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The lung in vasculitis 

The lung in vasculitis
Chapter:
The lung in vasculitis
Author(s):

A.U. Wells

and Roland M. du Bois

DOI:
10.1093/med/9780199204854.003.181105

Relevant case histories from Oxford Case Histories in Respiratory Medicine has been added to this chapter.

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Essentials

Lung involvement in vasculitic disease can manifest in two ways: (1) Diffuse alveolar haemorrhage—presenting features include fever, weight loss, and other systemic symptoms in association with cough, breathlessness, and clinical signs suggestive of pneumonia. Haemoptysis may be present but is not invariable. A fall in haemoglobin over a day or longer is diagnostically useful. Bronchoalveolar lavage is usually diagnostic. (2) Other pulmonary vasculopathies—present with breathlessness on exertion. Investigation reveals isolated reduction in gas transfer (carbon monoxide diffusing capacity, DLCO), with or without pulmonary hypertension.

Churg–Strauss syndrome—a prodromal phase of rhinitis with nasal polyps generally precedes the eventual development of treatment-resistant late-onset asthma that is followed, often years later, by vasculitic manifestations. Chest radiography shows patchy lung infiltration in up to 80% of patients: pulmonary nodules and pleural involvement can also occur. First-line treatment is with steroids, with cyclophosphamide added for severe disease.

Wegener’s granulomatosis—chronic rhinitis, sinusitis, or mastoiditis is typically followed by progression to generalized disease over months to years, with lower respiratory tract involvement in 65 to 85% often manifesting with cough, which may be purulent, and less frequently with haemoptysis. The main lung manifestations are with pulmonary nodules (one or more, which can cavitate), localized or diffuse infiltrates, alveolar haemorrhage that may be part of a pulmonary–renal syndrome, and large and small airway disease. Standard first-line treatment for the induction of remission is with prednisolone and cyclophosphamide, with the latter switched to azathioprine for maintenance treatment. Co-trimoxazole is effective for localized but not systemic disease. Rituximab therapy seems promising for disease that is refractory to standard treatments.

Other vasculitides—microscopic polyangiitis can present with diffuse alveolar haemorrhage, which can have a poor prognosis, and other primary systemic vasculitides occasionally present with respiratory features.

Introduction

It is useful to subdivide pulmonary vasculitides into primary systemic or secondary, and to differentiate them from nonvasculitic disorders that can affect the pulmonary circulation, listed in Table 18.11.5.1. The secondary and non-vasculitic diseases are discussed in other chapters: Table 18.11.5.2 summarizes the primary vasculitides, indicating those in which the lung is involved.

Table 18.11.5.1 Pulmonary vascular disease

Vasculitic

Nonvasculitic

Primary systemic

Thromboembolic

Secondary

Primary pulmonary hypertension

Rheumatological

Secondary pulmonary hypertension

Pulmonary–renal

Systemic sclerosis

Behçet’s syndrome

Idiopathic pulmonary haemosiderosis

Chronic infection

Arteriovenous malformations

Lymphoma

Drugs

Penicillamine

Hydralazine

Propylthiouracil

Nitrofurantoin

Table 18.11.5.2 Chapel Hill International Consensus nomenclature of systemic vasculitis (1992)

Lung disease

Large vessel

Giant-cell arteritis

Rare

Takayasu’s arteritis

Frequent

Medium-size vessel

Polyarteritis nodosa

Rare

Kawasaki disease

No

Small vessel (medium-size vessel involvement may be present)

Wegener’s granulomatosis

Frequent

Churg–Strauss syndrome

Frequent

Microscopic polyangiitis

Frequent

Henoch–Schönlein purpura

No

Essential cryoglobulinaemia

No

Clinical manifestations of pulmonary vasculitis

The lung in vasculitis Case History—A 70 yr old man with a short history of severe breathlessness and widespread consolidation on his chest radiograph.

The lung in vasculitis Case History—A 29 yr old woman with known asthma, now presenting with worsening respiratory and systemic symptoms.

Lung involvement in vasculitic disease can manifest as:

  • diffuse alveolar haemorrhage

  • an isolated reduction in gas transfer (carbon monoxide diffusing capacity, DLCO), with or without pulmonary hypertension.

Other features of the underlying or associated disease may be present, and the pulmonary disorder may present as part of a pulmonary–renal syndrome, of which Goodpasture’s disease (see Chapter 21.8.7) is the best-known example.

