with a number of diverse etiologies, including infection, drug reactions, connective tissue disease, and malignancy.

In the 1980s, the identification of antineutrophil cytoplasmic antibodies (ANCA), led to significant advances in the diagnosis and characterization of vasculitis, particularly the primary, small-vessel, pulmonary vasculitides. This identification allowed small-vessel vasculitis to be divided into ANCA-associated vasculitides (AAV) and immune-complex mediated vasculitides.

The AAV include necrotizing granulomatous vasculitis (NGV, formerly known as Wegener's granulomatosis), Churg-Strauss syndrome (CSS), and microscopic polyangitis (MPA). The immune complex mediated vasculitides are Goodpasture's syndrome, Henoch-Schönlein purpura, IgA nephrophathy, Behçet's disease, and essential cryoglobulinemia. Because the small-vessel vasculitides, particularly AAV, are most commonly encountered in pulmonary medicine, they are the focus of this chapter.

The diagnosis of vasculitis is a challenge because of the significant overlap in clinical, radiographic, and laboratory features with multiple disease processes, particularly infection and drug reactions. The complex nature of these disorders requires the clinician to utilize clinical, radiographic, laboratory, and pathologic data to recognize common patterns of vasculitis, rather than relying on strict clinical diagnostic guidelines. Once a diagnosis of vasculitis is established, immunosuppressive therapy is usually required.

The intensity of the immunosuppressive therapy is determined by the disease's severity and the degree of organ damage at the time of diagnosis. Therapy is initially geared toward inducing remission, followed by maintenance therapy with frequent evaluations for drug toxicity, infectious complications, and disease relapse.

Classification:

See Table 1.

Table 1

The Vasculitides.
Primary Vasculitis Small-vessel vasculitis     •  Necrotizing granulomatous vasculitis (NGV)     •  Microscopic polyangiitis (MPA)     •  Churg-Strauss syndrome (CSS)
Medium-vessel vasculitis     •  Polyarteritis nodosa     •  Kawasaki disease
Large-vessel vasculitis     •  Takayasu arteritis     •  Giant cell arteritis
Immune-complex mediated vasculitis     •  Goodpasture's syndrome     •  Henoch-Schönlein purpura     •  Behçet's disease     •  Essential cryoglobulinemia     •  IgA nephropathy
Secondary vasculitis Autoimmune Disease
SLE
Rheumatoid arthritis
Antiphospholipid antibody syndrome
Infection Drug-induced Inflammatory bowel disease
Hypocomplementemic urticarial vasculitis
Paraneoplastic

Are you sure your patient has pulmonary vasculitis? What should you expect to find?

The diagnosis of vasculitis poses a significant challenge because of the considerable overlap its presentation has with other entities, including infection, rheumatologic/connective tissue disease, malignancy, drug toxicity, and venous thromboembolic disease. Further complicating the diagnosis is the fact that individuals may present with diverse multi-system manifestations. The absence of well differentiated clinical criteria and a single diagnostic test amplifies the difficulty; however, certain clinical presentations can alert the clinician to consider the diagnosis of pulmonary vasculitis.

Constitutional Symptoms

Fatigue, fevers, weight loss, myalgias, and arthralgias are common nonspecific features of vasculitis. In fact, constitutional symptoms precede the development of renal failure by months in most patients with MPA.

Rapidly Progressive Glomerulonephritis (RPGN)

RPGN is a nephritic syndrome characterized by a 50 percent loss of renal function in less than three months and by histopathology revealing crescents in a least half of glomeruli. When renal failure and hematuria are appreciated, it is critical to evaluate a fresh urine sample microscopically for dysmorphic red cells and red cell casts that are suggestive of glomerulonephritis. Disorders that present with RPGN include AAV, SLE, Goodpasture's syndrome, post-infectious glomerulonephritis, Honoch-Schönlein purpura, membranoproliferative glomerulonephritis, idiopathic pauci-immune glomerulonephritis, essential cryoglobulinemia, and IgA nephropathy.

Diffuse Alveolar Hemorrhage (DAH)

The classic clinical syndrome of DAH includes hemoptysis, diffuse alveolar infiltrates, and a decrease in hematocrit. However, only two-thirds of patients have clinically recognized hemoptysis. The differential diagnosis in any patient with unexplained bilateral alveolar infiltrates includes alveolar hemorrhage. Bronchoalveolar lavage is diagnostic when serial lavage samples reveal persistently or increasingly bloody return. An increase in diffusion capacity (30% above baseline) can suggest the diagnosis if the patient is stable enough to perform breath-holding maneuvers in a pulmonary function laboratory. When DAH occurs in the setting of RPGN, the differential diagnosis includes the pulmonary renal syndromes associated with AAV, Goodpasture's syndrome, and SLE.