Diffuse alveolar haemorrhage

The presenting features of diffuse alveolar haemorrhage include fever, weight loss, and other systemic symptoms in association with cough, breathlessness and clinical signs suggestive of pneumonia. A history of previous haemoptysis is sometimes helpful, but in other cases diffuse alveolar haemorrhage presents acutely. Chest radiography shows consolidation, typically resolving within a matter of days, unlike the usual time-course in infective pneumonia. High-resolution CT may reveal an extensive ground-glass appearance, denoting partial alveolar filling. A fall in haemoglobin over a day or longer is diagnostically useful, and chronic iron-deficiency anaemia can arise from low-grade haemorrhage over a lengthy period.

Bronchoalveolar lavage is usually diagnostic in the absence of haemoptysis, revealing overt blood staining in sequential lavage in the acute presentation, or the presence of numerous macrophages containing iron, identified by Perl’s stain, in chronic disease. The gas transfer corrected for alveolar volume (Kco) is elevated in acute haemorrhage, but only if measured within 36 h, seriously limiting the diagnostic yield. Investigations listed in Box 18.11.5.1 should be performed if alveolar haemorrhage is suspected. Diffuse pulmonary haemorrhage occurring without identifiable cause or association is known as idiopathic pulmonary haemosiderosis (see Chapter 18.14.1).

Isolated gas transfer deficit with or without pulmonary hypertension

Pulmonary vasculopathies other than alveolar haemorrhage present with breathlessness on exertion. Clinical examination of the respiratory system and routine lung imaging are normal. Lung function tests show preservation of lung volumes with an isolated reduction of DLco. In severe pulmonary vascular disease pulmonary hypertension may be clinically overt, and in other cases it is detected by echocardiography, especially if tricuspid regurgitation allows Doppler estimation of pulmonary artery pressures. Vasculopathies other than vasculitis should be considered in this clinical context, including ablative vasculopathies (as in systemic sclerosis and primary pulmonary hypertension) and coagulopathies leading to thromboembolism or intrapulmonary microvascular thrombosis (see Chapter 16.15.2).

The following sections discuss lung involvement in specific vasculitic disorders, followed by discussion of key clinical problems, prognosis, and treatment.

Churg–Strauss syndrome

First described by Churg and Strauss in 1951, this rare condition has an estimated annual incidence of approximately 3 per million and mostly affects adults aged 30 to 50 (although the reported age range is 7–74 years). There is no strong gender predilection. Typically, asthma and eosinophilia are associated with the characteristic histological findings (Fig. 18.11.5.1), consisting of profuse eosinophilic infiltration, extravascular granulomatous inflammation, and necrotizing arteritis affecting small to medium-sized vessels. There is little information about geographical variation.

Fig. 18.11.5.1 A case of Churg–Strauss syndrome showing a pulmonary artery surrounded by granulomatous inflammation and a florid mixed inflammatory cell infiltrate that includes abundant eosinophils.

Fig. 18.11.5.1
A case of Churg–Strauss syndrome showing a pulmonary artery surrounded by granulomatous inflammation and a florid mixed inflammatory cell infiltrate that includes abundant eosinophils.

Aetiology and pathogenesis

The underlying pathogenetic mechanism is generally considered to be an eosinophilic granulomatous response to a foreign antigen, akin to the eosinophilic granulomatosis seen in schistosomiasis. In support of this hypothesis, immunological stimuli (vaccination or immunotherapy) have been reported to trigger the disease, although the pauci-immune nature of the histopathology has yet to be explained. The introduction of antileukotriene therapy for asthma has been associated with an increased incidence of Churg–Strauss syndrome, but it remains unclear whether the drug triggers the onset of disease. It is also possible that reduction or withdrawal of corticosteroids with better control of asthma unmasks the condition in some cases, although some individuals who have never received corticosteroids have developed the syndrome with the introduction of an antileukotriene agent.

Antineutrophil cytoplasmic antibodies (ANCA), first described in 1982, are frequently present in systemic vasculitides involving small and medium sized vessels, including Churg–Strauss syndrome, Wegener’s granulomatosis and microscopic polyangiitis. ANCA are directed against cytoplasmic antigens in polymorphonuclear leucocytes and monocytes and are subcategorized according to their immunofluorescent staining pattern as C (cytoplasmic), P (perinuclear), or A (atypical). The pathogenetic significance of ANCA is unclear, but ANCA receptors on the surface of neutrophils are up-regulated at disease sites, and ANCA can also interact with endothelial cells to cause injury and coagulation. All ANCA patterns have been reported in Churg-Strauss syndrome, but P-ANCA occur most frequently, usually directed against myeloperoxidase (MPO) and only very infrequently against proteinase 3 (PR3).

Clinical presentation

Two sets of diagnostic criteria have been used: Lanham’s criteria and the criteria of the American College of Rheumatology. In addition to systemic features such as fever and weight loss, Lanham defined the disease as requiring:

  1. 1 asthma

  2. 2 eosinophilia greater than 1.5 × 109/litre in the peripheral blood

  3. 3 evidence of systemic vasculitis in two or more organs other than the lung

The American College of Rheumatology definition requires the satisfaction of at least four of the following six criteria:

  1. 1 the presence of asthma

  2. 2 eosinophilia greater than 10% in the peripheral blood

  3. 3 evidence of a neuropathy in a vasculitic pattern (e.g. mononeuritis multiplex)

  4. 4 transient pulmonary infiltrates

  5. 5 a history of sinus disease

  6. 6 evidence of extravascular eosinophilia on biopsy

In most patients asthma precedes vasculitic manifestations, often by years, although these features develop simultaneously in up to 20% of cases. Typically the prodromal phase consists of rhinitis with nasal polyps, which often lasts for years before the eventual development of late-onset asthma that is generally resistant to treatment. The second phase is characterized by eosinophilia in the peripheral blood and tissues and often follows a relapsing and remitting course. The final phase, systemic vasculitis, often follows the onset of the second phase by several years and is immediately preceded by improvement in asthma. This pattern of evolution of disease is more than 95% specific and sensitive for Churg–Strauss syndrome. Table 18.11.5.3 lists the major pulmonary manifestations. Pulmonary infiltrates are much more common than pulmonary nodules and, in contrast to Wegener’s granulomatosis, cavitation of nodules in extremely rare. Respiratory failure and status asthmaticus account for 10% of deaths.

Table 18.11.5.3 Distinguishing thoracic features in primary vasculitis

Churg–Strauss syndrome

Wegener’s granulomatosis

Microscopic polyangiitis

Subglottic stenosis

+

+

Multiple nodules

+

+

Solitary nodules

+

Cavities

+

Localized infiltrates

+

+

Transient infiltrates

+

+

Pleural involvement

+

+

Cardiac involvement

+

Adapted from Specks U (1998). Pulmonary vasculitis. In: Schwarz MI, King TE Jr (eds) Interstitial lung disease, pp. 507–34. B C Dekker, Hamilton, Canada.

Other organ involvement

Skin lesions

These are seen in about 60% of patients, generally manifesting as palpable purpura or subcutaneous nodules. Skin infarcts also occur.

Cardiac involvement

The heart may be involved diffusely, producing congestive cardiac failure or restrictive cardiomyopathy. Eosinophilic myocarditis is present in up to 50% of cases, with coronary artery vasculitis and pericardial effusions much less frequent. Cardiac disease is the most common cause of death.

Renal disease

This is much less common than in Wegener’s granulomatosis or microscopic polyangiitis, but the histopathology is very similar, consisting of a focal segmental necrotizing glomerulonephritis. Renal disease is generally mild, but endstage renal failure is reported.

Central nervous system

Mononeuritis multiplex is the most common manifestation, occurring in up to 75% of patients. Cranial nerve involvement is less common, but cerebrovascular disease may occur.

Gastrointestinal involvement

Vasculitis of the mesenteric vessels may produce bowel abnormalities, including perforation, and less commonly eosinophilic infiltration may cause obstruction.

Musculoskeletal system

Arthritis is relatively common, as are myalgias.

Investigation

Chest radiography shows patchy lung infiltration in up to 80% of patients and pleural disease is present in up to 50%. High-resolution CT is much more sensitive than chest radiography, although the full spectrum of abnormalities has yet to be defined. The most frequent findings are patchy ground-glass infiltration and patchy consolidation. An extensive ground-glass appearance is usual in patients which alveolar haemorrhage due to capillaritis, whereas consolidation is more suggestive of granuloma formation in association with involvement of medium-sized vessels.