Cavitary or Nodular Lung Disease

Nodular or cavitary lung diseases are most commonly caused by infection or malignancy. However, in the right clinical setting, these findings may suggest pulmonary vasculitis, particularly AAV. Evidence that nodular or cavitary lung disease is not the result of malignancy or infection significantly raises the possibility of vasculitis.

Upper Airway Disease

Upper airway disease, including otitis, sinusitis, and rhinitis, are relatively common findings in patients with AAV. Disease that is refractory to conventional medical therapy, and ulcerative or destructive lesions should alert the clinical to the possibility of vasculitis. Tracheobronchial and endobronchial lesions occur in 10-50 percent of patients with NGV.

Neurologic Abnormalities

Mononeuritis multiplex, defined by the presence of peripheral nerve abnormalities in two or more distributions, is of particular concern in suggesting an AAV. Other nervous system abnormalities include parasthesias, weakness, pain, and functional deficiencies, such as footdrop.

Palpable Purpura

Palpable purpura is a finding of non-blanching purplish discolorations that signify a cutaneous vasculitis. Palpable purpura is a nonspecific finding, as it can be associated with AAV, as well as drug reactions, cryoglobulinemia, infections, rheumatologic disorders, and malignancy.

Adult Onset Asthma

Mature onset of asthma with or without eosinophilia is a universal finding in CSS that often presents several years prior to the diagnosis of vasculitis. Asthma that is steroid-dependent or refractory to standard medical therapy can suggest the diagnosis.

What are the most common findings associated with pulmonary vasculitis?

Necrotizing Granulomatous Vasculitis

Among the AAV syndromes, NGV is the most common. The syndrome is classically characterized by a combination of upper and lower respiratory tract disease along with renal disease. Constitutional symptoms (fatigue, fevers, and weight loss), and musculoskeletal (30-70%), skin (45-60%), eye (25-50%), and peripheral and central nervous system (10-30%) manifestations are common. The upper and lower respiratory manifestations occur in 75-95 percent of patients at onset of disease.

Renal disease is present in 40 percent of patients at the time of presentation, but 70-80 percent of patients eventually develop renal involvement. Upper airway disease with sinusitis, otitis, epistaxis, and subglottic and/or tracheal stenosis occurs in 70-95 percent of patients. The presence of ulcerating or destructive lesions is highly suggestive.

Churg-Strauss Syndrome

CSS is characterized by a classic triad of asthma, eosinophilia, and necrotizing vasculitis. CSS is unique among the AAVs, based on its clinical manifestations. The presence of asthma and eosinophilia causes significant overlap with many disorders common to pulmonary medicine, including eosinophilic pneumonia syndromes, allergic bronchopulmonary mycosis, steroid-dependent asthma, drug reactions, hypereosinophilic syndromes, and parasitic infections.

A three-phase presentation has been described to consist of a prodromal phase of asthma, rhinitis, and sinusitis, followed by an eosinophilic phase and a vasculitis phase. Asthma is virtually universal and is often steroid-dependent. Between 20 percent and 70 percent of patients have upper respiratory symptoms. Cardiac involvement is more common in CSS than in the other AAVs, occurring in 15-50 percent of patients, and it is disproportionately associated with high mortality. Mononeuritis multiplex and skin involvement are common (50-70%), as is gastrointestinal involvement with pain, infarction, hemorrhage, and viscus perforation.21

Microscopic Polyangiitis

Classically, MPA patients present after weeks to months of constitutional symptoms that include fever, night sweats, arthralgias, and weight loss. These symptoms are often followed by rapidly progressive glomerulonephritis. In comparison to NGV and CSS, RPGN occurs in virtually all patients, while the pulmonary involvement that occurs most commonly with DAH is less common (10-30%). Palpable purpura occurs in 50-70 percent of patients, peripheral nervous system in 10-50 percent, upper airway disease in 5-30 percent, and gastrointestinal manifestations with ischemia, pain, and/or bleeding in 35-55 percent. Cardiac disease with pericarditis and CHF have been described but are thought to be rare.21

Beware: there are other diseases that can mimic pulmonary vasculitis:

Signs and symptoms of vasculitis can overlap significantly with other disease processes, including infection, malignancy, connective tissue disease, drug toxicity, and venous thromboembolic disease. Diffuse alveolar hemorrhage has myriad etiologies, and pulmonary capillaritis (suggestive of vasculitis) must be differentiated from diffuse alveolar damage and bland hemorrhage (e.g., coagulopathy, mitral stenosis, inhalation injury, drug-associated disease). (See the DAH chapter.)

How and/or why did the patient develop pulmonary vasculitis?

It is difficult to ascertain the true incidence and prevalence of primary systemic vasculitis because of the limitations in the available data. Studies have not been able to incorporate the geographic and ethnic variance of disease and have included varying diagnostic criteria. In addition, case findings of AAV have increased significantly with the advent of ANCA testing in the last twenty to thirty years. With regard to specific AAV, NGV has an annual incidence of 4.9-10.5 per million, CSS from 0.5-4.2 per million, and MPA from 2.7 to 11.6 per million.1

NGV and CSS occur most often in more northern and more southern latitudes, perhaps because of decreased UV light exposure.2 NGV has an average age of onset of 55-65 years, while MPA increases in frequency with advancing age. MPA is more common than other AAV in Japanese and Chinese populations. NGV and CSS affect both sexes equally, while MPA more commonly affects men.

Which individuals are at greatest risk of developing pulmonary vasculitis?

Specific risk factors are poorly understood. Beyond an increased prevalence of disease in the more northern and southern latitudes and the increased risk of MPA in Asian populations, no clinically identified risks are universally recognized for AAV. As secondary vasculitis can complicate a number of disorders, including autoimmune or connective tissue disease, infection, drug reactions, inflammatory bowel disease, and malignancy, the presence of the primary disease raises the risk of vasculitis.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Routine Testing

When the diagnosis of vasculitis is entertained, initial testing should be directed at excluding competing diagnoses and evaluating the degree of organ involvement. Particularly important is the exclusion of infection using blood cultures and cultures of tissue or fluid from affected organs. Routine laboratory tests include complete blood count with differential, chemistries, renal function, and liver function tests. Urinalysis on a freshly obtained sample should include microscopic examination for red cell casts and/or dysmorphic red cells.

Serologic Testing

Evaluation with antinuclear antibodies, rheumatoid factor, and disease-specific antibodies (e.g., anti-CCP, anti-SSA/anti-SSB, anti-RNP, anti-JO-1, anti-dsDNA, anti-SCL-70) can suggest a diagnosis of connective tissue disease. In the proper clinical setting, anti-glomerular basement membrane antibodies, cryoglobulins, hepatitis serologies, and antiphospholipid antibodies should be considered. EKG should be performed to evaluate for conduction abnormalities in all patients with vasculitis.

Antinuclear Cytoplasmic Antibodies

Our understanding of the role that ANCA testing plays in the diagnosis of vasculitis has advanced immensely since the 1980s. Immunofluorescent staining of ethanol-fixed neutrophils shows a diffuse pattern in the cytoplasm of patients with NGV, while a perinuclear pattern is most commonly noted in patients with MPA and pauci-immune glomerulonephritis. These staining patterns are referred to as cytoplasmic (c-ANCA) and perinuclear (p-ANCA).

c-ANCA is most commonly directed against a proteinase (PR3) in azuophilic granules, while p-ANCA is most commonly directed against myeloperoxidase (MPO) and is known to have a more diverse group of intracellular targets (i.e., lactoferrin, cathepsin, elastase, lysozyme, bacterial permeability protein) than c-ANCA has.

The detection of PR3 and MPO can be obtained by enzyme-linked immunosorbent assay (ELISA). A positive ANCA has high sensitivity and low specificity and should be confirmed with ELISA. Therefore, specific ELISA for PR3 and MPO should be obtained along with ANCA at the time a diagnosis of vasculitis is entertained. c-ANCA/anti-PR3 is commonly seen with NGV, while p-ANCA/anti-PR3 is most commonly associated with CSS and MPA.

The use of ANCA testing as a screening tool to a large population has a low positive-predictive value. However, utilization of ANCA testing in at-risk patients based on clinical guidelines increases the positive predictive value without sacrificing sensitivity. 3 When applied to at risk populations, c-ANCA has a sensitivity of 85-90 percent and specificity of 90-95 percent in active systemic NGV. In organ-limited disease, the sensitivity decreases to 65-86 percent.4 False-positive c-ANCA results are rare but have been described in other autoimmune diseases and in pseudomonas infections.

p-ANCA/anti-MPO has a much lower sensitivity and specificity for generalized MPA and CSS compared to c-ANCA/anti-PR3 in NGV, and p-ANCA has a higher association with other disorders, including Goodpasture's syndrome, ulcerative colitis, infective endocarditis, rheumatoid arthritis, and other autoimmune disorders. p-ANCA/anti-MPO has a sensitivity of 50-75 percent in active MPA and a 35-50 percent sensitivity for CSS. However, in CSS patients with a peripheral eosinophilia, ANCA is positive in 40-70 percent.5,20 A negative ANCA does not exclude the diagnosis, as ANCA is not always positive even in the presence of active disease.

What imaging studies will be helpful in making or excluding the diagnosis of pulmonary vasculitis?

Imaging is critical to the diagnosis and monitoring of pulmonary vasculitis. Specifically, imaging should be performed on organs that are implicated in the disease process and on those that are likely to contribute to the morbidity or mortality of the specific disease. When a diagnosis of pulmonary vasculitis is being considered, high-resolution CT of the chest should be obtained (see below); transthoracic echocardiogram, and CT of the sinuses may also provide helpful information. CT angiography or MRI of the affected organs/regions can be useful if a large-vessel or medium-vessel vasculitis is suspected.