There is a peripheral blood eosinophilia, matched by a marked eosinophilia on bronchoalveolar lavage. The diagnostic role of ANCA continues to be debated. ANCA, usually P-ANCA, are present in up to two-thirds of patients, but in some series their prevalence is much lower and P-ANCA also occur in many other nonvasculitic autoimmune and infectious conditions. Thus, the presence of P-ANCA is no more than a useful ancillary finding, increasing the diagnostic likelihood, and the absence of P-ANCA should not materially influence the diagnostic algorithm.

The classical triad at lung biopsy consists of necrotizing angiitis, granulomas, and tissue eosinophilia (Fig. 18.11.5.1). Giant cells and fibrinoid necrosis are present. However, it is not uncommon for histological appearances to be indeterminate, with the presence of some but not all of the characteristic features, and in some cases there is overlap with the histopathological appearances of Wegener’s granulomatosis or microscopic polyangiitis. Surgical biopsies have a much higher diagnostic yield than transbronchial biopsies, which seldom disclose vasculitis.

Wegener’s granulomatosis

The systemic features of Wegener’s granulomatosis are described in Chapter 21.10.2. This condition, the third most prevalent systemic vasculitis (after giant cell arteritis and vasculitis in rheumatoid arthritis), occurs throughout the world with an annual incidence of 3 to 11 per million, depending upon the geographic region. It mainly affects adults aged 30 to 50 (although it may occur in any age group), and there is no gender predilection. The histological abnormalities consist of granulomatous inflammation associated with necrotizing vasculitis, affecting small to medium-sized vessels (Fig. 18.11.5.2). Lung involvement occurs at some stage of disease in up to 85% of cases; upper respiratory tract and renal involvement (due to necrotizing glomerulonephritis) are frequent.

Fig. 18.11.5.2 A case of Wegener’s granulomatosis showing an area of geographic necrosis around a partly destroyed pulmonary vessel. This focus is surrounded by chronic inflammation and fibrosis, within which there is granulomatous inflammation with the giant cells showing a somewhat pyramidal morphology.

Fig. 18.11.5.2
A case of Wegener’s granulomatosis showing an area of geographic necrosis around a partly destroyed pulmonary vessel. This focus is surrounded by chronic inflammation and fibrosis, within which there is granulomatous inflammation with the giant cells showing a somewhat pyramidal morphology.

Aetiology and pathogenesis

Studies of possible genetic associations have yielded conflicting results, with linkage to HLA DR1 or HLA DR2 in some but not all populations. The importance of environmental factors is equally uncertain. Case–control studies have suggested that exposure to silica or silicone might be pathogenetic in some cases. ANCA-positive vasculitis mimicking Wegener’s granulomatosis has been induced by propylthiouracil, hydralazine, and penicillamine, possibly by modifying MPO and thereby creating an antigenic stimulus. However, the most suggestive data relate to infection, especially with Staphylococcus aureus. Chronic nasal carriage of S. aureus is substantially more prevalent in Wegener’s granulomatosis than in control populations, and it has been suggested that staphylococcal acid phosphatase might be antigenic in susceptible individuals. An immunostimulatory role for S. aureus B-cell superantigens has also been proposed. The partial efficacy of prophylactic trimethoprim–sulfamethoxazole in reducing both infection and the likelihood of relapse of Wegener’s granulomatosis provides further indirect support for an infectious pathogenesis.

Pathogenetic concepts are complicated by the histological spectrum of disease, ranging from prominent granulomatous lesions, associated with a lymphocytosis on bronchoalveolar lavage, to fulminant necrotizing vasculitis, in which a bronchoalveolar lavage neutrophilia is the rule. The genesis of granulomata is not well understood, but there is strong indirect evidence that neutrophils play a key role in initiating vasculitis. PR3 is the main target antigen for C-ANCA, which is found in about 90% of patients with generalized Wegener’s granulomatosis (as compared to 50% of patients with localized disease). As in other ANCA-positive vasculitides, there is in vitro and animal model evidence to suggest that PR3-ANCA might interact with primed neutrophils, leading to neutrophil degranulation and thus to endothelial damage and further neutrophil recruitment.