Necrotizing Granulomatous Vasculitis

Chest imaging reveals at least one abnormality in nearly all patients. HRCT can reveal the presence of nodules (solitary or multiple), cavities, endobronchial disease, and pulmonary infiltrates (alveolar, interstitial, or mixed). The variable imaging findings and their overlap with infection and malignancy require careful evaluation in order to discern their etiology.

Churg-Strauss Syndrome

Chest imaging with HRCT is abnormal in 90 percent of patients, and parenchymal opacities, which are frequently migratory, are common. Similar to asthma, bronchial wall thickening with hyperinflation and air trapping can be seen. Nodules are less common, and pleural effusions are seen in 10 percent of patients.

Microscopic Polyangiitis

Chest imaging is highly variable in MPA, ranging from normal to bilateral heterogeneous ground-glass abnormalities suggestive of alveolar hemorrhage. Pulmonary fibrosis is rare, but it is associated with high mortality rates.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of pulmonary vasculitis?

Pulmonary functioning testing is rarely useful in the diagnosis of pulmonary vasculitis. However, the finding of an elevated diffusion capacity for carbon monoxide (DLCO) to 30 percent above baseline can suggest the diagnosis of alveolar hemorrhage, although it is also occasionally seen in asthmatics. Pulmonary function testing can be followed once the diagnosis is made to evaluate for progression of disease (i.e., fibrosis).

What diagnostic procedures will be helpful in making or excluding the diagnosis of pulmonary vasculitis?

Bronchoscopy

Bronchoscopy plays several important roles in the diagnosis of pulmonary vasculitis, including evaluation for DAH, malignancy, infection, and eosinophilia and assessing for ulcerative and stenotic upper airway and endobronchial disease. Lower respiratory samples can be obtained by bronchoalveolar lavage and should be sent for culture, cytology, and cell count with differential. The decision to obtain endobronchial or transbronchial biopsy specimens is dependent on the clinical, laboratory, and radiographic differential. These biopsies can be useful in excluding infections and malignancy, but they only rarely provide a positive diagnosis of vasculitis. For example, in a study by Schnabel et al., transbronchial biopsies supported a diagnosis of NGV in only two of seventeen patients.6

Tissue biopsy

While the high sensitivity and specificity of c-ANCA-anti-PR3 in the clinical setting of a high pretest probability of NGV can occasionally obviate the need for invasive biopsy, the same cannot often be said for p-ANCA/anti-MPO. Therefore, diagnostic tissue biopsy is often necessary in order to diagnose vasculitis definitively. Considerations regarding the site of biopsy include the accessibility of involved organs, the morbidity/mortality associated with the procedure, and the likelihood of obtaining diagnostic tissue.

The skin and sinuses, which are often involved, are frequently the most accessible biopsy sites. However, the pathologic findings from biopsies obtained from these sites are less specific than biopsies obtained from lung or kidney, as skin biopsies often show a leukocytoclastic vasculitis, a nonspecific result. Upper airway specimens reveal the classic combination of necrosis, granulomatous inflammation, and vasculitis only 15-20 percent of the time7 so skin and upper respiratory sites are useful in supporting the diagnosis of vasculitis but may not allow for definitive diagnosis.

Percutaneous renal biopsy is performed in the setting of acute glomerulonephritis. The histopathologic finding of a segmental, necrotizing glomerulonephritis is highly suggestive of vasculitis. Immunofluorescence should be performed to evaluate for immune-deposition that would suggest immune-complex mediated vasculitis (e.g., IgA deposits in HSP, linear IgG in Goodpasture's syndrome, and clumped IgG in SLE). The absence of immune deposits defines pauci-immune glomerulonephritis, which, in the right clinical setting, is consistent with AAV.

Surgical lung biopsy in patients with small-vessel vasculitis identifies diagnostic features in up to 90 percent of patients.8 The procedure is most commonly performed via video-assisted thorascopic surgical (VATS) techniques, which significantly decrease the risk of complications and the recovery time compared to those of open surgical lung biopsy. Although VATS carries a slightly higher morbidity/mortality risk than renal, skin, or upper respiratory biopsies, the procedure has a high diagnostic yield, and it should be considered early in the course of disease.

Tissue should be evaluated by conventional histopathology for evidence of vasculitis, such as granulomatous inflammation or vascular necrosis. Frozen sections of tissue should also be evaluated for immune deposits by immunofluorescence and placed in saline for culture.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of pulmonary vasculitis?

There are no genetic tests currently available that assist in the diagnosis of vasculitis. Cytology from bronchoalveolar lavage can be helpful if the differential includes malignancy. Pathologic specimens should be evaluated by conventional histopathology for evidence of vasculitis (e.g., granulomatous inflammation, vascular necrosis, necrotizing glomerulonephritis), as well as by immunofluoresence for evidence of immune-complex deposition. As infection is always in the differential, tissue obtained by biopsy should also be sent for culture.

If you decide the patient has pulmonary vasculitis, how should the patient be managed?

Therapy for pulmonary vasculitis generally involves immunosuppressive treatment with corticosteroids and cytotoxic agents, with escalating intensity based on disease severity. The European Vasculitis Study Group (EUVAS) has outlined a grading system that is useful in categorizing disease severity to guide therapy: (1) limited, (2) early generalized, (3) active generalized, (4) severe, and (5) refractory. Initial therapy is geared toward achieving remission, followed by maintenance therapy. Treatment considerations must take into account the risk of treatment complications, weighed against prevention of further organ dysfunction. Close monitoring for adverse effects of medications, infectious complications, and disease relapse are critical.

Induction Therapy

Limited disease ,the first of the EUVAS categories, includes patients who lack constitutional symptoms and who have normal renal function (Cr < 1.4 mg/dL). Disease is localized to the upper airway. Therapy is usually limited to monotherapy with corticosteroids, azathioprine, or methotrexate. Trimethoprim-sulfamethoxazole in limited disease has been debated, and its role remains unclear. Escalation of therapy is recommended with progressive or refractory disease.

The early generalized disease category refers to patients who have constitutional symptoms but no specific threat to organ function. Historically, treatment recommendations have included cyclophosphamide and corticosteroids, but this recommendation was modified with the publication of the Non-renal Alternative with Methotrexate (NORAM) trial, which compared the use of methotrexate with cyclophosphamide for induction therapy.9 Cyclophosphamide was associated with an earlier time to remission (three months vs. five months) and a lower relapse rate (42% vs. 74%), although methotrexate was better tolerated. Therefore, methotrexate can be considered as an alternative to cyclophosphamide in certain clinical scenarios.

Other therapies considered for induction of remission include azathioprine and mycophenolate mofetil. A randomized clinical trial that compares mycophenolate mofetil to cyclophosphamide for remission induction in ANCA-associated vasculitis (MYCYC) is currently enrolling and may lead to additional alternative agents to consider in this group of patients.

The active generalized disease category includes patients with evidence of renal dysfunction (Cr < 5.7 mg/dL) and threatened organ function. Cyclophosphamide and corticosteroids are used to treat patients this group. Historically, daily oral cyclophosphamide has been used, but the CYCLOPS trial compared daily oral (2mg/kg/d) with pulse intravenous cyclophosphamide (15mg/kg every 2-3 weeks) in newly diagnosed patients with active generalized AAV10 (all patients were also treated with prednisone) and found no significant difference in the time to remission or percentage of patients who obtained remission. These findings, combined with a lower rate of side effects and decreased cumulative cyclophosphamide dose in the pulse group, suggests that the intravenous route of delivery may be preferred.

The severe disease category includes patients with severe renal disease (Cr > 5.7 mg/dL), DAH, or other organ-threatening disease. Like patients with active generalized disease, they are usually treated with cyclophosphamide and corticosteroids, although consideration should be given to the addition of plasma exchange therapy in this group of patients. A study that compared plasma exchange to high-dose intravenous methylprednisolone found that 69 percent of the plasma exchange group was alive and independent of dialysis compared to only 49 percent in the high-dose intravenous corticosteroid group.11

The role for plasma exchange is less clear in patients with evidence of disease that threatens an organ other than the kidney. However, several reports and case series have suggested that the addition of plasma exchange may be beneficial in the setting of DAH. Rarely, patients with severe respiratory failure may require extracorporeal membrane oxygenation while awaiting the beneficial effects of immunosuppressive therapy.

In the refractory category are patients who do not respond to conventional therapy with cytotoxic medications, corticosteroids, and plasma exchange. Rituximab, a monoclonal B cell-depleting antibody, has shown significant promise as an additional therapy for AAV. In July 2010, two large randomized, controlled trials found that rituximab was not inferior to standard cyclophosphamide treatment for induction of remission in severe AAV.

The data also suggest that rituximab may be superior to cyclophosphamide for induction of remission in relapsing disease, although this endpoint requires further studies.12,13 Currently, rituximab is a suitable alternative to cyclophosphamide for initial therapy or in the setting of relapsed disease, particularly if there are contraindications to the use of cyclophosphamide.

Multiple other agents have been utilized for the treatment of refractory disease. Anithymocyte globulin has been studied for such treatment, but questions regarding efficacy and safety remain. Intravenous immunoglobulin (IVIg) acutely reduces disease activity, but the effect is not durable. IVIg may have a role where acute disease is present and conventional therapy is contraindicated because of severe infection. Tumor necrosis factor antagonist therapy has been evaluated with infliximab and etanercept, but high infectious complication rates in initial studies point to the need for further investigation prior to their routine clinical use for AAV.