Pulmonary presentation

Involvement of the upper and/or lower respiratory tract is the presenting feature in 90% of cases. Disease usually evolves in two phases. Initially there is chronic rhinitis, sinusitis, or mastoiditis, after which most patients progress to generalized disease over months to years, with lower respiratory tract involvement in 65 to 85% often manifesting with cough, which may be purulent, and less frequently with haemoptysis due to diffuse alveolar haemorrhage. Systemic symptoms, including fever and weight loss, are frequent in generalized disease, along with variable involvement of other organs as described in Chapter 21.10.2. Lung involvement is asymptomatic in about one-third of cases, with the main lung manifestations being (see Table 18.11.5.3):

  • one or more nodules, which can cavitate (Fig. 18.11.5.3a)

  • localized or diffuse infiltrates (Fig. 18.11.5.3b)

  • alveolar haemorrhage that may be part of a pulmonary–renal syndrome

  • large and small airway disease

Fig. 18.11.5.3 Wegener’s granulomatosis most often presents radiologically. CT scans may reveal one or more nodules, which can cavitate (a), or localized (b) or diffuse infiltrates.

Fig. 18.11.5.3
Wegener’s granulomatosis most often presents radiologically. CT scans may reveal one or more nodules, which can cavitate (a), or localized (b) or diffuse infiltrates.

Investigations

As in other vasculitides, classical features are not always present at biopsy, with many patients having only one or two of the three cardinal histological features (granuloma, necrosis, vasculitis). If a lung biopsy is required, surgical biopsy is preferred, transbronchial biopsies having a much lower diagnostic yield, especially when not targeted to areas with overt abnormalities on chest radiography or high-resolution CT. In advanced pulmonary disease the hazards of biopsy should prompt a search for an alternative biopsy site, including the kidney, skin, and skeletal muscles. Endoscopic nasal biopsy appearances are most often nonspecific, although positive features in a few cases provide a definitive diagnosis. Irrespective of the biopsy site, suggestive appearances may be diagnostic when combined with clinical and serological information even when diagnostic histological features are absent.

The two main patterns on chest radiography and high-resolution CT are nodules and consolidation, with pleural effusions an occasional finding. High-resolution CT offers the important advantage of better definition of nodule cavitation, a key diagnostic feature, and may also disclose abnormalities of the large intrathoracic and extrathoracic airways, including subglottic stenosis, stenosis of large airways, and bronchiectasis. Subglottic stenosis is present in up to 25% of cases and can develop without concomitant systemic disease activity.

Fibre-optic bronchoscopy may show tracheobronchitis, including ulceration and ‘cobblestoning’ of the mucosa, or airway stenosis. Bronchoalveolar lavage fluid contains an excess of neutrophils and usually of eosinophils (with diffuse infiltrates) or lymphocytes (more interstitial disease), but is most useful in excluding alveolar haemorrhage or infection, including opportunistic infection in treated patients.

Haematological and biochemical investigations reflect the inflammatory process. The diagnosis should never be based upon C-ANCA positivity in isolation because these are also found in other contexts, including other vasculitides, chronic bacterial infections and cryoglobulinaemia.

Microscopic polyangiitis

The main description of microscopic polyangiitis occurs elsewhere (see Chapter 21.10.2), but this necrotizing vasculitis affects small to medium-sized vessels, with few or no immune complex deposits, and lung disease occurs in 35 to 55% of cases.

Pulmonary presentation

The major presentation in the lung (Table 18.11.5.3) is diffuse alveolar haemorrhage, which can have a poor prognosis. Pulmonary capillaritis may be associated with evidence of disease outside the lung, particularly necrotizing glomerulonephritis, mononeuritis multiplex, and skin lesions.

It is often difficult to distinguish microscopic polyangiitis from Wegener’s granulomatosis clinically. The key histological distinction is the absence of granulomas, which are characteristically present in Wegener’s. Renal biopsies can be identical in the two conditions. Microscopic polyangiitis also needs to be distinguished from polyarteritis nodosa that, by definition, only affects arteries, rarely arterioles, and never small vessels. Renal vasculitis with microaneurysm formation occurs in polyarteritis nodosa but not microscopic polyangiitis, and diffuse alveolar haemorrhage does not occur in polyarteritis nodosa.

Other diseases

Other primary systemic vasculitides occasionally present with respiratory features.

Takayasu’s arteritis

This arteritis affects predominantly the aorta and its main branches but involves the pulmonary arteries in up to 50% of patients, presenting with pulmonary vascular occlusion.