Maintenance Therapy

Following the induction of remission, patients are transitioned to maintenance therapy, the goal of which is to sustain remission with medications associated with less severe side effects. Historically, patients have been transitioned off of the induction agent to methotrexate, azathioprine, or leflunomide after twelve months of therapy.

However, the Cyclophosphamide versus Azathioprine for Remission in Generalized Vasculitis (CYCAZAREM) trial revealed that an earlier transition to azathioprine maintenance therapy is acceptable.14 In this study, no increase in the rate of relapse or worsening in renal function was found when most patients were transitioned to maintenance at between three and six months. Hiemstra et al. compared mycophenolate mofetil to azathioprine for maintenance therapy and found that mycophenolate mofetil was less effective than azathioprine at maintaining disease remission in AAV.15 Therefore, azathioprine is the preferred agent for maintenance therapy.

The role of trimethoprim-sulfamethoxazole or nasal mupirocin use for reduction of Staphylococcus aureus carriage in the prevention of relapse in unclear at this time. Currently, trimethoprim-sulfamethoxazole is recommended as Pneumocystis jirovecci prophylaxis while patients are on systemic immunosuppression; an added benefit may be a reduction in the rate of relapse based on eradication of nasal Staphylococcus aureus. Most experts recommend that maintenance therapy be continued for about two years before discontinuation is considered. When relapse occurs, reinduction therapy is typically required.

What is the prognosis for patients managed in the recommended ways?

The survival rate of patients with pulmonary vasculitis has improved dramatically with the initial studies by Fauci that introduced the therapy with cyclophosphamide and prednisone. 16Despite these advances, however, relapse is common, as two-thirds of patients with NGV and a third of patients with MPA have at least one relapse within five years of diagnosis. The majority of deaths can be attributed to vasculitis itself, followed by infectious complications as the etiology in 13-26 percent of patients. Therefore, careful monitoring for infectious complications (which can mimic disease relapse) is critical in the longitudinal management of patients with pulmonary vasculitis.

The five-year survival rate among appropriately managed patients with NGV is 75 percent. The survival rate decreases with advancing age, severe renal dysfunction, pulmonary involvement (DAH), low albumin, and high anti-PR3 levels. CSS carries a higher five-year survival rate of 70-100 percent, while MPA has a lower five-year survival rate of 45-75 percent.17

Guillevin et al. developed a validated five-factor prognostic scoring system for CSS and MPA 18 that consists of proteinuria (>1g/24 hours), elevated serum creatinine (>1.58 mg/dL), and clinically significant cardiac, gastrointestinal, or central nervous system involvement. In CSS, the mortality rate increases significantly when two or more organs are involved, with a relative-risk of 1.36. In MPA, a clinical severity score of 0 confers an 88 percent five-year survival rate, while a score of two or higher is associated with 54 percent survival rate.

What other considerations exist for patients with pulmonary vasculitis?

Longitudinal monitoring of patients with AAV requires careful evaluation for disease relapse and complications of therapy. The clinician must be cautious that signs or symptoms consistent with a flare of vasculitis may also represent signs of infection or drug toxicity. In addition, the incidence of venous thromboembolic disease in patients with AAV is several times higher than that of the general population, so it should be considered in the differential diagnosis of disease flare.

Significant concern has been raised about the use of leukotriene inhibitors and omalizumab in severe steroid-dependent asthma regarding their conversion of severe asthma to CSS. However, after the initial concerns for each of these therapies were raised, data has not supported a pathogenic role for either; instead, this effect was likely related to a withdrawal of corticosteroids in patients with pre-existing CSS.

What’s the evidence?

Lane, SE, Watts, R, Scott, DG. "Epidemiology of systemic vasculitis.". Curr Rheumatol Rep. vol. 7. 2005. pp. 270.

This excellent overview of the epidemiology of systemic vasculitis discusses regional and ethnic variations in the published data.

Gatenby, PA, Lucas, RM, Engelsen, O, Ponsonby, AL, Clements, M. "Antineutrophic cytoplasmic antibody-associated vasculitides: could geographic patterns be explained by ambient ultraviolet radiation?". Arthritis Rheum. vol. 61. 2009. pp. 1417.

This ecological study attempts to describe and quantify a possible association between UV radiation levels and the incidence of ANCA-associated vasculitis. The authors conclude that ambient UV radiation may provide a protective immunomodulatory effect on the onset of NGV and CSS.

Mandl, LA, Solomon, DH, Smith, EL, Lew, RA, Katz, JN, Schmerlin, RH. "Using antineutrophil cytoplasmic antibody testing to diagnose vasculitis: can test-ordering guidelines improve diagnostic accuracy?". Arch Intern Med. vol. 162. 2002. pp. 1509.

Mandl and colleagues used a retrospective case series from two academic medical centers to measure the diagnostic accuracy of ANCA testing and to determine how applying proposed ANCA ordering guidelines can affect test performance. The authors conclude that using guidelines for testing would decrease the false-positive rate by 27 percent and that no cases of AAV would be missed. This study adds to the data suggesting that ANCA is not a screening test and that it should be applied in appropriate clinical scenarios to reduce the number of false-positive results and expenditures.

Finkielman, JD, Lee, AS, Hummel, AM, Viss, MA, Jacob, GL, Homburger, HA. "ANCA are detectable in nearly all patients with active severe Wegener's granulomatosis.". Am J Med . vol. 120. 2007. pp. 643.

Finkielman and colleagues prospectively evaluated serum samples from 180 patients using three methods to detect ANCA and stratified patients by disease activity. The authors conclude that ANCA are detectable in 96 percent of patients with severe NGV and in 83 percent of patients with limited disease if all three detection methods are used.

Choi, HK, Liu, S, Merkel, PA, Colditz, GA, Niles, JL. "Diagnostic performance of antineutrophil cytoplasmic antibody tests for idiopathic vasculitides: meta-analysis with a focus on myeloperoxidase antibodies.". J Rheumatol. vol. 28. 2001. pp. 1584.

This meta-analysis focused on the diagnostic value for ANCA and anti-MPO antibody testing for idiopathic systemic vasculitis. The results suggest that immunoassays for anti-MPO and immunofluorescence for pANCA is highly specific and that both tests should be used together. The authors recommend combining anti-PR3 and anti-MPO testing with ANCA to optimize diagnostic precision.

Schnabel, A, Holl-Ulrich, K, Dalhoff, K, Reuter, M, Gross, WL. "Efficacy of transbronchial biopsy in pulmonary vasculitides.". Eur Respir J. vol. 10. 1997. pp. 2738-2743.

Schnable and colleagues evaluated the role for transbronchial biopsy in patients with mild to moderate pulmonary involvement from NGV and CSS. This small case series found that transbronchial biopsies are seldom positive in NGV unless they are taken from areas that are grossly abnormal. In contrast, tracheobronchial lesion biopsies had a high rate of positive findings. CSS patients had a similar yield from upper and lower respiratory tract biopsies.

Devaney, KO, Travis, WD, Hoffman, G, Leavitt, R, Lebovics, R, Fauci, AS. "Interpretation of head and neck biopsies in Wegener's granulomatosis: a pathologic study of 126 biopsies in 70 patients.". Am J Surg Pathol . vol. 14. 1990. pp. 555.

The authors propose criteria for the diagnosis of NGV based on biopsy specimens from the head and neck region based on 126 biopsies of this body region. Of note, the combination of vasculitis, necrosis, and granulomatous inflammation were seen together in only 16 percent of specimens.

Hoffman, GS, Kerr, GS, Leavitt, RY, Hallahan, CW, Lebovics, RS, Travis, WD. "Wegener's granulomatosis: an analysis of 158 patients.". Ann Intern Med . vol. 116. 1992. pp. 488.

The authors prospectively studied the clincal features, pathophysiology, treatment, and prognosis in 158 patients with NGV for 1229 patient-years and concluded that the clinical course of NGV has improved significantly with the addition of cyclophosphamide and glucocorticoids. The authors raise concerns about the toxicity of long-term cyclophosphamide therapy and encourage further investigation of alternative regimens.

de Groot, K, Rasmussen, N, Bacon, PA, Tervaert, JW, Feighery, C, Gregorini, G. "Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis.". Arthritis Rheum . vol. 52. 2005. pp. 2461.

This randomized clinical trial compared cyclophosphamide and methotrexate for induction in early AAV in an unblinded fashion. The authors conclude that methotrexate can replace cyclophosphamide for initial treatment in early disease. However, methotrexate was less effective in patients with extensive pulmonary disease.

de Groot, K, Harper, L, Jayne, DR, Flores Suarez, LF, Gregorini, G, Gross, WL. "Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial.". Ann Intern Med . vol. 150. 2009. pp. 670.

This randomized controlled trial by de Groot and colleagues has had a significant impact on dosing of cyclophosphamide in AAV. The pulse regimen was noninferior to daily oral cyclophosphamide for inducing remission of AAV, and it had a reduced cumulative dose of drug and less leukopenia.

Jayne, DRW, Gaskin, G, Rasmussen, N, Abramowicz, D, Ferrario, F, Guillevin, L. "Randomised trial of plasma exchange or high dose methylprednisolone as adjunctive therapy for severe renal vasculitis.". J Am Soc Nephrol . vol. 18. 2007. pp. 2180.

The role for plasma exchange in severe AAV with renal failure has been controversial. This randomised trial in patients with AAV and renal failure found improved survival and freedom from dialysis at three months with plasma exchange in addition to standard therapy (69% vs. 33%).

Stone, JH, Merkel, PA, Spiera, R, Seo, P, Langford, CA, Hoffman, GS. "Rituximab versus cyclophosphamide for ANCA-associated vasculitis.". N Engl J Med . vol. 363. 2010. pp. 221.