Giant-cell arteritis

There is rarely objective evidence of lung involvement, but 25% of patients with giant-cell arteritis have cough, hoarseness, and sore throat at presentation.

The other systemic vasculitides that feature in the Chapel Hill International consensus nomenclature, but which rarely if ever present with lung disease, are Henoch–Schönlein purpura and essential cryoglobulinaemia.

Behçet’s disease

This occurs predominantly in Mediterranean countries and can produce pulmonary vascular inflammation affecting all sizes of vessels and resulting in pulmonary arterial aneurysms, arterial and venous thrombosis, pulmonary infarcts, and pulmonary haemorrhage. It is crucial to differentiate haemorrhage from thrombosis because of the treatment implications.

Pulmonary veno-occlusive disease

This is a disorder of unknown cause that manifests with progressive occlusion of the postcapillary venules, resulting in features similar to those of pulmonary oedema. There is no known effective treatment. Differentiation from cardiogenic causes of raised pulmonary venous pressure must be made.

Lymphomatoid granulomatosis

This has been included historically within the category of pulmonary vasculitis but is now believed to be a lymphoproliferative disease.

Key clinical problems in vasculitis

Diagnosis

Ideally, typical histological appearances should be present, and when they are not present the requisite number of clinical criteria should be met. However, formal diagnostic criteria are merely a basis for diagnostic negotiation in many cases. Classification systems fail to capture the entire spectrum of vasculitic disease, with many patients having features overlapping between diagnostic entities. With the advent of ANCA antibodies, formes frustes of full blown vasculitic syndromes are increasingly diagnosed, with transient or no fulfilment of full diagnostic criteria in many instances. Even in cases satisfying diagnostic criteria, the clinical heterogeneity of the vasculitic syndromes is notorious, it often being stated that no two patients are alike.

An appreciation of these difficulties informs the clinician of the need for a versatile diagnostic approach. When vasculitis is suspected but full clinical criteria are not satisfied, a histological diagnosis should generally be sought, targeted to involved organs. Failure to capture typical appearances at biopsy does not necessarily exclude a diagnosis of vasculitis as vasculitic processes may be patchy and nonspecific inflammatory change may be evident: this applies especially to upper airway biopsies in patients with Wegener’s granulomatosis. An empirical diagnosis of a vasculitic syndrome must sometimes be made, and in these cases—which tend to foment a great deal of insecurity in patients and clinicians alike—it is essential to do everything possible to exclude the most frequent differential diagnoses, namely infection and malignancy.

When formal diagnostic criteria for a vasculitic syndrome are not fulfilled and empirical treatment is required, the general approach—including initial treatment and monitoring—should be as for the vasculitic syndrome most closely resembling the particular clinical presentation of the patient. When the diagnosis is uncertain the initial treatment should be definitive because a satisfactory response provides useful ancillary diagnostic support (‘diagnosis by therapeutic challenge’): a tentative initial therapeutic approach often merely serves to prolong diagnostic uncertainty.

Prognosis

The outcome of the more frequent vasculitic syndromes was poor when they were first described but has improved strikingly, as best illustrated by the mortality of Wegener’s granulomatosis: the mean survival of 5 months in early reports has now been transformed, with complete initial remission in 75% of cases, increasing further with the recent use of rituximab. However, long-term follow-up continues to be needed in Wegener’s granulomatosis (with relapse occurring in 50–70% of cases) and in other vasculitides despite these improvements.

The improvement in prognosis in Wegener’s granulomatosis, also seen in Churg–Strauss syndrome, in part reflects the increasing use of immunosuppressive agents in combination with corticosteroid therapy. However, the increasing detection of milder disease, including patients with limited involvement, has also undoubtedly improved average outcome. Localized Wegener’s granulomatosis has a better outcome than disease with multiorgan involvement. The prognosis of Churg–Strauss syndrome is generally good for those with isolated intrathoracic disease (5-year survival 88%), but worsens with two or more extrapulmonary complications (5-year survival 54%), particularly with proteinuria more than 1 g/day, renal insufficiency (creatinine >140 µmol/litre), cardiomyopathy, gastrointestinal disease, or central nervous system involvement.

The causes of death in vasculitis can be broadly subdivided into sepsis (as a complication of treatment) and disease progression. In Wegener’s granulomatosis death from progressive disease is most commonly due to renal failure or lung involvement. In Churg–Strauss syndrome the main cause of death is cardiac disease, followed by renal failure, cerebrovascular involvement, and gastrointestinal disease, with lung disease accounting for 10% of deaths.