Stone and colleagues conducted a randomized, controlled noninferiority trial that compared rituximab to standard cyclophosphamide therapy for the induction of remission in patients with severe NGV or MPA. The results met criteria for noninferiority with a primary end point of remission of disease without the use of prednisone at six months. The data also suggests that rituximab may be superior in patients with relapsing disease.

Jones, RB, Tervaert, JW, Hauser, T, Lugmani, R, Morgan, MD, Peh, CA. "Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis.". N Engl J Med . vol. 363. 2010. pp. 211.

This study evaluated rituximab in AAV with renal involvement compared to therapy with cyclophosphamide. Patients who received rituximab were given two IV doses of cyclophosphamide and then were compared to patients who received cyclophosphamide for 3-6 months, followed by azathioprine therapy. Rituximab was found to be non-inferior, and both groups had high rates of sustained-remission. This study and the Stone et al. study showed no significant difference in adverse events between treatment groups.

Jayne, D, Rasmussen, N, Andrassy, K, Bacon, P, Tervaert, JW, Dadoniene, J. "A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies.". N Engl J Med . vol. 349. 2003. pp. 36.

Prolonged cyclophosphamide therapy can be associated with adverse effects. This study by Jayne and colleagues evaluated the role for azathioprine in reducing the exposure to cyclophosphamide in patients with generalized AAV. After remission was obtained on standard cyclophosphamide therapy (at least three months), patients were randomly assigned to continued therapy versus azathioprine. The primary end point was relapse, and no difference was noted in the two study groups, suggesting that azathiopriine may be substituted for cyclophosphamide after remission has been achieved in generalized vasculitis.

Hiemstra, TF, Walsh, M, Mahr, A, Savage, CO, de Groot, K, Harper, L. "Mycophenolate mofetil vs. azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial.". JAMA. vol. 304. 2010. pp. 2381.

Azathioprine has been shown as an effective alternative to cyclophosphamide once remission has been achieved in AAV. The IMPROVE trial tested the hypothesis that mycophenolate mofetil may be more effective than azathioprine in preventing relapses in AAV. This open-label, randomized trial found that mcyophenolate mofetil was less effective for maintaining remission than azathioprine was, and both groups had similar rates of adverse events. Therefore, based on the current literature, azathioprine should be chosen as a cyclophosphamide-sparing agent over mycophenolate mofetil to maintain remission in AAV.

Fauci, AS, Haynes, BF, Katz, P, Wolff, SM. "Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years.". Ann Intern Med . vol. 98. 1983. pp. 76.

This seminal paper revolutionized therapy for NGV. Fauci and colleagues prospectively evaluated eighty-five patients over twenty-one years and showed that 93 percent of patients achieved complete remission with cyclophosphamide and prednisone therapy.

Phillip, R, Luqmani, R. "Mortality in systemic vasculitis: a systematic review.". Clin Exp Rheumatol. vol. 26. 2008. pp. S94.

This review by Phillip and Luqmani documents the improvement in survival of patients with systemic vasculitis, as well the improvements in our diagnostic tools over time.

Guillevin, L, Cohen, P, Gayraud, M, Lhote, F, Jarrhousse, B, Casassus, P. " Churg-Strauss syndrome: clinical study and long-term follow-up of 96 patients.". Medicine . vol. 78. 1999. pp. 26.

Guillevin and colleagues retrospectively evaluated clinical manifestations, prognostic factors, and long-term outcome in ninety-six patients with CSS between 1963 and 1995. The article provides an excellent overview of the clinical manifestations and course of patients with CSS.

Merkel, PA, Lo, GH, Holbrook, JT, Tibbs, AK, Allen, NB, Davis, JC. "Brief communication: high incidence of venous thrombotic events among patients with Wegener granulomatosis: The Wegener's Clinical Occurrence of Thrombosis (WeCLOT) study.". Ann Intern Med . vol. 142. 2005. pp. 260.

The WeCLOT study prospectively followed a cohort of 180 patients with NGV and documented venous thrombotic events. The authors found 16 VTEs in 167 patients with a median time from enrollment (active disease) to VTE of 2.1 months. The incidence of VTE was 7 per 100 person-years. The authors comment on this high rate in comparison to patients with lupus and RA and to the general population.

Frankel, SK, Jayne, D. "The pulmonary vasculitides.". Clin Chest Med . vol. 31. 2010. pp. 519.

This excellent review discusses the epidemiology, diagnosis, and therapy of patients with AAV.

Brown, KK, Cool, CD, Murray, JF, Nadel, JA. "Pulmonary vasculitis.". Murray and Nadel's textbook of respiratory medicine. Elsevier Saunders. 2010. pp. 1244-1260.

The book chapter discusses the epidemiology, pathology, diagnosis, and therapy of pulmonary vasculitis.
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