Treatment

Wegener’s granulomatosis

Intense immunosuppression is used to induce remission, followed by less intense maintenance therapy. First-line treatment for the induction of remission should consist either of oral cyclophosphamide (2.0 mg/kg per day) or intravenous cyclophosphamide (600 mg/m2, at intervals dependent on disease severity). These are equally successful in inducing remission, but intravenous therapy tends to be much less toxic, although possibly associated with a higher likelihood of relapse. The particular toxicities of concern are haemorrhagic cystitis and subsequent malignancy, both of which are seen with prolonged oral treatment. However, irrespective of the mode of administration, these complications justify an early change to alternative treatments once remission has been induced in all forms of vasculitis, with standard maintenance treatment being azathioprine (2.0 mg/kg per day).

In the absence of major organ involvement, methotrexate (0.3 mg/kg per week) may be as effective as daily oral cyclophosphamide in the induction of remission, but relapse is more likely following the cessation of treatment at 12 months, suggesting that methotrexate therapy should be extended beyond 12 months if used instead of cyclophosphamide.

Low-dose corticosteroid therapy is generally used in combination with immunosuppressive agents. High-dose corticosteroids are less frequently used than formerly (in combination with cyclophosphamide) to induce remission, but a combination of cyclophosphamide and intravenous methyl prednisolone should be considered in life-threatening disease.

Co-trimoxazole has been efficacious in Wegener’s granulomatosis for localized upper respiratory tract or minor lower respiratory tract disease, but is not recommended for aggressive systemic disease, although it may have an ancillary role in maintaining remission. Intravenous immunoglobulin and antithymocyte globulin have been used with variable success in resistant disease, but rituximab therapy has provided the most promising recent data in patients with Wegener’s granulomatosis that is refractory to standard treatments.

Churg–Strauss syndrome

Initial treatment depends upon severity of presentation and the organs involved. In isolated pulmonary disease the first-line treatment is oral prednisolone (1 mg/kg per day, up to 60 mg/day) or—in more severe disease such as alveolar haemorrhage—intravenous methylprednisolone (up to 1 g/day on three successive days). Response is usually good. Cyclophosphamide is added in life-threatening disease, either orally or intravenously at doses used in Wegener’s granulomatosis. Evidence for other immunosuppressive agents (azathioprine, methotrexate, mycophenolate mofetil) is inconclusive.

There is no evidence that plasma exchange has a routine place in Churg–Strauss syndrome or other pauci-immune pulmonary vasculitides. Prophylactic co-trimoxazole (trimethoprim 160 mg/sulphamethoxazole 800 mg) three times a week is often used when prolonged intense immunosuppression is needed, to reduce the risk of Pneumocystis jirovecii opportunistic infection.

Further reading

Conron M, Beynon HLC (2000). Churg–Strauss syndrome. In: du Bois RM, Tattersfield A (eds) Thorax Rare Disease Series. Thorax, 55, 870–7.Find this resource:

Guillevin L, et al. (1996). Prognostic factors in polyarteritis nodosa and Churg–Strauss syndrome. A prospective study in 342 patients. Medicine, 75, 17–28.Find this resource:

Jayne D, et al. (2003). A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. New Engl J Med, 349, 36–44.Find this resource:

Jennette JC, et al. (1994). Nomenclature of systemic vasculitides. Proposal of an International consensus conference. Arthritis Rheum, 37, 187–92.Find this resource:

Keogh KA, et al. (2006). Rituximab for refractory Wegener’s granulomatosis: report of a prospective, open-label pilot trial. Am J Respir Crit Care Med, 173, 180–7.Find this resource:

Lanham JG, et al. (1984). Systemic vasculitis with asthma and eosinophilia: the clinical approach to the Churg–Strauss syndrome. Medicine (Baltimore), 63, 65–81.Find this resource:

Lhote F, Guillevin L (1998). Polyarteritis nodosa, microscopic polyangiitis and Churg–Strauss syndrome. Semin Respir Crit Care Med, 19, 27–46.Find this resource:

Specks U (1998). Pulmonary vasculitis. In: Schwarz MI, King TE Jr (eds) Interstitial lung disease, pp. 507–34. B C Dekker, Hamilton, Canada.Find this resource: