Richard A Watts
Consultant Rheumatologist, Ipswich Hospital NHS Trust/Clinical Senior Lecturer, Norwich Medical School, University of East Anglia
Specialist Registrar, Ipswich Hospital NHS Trust
Issue 1 (Topical Reviews Series 7) Autumn 2012
First published May 2003; revised May 2005, Oct 2012
The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are rare diseases for which classification systems have been developed
Modern therapy has converted these from fatal conditions to ones with a relapsing and remitting course
Cyclophosphamide and corticosteroids are the initial choice of treatment for most patients, although methotrexate can be used in less severe disease. Remission can usually be achieved but relapse is common
Cyclophosphamide, because of its toxicity, should be used for as short a time as possible
Rituximab can be effective in refractory disease and may have a role where there are contraindications to the use of cyclophosphamide Introduction
The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of uncommon diseases characterised by inflammatory cell infiltration and necrosis of blood vessel walls. The severity of vasculitis is related to the size, site and number of vessels affected.
Classification of systemic vasculitis remains confusing and controversial because the aetiology is usually unknown and there is considerable overlap in the clinical expression of the different vasculitic syndromes. Classification generally reflects dominant vessel size and ANCA status (Figure 1). The AAV form a separate group because they (a) often involve small and sometimes medium-sized arteries, (b) are most frequently associated with ANCA, (c) are associated with a high risk of glomerulonephritis, and (d) respond well to immunosuppression with cyclophosphamide. The aetiology of these diseases is probably unrelated to immune complex formation in contrast to pure small-vessel vasculitis such as IgA vasculitis (Henoch–Schönlein purpura) and cryoglobulinaemic vasculitis.
In 1990 the American College of Rheumatology (ACR) developed classification criteria for systemic vasculitis.
They considered Wegener’s granulomatosis, Churg–Strauss syndrome and polyarteritis nodosa but not microscopic polyangiitis. The criteria are specific (87–92%) and sensitive (82–87%) but were never validated against patients without vasculitis. In 1994 the Chapel Hill Consensus Conference (CHCC) presented definitions of AAV including microscopic polyangiitis but not diagnostic criteria. 1-3 These were revised and updated in 2012 (Table 1) and a revised nomenclature introduced – granulomatosis with polyangiitis (Wegener’s granulomatosis) (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome) (EGPA). 4 5
TABLE 1. Chapel Hill Consensus definitions (2012) for ANCA-associated vasculitis.
(©2012 Wiley. Adapted with permission from Jennette et al, 2012 Revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Arthritis Rheum 2012 Oct 8. doi 10.1002/art.37715. American College of Rheumatology.) 5
ANCA-associated vasculitis (AAV) Necrotising vasculitis, with few or no immune deposits, predominantly affecting small vessels (i.e. capillaries, venules, arterioles or small arteries) associated with MPO-ANCA or PR3-ANCA. Not all patients have ANCA. Add a prefix or suffix indicating ANCA reactivity, e.g. PR3-ANCA, MPO-ANCA, ANCA-negative.
Granulomatosis with polyangiitis (Wegener’s granulomatosis) (GPA) Necrotising granulomatous inflammation usually involving the upper and lower respiratory tract, and necrotising vasculitis predominantly affecting small to medium vessels (e.g. capillaries, venules, arterioles, arteries and veins). Necrotising glomerulonephritis is common.
Eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome) (EGPA) Eosinophil-rich and necrotising granulomatous inflammation often involving the respiratory tract, and necrotising vasculitis predominantly affecting small to medium vessels, and associated with asthma and eosinophilia. ANCA is more frequent when glomerulonephritis is present.
Microscopic polyangiitis (MPA) Necrotising vasculitis, with few or no immune deposits, predominantly affecting small vessels (i.e. capillaries, venules or arterioles). Necrotising arteritis involving small and medium arteries may be present. Necrotising glomerulonephritis is very common. Pulmonary capillaritis often occurs. Granulomatous inflammation is absent.
The annual incidence of AAV in Norfolk during 1988–2010 was estimated to be 19.5/million (GPA 11.3/million, MPA 5.9/million) with a prevalence of 255/million. The peak age at diagnosis was 65–74 years, with a male preponderance.
The high age at onset has been confirmed from other centres in Europe (Spain and Scandinavia). A cyclical pattern of occurrence has been noted for GPA but not MPA. 6 7
There are geographical differences in the incidence of AAV. For example a comparative study in Europe using the same classification criteria in three populations (Lugo, Northwestern Spain; Norwich, UK; and Tromsø, Northern Norway) reported that GPA was more common in Norway than in Spain, while MPA had the reverse distribution.
In South-East Asian populations (Japan, China) myeloperoxidase (MPO)-AAV is relatively more common than vasculitis associated with antibodies to PR3 (PR3-AAV), although the overall incidence of AAV is similar. 7 8 Aetiology and pathogenesis
The AAV are of unknown aetiology but generally considered to be autoimmune diseases due to the strong association with ANCA. Evidence for an important genetic contribution to AAV has been growing, including a familial association.
A recently published genome-wide association study has confirmed that the pathogenesis of AAV has a genetic component, and that there are genetic distinctions between GPA and MPA that are associated with ANCA specificity. 9 This study showed that PR3-ANCA was associated with 10 HLA-DP, SERPINA1 (which encodes α1 antitrypsin, a serine proteinase inhibitor for which PR3 is one of several substrates) and PRTN3 (which encodes PR3), while MPO-ANCA was associated with HLA-DQ.
ANCA, first described by Davies et al in 1982, were associated with GPA in 1985. 11 They are antibodies directed against neutrophil granule constituents. Two main patterns of staining are recognised using indirect immunofluorescence: cytoplasmic (cANCA), a coarse granular staining of the cytoplasm, and perinuclear (pANCA), with staining chiefly around the nucleus, leaving the cytoplasm unstained. The main target antigen for cANCA is serine PR3 located in azurophilic granules, and for pANCA is MPO, an enzyme from azurophilic granules that catalyses peroxidation of chloride to hypochlorite. Anti-PR3 antibodies are highly specific (>90%) for GPA. 12 MPO antibodies are more typically found in MPA and EGPA but are much less specific. 13
ANCA often correlate with disease activity, and there is increasing evidence to support their role in pathogenesis.
One model for the development of AAV envisages environmental factors such as infectious agents, silica and drugs triggering release of proinflammatory cytokines and chemokines which then cause upregulation of the expression of adhesion molecules and prime neutrophils. Translocation of the ANCA antigens (PR3 and MPO) from the lysomal compartment to the cell surface occurs and engagement with ANCA. This results in endothelial activation with increased transmigration and adherence of neutrophils to vessel walls. ANCA-mediated neutrophil activation also triggers production of reactive oxygen radicals, neutrophil degranulation and release of proteolytic enzymes. The combination of neutrophil and endothelial activation leads to the development of vasculitis.
In vivo studies have shown the pathogenic potential of MPO-ANCA for necrotising glomerulonephritis and pulmonary capillaritis. For PR3-AAV an animal model is lacking. 14 14 Trigger factors
The predominance of respiratory involvement, especially in GPA, led Duna et al to investigate the role of inhaled agents in the development of GPA. They observed no increase in inhaled particulates and fumes in GPA in general, but a significant increase in those with respiratory disease.
A number of other possible trigger factors have also been reported, including silica, solvents, allergy and vaccination. A number of drugs have been implicated in the development of AAV. Patients with high-titre MPO antibodies are more likely to have taken hydralazine, propylthiouracil or allopurinol. 15 Leucotriene antagonists have been associated with development of EGPA, probably by unmasking pre-existing disease. 16 17 Clinical features
Granulomatosis with polyangiitis (GPA)
GPA is characterised by necrotising granulomata of the upper and lower respiratory tract, necrotising vasculitis and focal glomerulonephritis. A more limited form, with lesions limited to the upper and lower respiratory tract, can occur. Upper-airways disease is the most common presenting feature, occurring in more than 70% of patients at presentation, and develops in >90% of patients. Nasal disease presents with obstruction, nasal ulcers and septal perforation, serosanguinous discharge or epistaxis. Destruction of the nasal septum results in the typical saddle-nose deformity. Sinusitis is present in 85% at some time during the disease. Laryngotracheal disease may be asymptomatic, but can present with hoarseness or stridor and upper-airways obstruction.
Renal disease is a feature of GPA, occurring in 18% of patients at presentation and in 77% subsequently.
It may not be clinically apparent and must be constantly sought. Patients may present with life-threatening renal failure due to rapidly progressive glomerulonephritis requiring urgent dialysis and immunosuppression. At the other end of the spectrum are patients with proteinuria or haematuria with no impairment of renal function. Any renal involvement is associated with a significantly worse outcome. 18
Pulmonary involvement is one of the main features of GPA, occurring in 45% at presentation and 87% during the course of the disease.
Cough, haemoptysis and pleuritis are most common. The most frequent radiological features are pulmonary infiltrates, haemorrhage and hilar lymphadenopathy. 18
Cutaneous manifestations occur in around 50% of patients, and include ulcers, palpable purpura, papules and nodules.
Neurological involvement with peripheral neuropathy or mononeuritis multiplex is less common at presentation but can be detected (often subclinically) in ≤50% of patients with time.
Ocular disease occurs in 50%, with any compartment of the eye potentially being affected – keratitis, conjunctivitis, scleritis, episcleritis, uveitis, retro-orbital pseudotumour, retinal vessel occlusion and optic neuritis. Visual loss is reported in ≤8% of patients.
Musculoskeletal symptoms are common, with most patients experiencing arthralgias and/or myalgias. A true synovitis can be seen in 25% of patients.
Microscopic polyangiitis (MPA)
Kussmaul and Maier
described a patient with periarteritis nodosa characterised by inflammation and necrosis of medium-sized arteries, resulting in aneurysm formation and organ infarction. Wainwright and Davson 19 subsequently described patients with segmental glomerulonephritis who also had features of polyarteritis nodosa (PAN) with extra-renal involvement. They were the first to use the term microscopic polyarteritis nodosa for this group of patients, whose dominant feature was rapidly progressive renal failure. This syndrome is now usually called microscopic polyangiitis (MPA). Patients with MPA share some features with GPA patients 20 and in early disease distinction may be difficult. Renal disease is characteristic and the typical histological appearance is a pauciimmune focal segmental necrotising glomerulonephritis similar to that seen in GPA. Pulmonary haemorrhage is also common (≤29%). Mononeuritis multiplex as in GPA is uncommon (≤20%), and ocular and nasopharyngeal symptoms are less common than in GPA (<30%). 21 Eosinophilic granulomatosis with polyangiitis (EGPA)
The characteristic features of EGPA are asthma (typically late-onset), peripheral blood and tissue eosinophilia, fever, and systemic vasculitis. Asthma especially distinguishes EGPA from GPA and MPA. Histologically there is a granulomatous necrotising vasculitis. Renal involvement is relatively uncommon. Asthma is the cardinal feature and precedes systemic features in virtually all cases; onset is late in life and becomes more severe until the onset of vasculitis. Chest x-ray shows infiltrates in ≤77%.
Cardiac disease is common (≤47%) and is an important cause of mortality, due to congestive heart failure, pericardial effusion and restrictive cardiomyopathy.
Mononeuritis multiplex is a common (70%) feature of EGPA, where it is much more frequent than in GPA and MPA.
Investigation and diagnosis
Investigation is directed towards (a) establishing and confirming the diagnosis, (b) assessing the extent of organ involvement, and (c) assessing disease activity.
It is important to consider systemic vasculitis as a potential diagnosis in any patient with multisystem disease. It is important to differentiate between AAV and syndromes that may mimic AAV, particularly infection, malignancy and connective tissue disease (Table 2). It is especially important to exclude infection as AAV is treated with high-dose corticosteroids and immunosuppressive agents.
TABLE 2. Mimics of systemic vasculitis.
1. Systemic multisystem disease
Subacute bacterial endocarditis
Connective tissue disorders
2. Vessel occlusion
Severe Raynaud’s phenomenon
Acute digital loss (atheromatous)
3. Angiographic appearances
Coarctation of the aorta
Urinalysis is the single most important investigation. The extent of renal impairment and rate of deterioration in renal function is a major determinant of prognosis. The detection of proteinuria and/or haematuria in a patient with a systemic illness mandates immediate further investigation and is a medical emergency.
Assessment of organ involvement
Urinalysis is a sensitive means of detecting renal involvement, and an active urinary sediment with red blood cells (RBC) and casts indicates glomerular disease. Serum urea and creatinine may be normal despite active renal disease. Renal biopsy will serve to confirm the diagnosis and document the extent of renal inflammation or scarring.
Leucocytosis suggests either a primary vasculitis or infection. Leucopaenia is a rare presenting feature of vasculitis and if present suggests vasculitis secondary to systemic lupus erythematosus or the effects of previous immunosuppressive therapy. A significant peripheral blood eosinophilia (1.5 x 10
/l) suggests EGPA or a drug reaction. A hypochromic microcytic anaemia may be indicative of gastrointestinal bleeding, pulmonary haemorrhage or active persistent inflammation. 9
The degree of inflammation may be assessed by measurement of the acute phase response (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)). Neither is specific and each may be elevated in any inflammatory condition, including vasculitis. A disproportionate increase in CRP compared with ESR should raise the suspicion of infection.
Chest x-ray should be performed in all patients with suspected systemic vasculitis to assess the presence of infiltrates, haemorrhage or granulomata and to exclude infection. High-resolution computerised tomography (CT) improves the detection of pulmonary lesions of GPA and pulmonary fibrosis, and can be useful in assessing response to treatment. Infection (especially tuberculosis), sarcoidosis and malignancy can mimic the CT appearance of GPA. Suspicious lesions should be biopsied to exclude malignancy or infection.
Magnetic resonance imaging (MRI) or CT should be obtained to assess the extent of sinus involvement; however there is difficulty in distinguishing scarring from active disease. Patients with active ear, nose and throat (ENT) symptoms should have formal endoscopy by an otolaryngologist and biopsies obtained from areas of inflammation. Histology in active disease is often non-specific and is difficult to distinguish from chronic infection.
Echocardiography is essential as part of the investigation to exclude bacterial endocarditis and atrial myxoma. Myocarditis is especially frequent in EGPA and poor ventricular function can be demonstrated by echocardiography.
Neurological signs may be subtle with evidence only of minor sensory impairment. Comprehensive nerve conduction studies are required to demonstrate evidence of mononeuritis multiplex.
Confirmation of diagnosis
Tissue biopsy is vitally important to confirm the diagnosis prior to treatment with potentially toxic immunosuppressive drugs. The choice of tissue to biopsy is crucial. Biopsy of uninvolved tissue is less likely to yield a positive result. In the acutely sick patient in whom the evidence for vasculitis is strong and infection has been ruled out treatment should not be delayed solely to obtain the biopsy. Biopsy on occasion may reveal clinically unexpected findings such as cholesterol crystals or myxomatous emboli (Table 2). It is not usually necessary to biopsy more than one organ to confirm the diagnosis; however, multiple biopsies of clinically affected organs may be required to assess the extent of organ involvement and to exclude alternative diagnoses.
Blood cultures, clotting screen, viral serology and echocardiography are important to exclude infection and other conditions that may present as systemic multisystem disease and hence mimic vasculitis (Table 2).
Assessment of disease activity
Modern therapy of the systemic vasculitides has dramatically altered the prognosis of AAV from acute fulminating life-threatening conditions to chronic diseases with considerable morbidity arising from either disease activity or therapy. Several systems have been developed to assess disease activity and damage (as reviewed by Carruthers and Bacon).
These include the Birmingham Vasculitis Activity Score (BVAS), Groningen index and the Vasculitis Activity Index (VAI). The BVAS is the most widely applicable to different types of necrotising vasculitis and has been systematically validated. 23 It is a comprehensive scoring system, which includes nine organ systems. New-onset clinical features that are attributable to active vasculitis and that have been present within the previous 4 weeks are recorded. Organ involvement associated with a worse prognosis is given a greater weighting. BVAS has also been used to develop definitions of remission and relapse which are now being used in multicentre trials. 24
Vasculitis results in organ damage due either to the disease itself or to therapy. Damage is defined as an irreversible process that is the result of scars and is not due to acute inflammation or grumbling disease activity. The Vasculitis Damage Index (VDI) is also an organ-based system and is scored after 3 months. The VDI is comprehensive, permits accumulation of damage with time and has been validated.
The final component of patient assessment is function. The SF-36 has been validated for use in patients with vasculitis and is included in the Vasculitis Integrated Assessment Log (VITAL) for disease assessment.
The natural history of untreated AAV is of a rapidly progressive, usually fatal disease.
The introduction of cyclophosphamide (CYC) in the 1970s, combined with prednisolone, resulted in a significant improvement in the mortality of GPA with a 5-year survival of 82%, 27 and most modern series report 5-year survival figures of 80–90%. The mortality for patients treated with current treatments is 2.6 times higher than that of age-matched controls. 28,29 Infections and active vasculitis account for most early deaths in the first year after diagnosis. Mortality in patients who survive the first year after diagnosis is still 1.3 times higher than that of age-matched population controls and is mainly caused by infection, cardiovascular disease and cancer. 30 30
Overall however the extent and number of organs determine the prognosis involved. The ‘five factor score’ (FFS) was developed in a retrospective study of PAN and EGPA by Guillevin et al.
A poor prognosis was associated with age >50 years and the presence of cardiomyopathy, nephropathy (proteinuria >1 g/l; creatinine >1.58 mg/dl), gastrointestinal tract involvement (bleeding, perforation, infarction or pancreatitis) and central nervous system (CNS) involvement. An FFS of ≥2 is associated with 53% mortality at 6 years, compared with 14% in patients with an FFS of 0. 31
The BVAS at presentation is also indicative of prognosis. In a cross-sectional study patients with a subsequent fatal outcome had a median initial BVAS of 20.5, those with active untreated disease 7.5, and those with inactive disease 0.24
The treatment of AAV consists of two phases: remission induction and maintenance of remission. Treatment depends on the severity and extent of organ involvement.
Conventional first-line therapy
Remission induction therapy
For generalised disease or threatened organ involvement, the gold standard for the initial treatment is corticosteroids and CYC. The original National Institutes of Health (NIH) regimen
combined low dose oral CYC (2.0 mg/kg/day) with prednisolone initially at a dose of 1.0 mg/kg/day. CYC was continued for at least 1 year after the patient achieved complete remission and was then tapered. The regimen was effective in controlling active vasculitis but there was an unacceptable long-term toxicity secondary to high cumulative doses of CYC, especially bladder cancer. The CYCAZAREM (Cyclophosphamide versus Azathioprine as Remission Maintenance therapy for ANCA-associated vasculitis) study showed that 3–6 months oral CYC was effective in inducing remission. 29 Further cumulative dose reduction can be achieved by using pulse IV CYC. The CYCLOPS (Cyclophosphamide daily Oral versus Pulsed) trial compared pulse IV CYC (15 mg/kg every 2 weeks for the first month and then every 3 weeks for a total of 6 months) with daily oral CYC (2 mg/kg per day for months 0–3, and 1.5 mg/kg per day for months 4–6). 32 There was no difference in the time to remission or the percentage of patients who achieved remission by 9 months (88% in both groups). The long-term outcome data from this trial 33 suggest that although the risk of relapse was significantly lower in the daily oral CYC limb (probably attributable to the lower cumulative CYC dose in the IV group), there was no difference in survival. 34 Therapy in localised or early systemic disease
The NORAM (Non-Renal vasculitis Alternative treatment with Methotrexate) study
compared the effectiveness and safety of methotrexate (MTX) plus corticosteroids with oral CYC plus corticosteroids for induction of remission. 6 months after initiation of therapy the remission rate in the MTX group (89.8%) was not significantly lower than in the CYC group (93.5%). Of note, remission was delayed among patients in the MTX group who had more extensive disease or pulmonary involvement. 35
Patients with severe disease (creatinine >500 μmol/l) may benefit from plasma exchange. In the multicentre MEPEX (Methylprednisolone versus Plasma Exchange as additional therapy for ANCA associated glomerulonephritis) trial
137 patients with severe renal vasculitis (serum creatinine >500 μmol/l) were randomly assigned to undergo plasma exchange or receive pulsed methylprednisolone after a standard remission induction regimen. The renal recovery at 3 months was significantly higher in the plasma exchange group (69% vs 49%). 36 Remission maintenance therapy
The conventional remission maintenance drug is AZA. In the CYCAZAREM trial
73 patients were randomly assigned to continue CYC and 71 switched to AZA after remission was achieved with CYC and corticosteroids. No difference was found in the relapse rate between the 2 groups at 18 months (15.5% vs 13.7%) suggesting that CYC can safely be withdrawn following induction of remission and that AZA is an effective remission maintenance drug. 32 Methotrexate (MTX)
MTX has been advocated as an alternative to AZA for maintenance of remission. In the WEGENT (Wegener’s Granulomatosis-Entretien) trial
(following remission induction with CYC and corticosteroids), AZA (2 mg/kg/day) was compared with MTX (≤25 mg once a week) with regard to remission maintenance. Although the two drugs appeared to be similarly efficacious in maintaining remission, the MTX group experienced more serious adverse events. This might be related to the relatively high MTX dose and prevalence of renal impairment in GPA patients. 37 Mycophenolate mofetil (MMF)
The IMPROVE (International Mycophenolate mofetil Protocol to Reduce Outbreaks of Vasculitides) trial
compared the effects of MMF with AZA on the prevention of relapses in patients with AAV. 80 patients were assigned to AZA (starting at 2 mg/kg/day) and 76 to MMF (starting at 2000 mg/day) after induction of remission with CYC and prednisolone. Follow-up was for a median of 39 months. Relapses were more common in the MMF group (42/76 patients) compared with the AZA group (30/80 patients). The trial showed that MMF is less effective than AZA for the prevention of relapses in AAV. 38 Leflunomide (LEF)
In a multicentre prospective randomised controlled trial,
patients with generalised GPA were treated with either oral LEF 30 mg/day or oral MTX (starting with 7.5 mg/week reaching 20 mg/week after 8 weeks) for 2 yrs following induction of remission with CYC. The trial was stopped early because of a statistically significant increased relapse rate in the MTX arm. LEF at a dosage of 30 mg/day appeared to be effective in the prevention of major relapses in GPA; however, this was associated with an increased frequency of adverse events. 39
In conclusion AZA remains the drug of first choice for remission maintenance. MMF, LEF and MTX may all be considered in those intolerant of or refractory to AZA.
Treatment of refractory disease
In disease refractory to standard induction regimen, the addition of a course of intravenous immunoglobulin (IVIg) (total dose 2 g/kg) led to an improvement in disease activity in a placebo-controlled trial of refractory disease, but this was not sustained beyond 3 months. IVIg has also been effective in maintaining remission in relapsing disease.
40,41 Rituximab (RTX)
In GPA and MPA the presence of activated B-cells correlates with disease activity and autoantigen specific B-cells are present at sites of inflammation. The regulation of T-lymphocytes is dependent on B-cell function. B-cell depletion using RTX has therefore been developed as a therapeutic strategy for AAV. At present the main role for RTX is in the treatment of refractory disease (see below).
RAVE and RITUXVAS are two randomised controlled trials that have evaluated the efficacy of B-cell depletion in the remission induction of AAV (Table 2).
The RAVE (Rituximab in ANCA-associated Vasculitis) trial
compared RTX (375 mg/m 42,43 IV weekly x 4) with oral CYC (2 mg/kg/day) in patients with new or relapsing AAV, excluding those with severe renal disease or severe alveolar haemorrhage. Patients were followed for a minimum of 18 months. CYC was replaced by AZA between 3 and 6 months if remission was achieved, and AZA was then continued for a total treatment duration of 18 months, whereas the RTX group received placebo. All patients received 1–3 g IV methylprednisolone followed by 1 mg/kg/day prednisolone tapered over 5.5 months. The primary endpoint was remission defined as BVAS/GPA of 0 in the absence of prednisolone at month 6. 2
197 patients with severe active (mean BVAS/GPA 8.4) GPA or MPA were enrolled (3:1). All patients were ANCA-positive. The groups were matched for disease severity, subtype, organ involvement and ANCA type. Patients with a new diagnosis of AAV comprised 49% of patients in each arm.
64% of the RTX group and 53% of the CYC group achieved primary endpoint at 6 months. At 12 and 18 months, 42% and 36% in the RTX arm compared with 38% and 31% in the CYC arm remained in remission off glucocorticoids. Relapse rates were not different, but relapse was more common in the PR3-positive patients. The average cumulative glucocorticoid dose was significantly lower in the RTX arm (3270 mg vs 3678 mg) by 12 months but not at 18 months. There was no difference in the frequency of adverse events between the two arms at 18 months. A planned subgroup analysis of those entering with relapsing disease demonstrated the superiority of RTX over CYC for this group of patients.
The RITUXVAS (randomized trial of Rituximab versus cyclophosphamide in ANCA-associated Vasculitis) trial
compared an RTX regimen (375 mg/m 44,45 IV weekly x 4 along with 2 x 15 mg/kg IV CYC) to a ‘standard’ IV CYC regimen (6–10 x 15 mg/kg), both with the same IV and oral glucocorticoid regimen, in 44 (33 RTX arm, 11 CYC arm) newly diagnosed patients with AAV and renal involvement, and mean estimated glomerular filtration rate (eGFR) at entry of 21 ml/min. The primary endpoint at 12 months was BVAS=0 for ≥6 months. 2
Initial follow-up at 1 year showed a 76% remission rate in the RTX arm and 82% in the CYC arm. At 2 years the primary composite outcome of relapse, death or end-stage renal failure occurred in 42% in the RTX group compared with 36% in the CYC group. There was no difference in safety.
RTX seems to be as effective as CYC for induction of remission but the expected benefit in reduction of side-effects was not seen, suggesting that many of the side-effects might be due to corticosteroids.
The role of RTX in remission maintenance is uncertain and there is no clear evidence as to the best strategy. There are several possible approaches: (i) treat only on relapse; (ii) treat prophylactically on rising ANCA level; (iii) treat routinely every 4–6 months irrespective of clinical status or ANCA level for 2 years. RTX is however effective at relapse. Jones et al in a single-centre open study compared protocolised retreatment with RTX using 2 x 1 g followed by 1 g every 6 months for 2 years (total 5 g) with early immunosuppression and glucocorticoid withdrawal vs non-protocolised treatment (either 2 x 1 g or 375 mg/m x 4) only repeated at relapse. At 2 years 2 relapse had occurred in 11/49 (22%) patients in the protocol group vs 26/34 (76%) in the non-protocol group. Infection rates were similar (14% vs 18%). 45
There remain concerns about long-term toxicity, especially development of progressive multifocal leucoencephalopathy
in patients with autoimmune disease. Hypogammaglobulinaemia occurs with repeat dosing with ≤47% developing immunoglobulin G (IgG) <7.0 g/l and 4% IgG <3.0 g/l, and is associated with severe infection. Previous immunosuppression is a probable contributor to development of hypogammaglobulinaemia. 46 Late-onset neutropaenia following RTX is well recognised in lymphoma patients and has been reported in 23% of patients receiving RTX for GPA. The median time to onset of neutropaenia in an open study was 102 days and occurrence was associated with B-cell depletion and a significant risk of infection. 47 Treatment with granulocyte colony stimulating factor may be required. 48
In conclusion there are several groups in whom the use of RTX is justified. Patients with relapsing disease who have been treated with CYC respond to RTX and therefore should receive RTX in place of a second or more courses of CYC, because CYC toxicity (infection and bladder cancer) is closely related to cumulative CYC dose. Pre-menopausal women in whom the risk of permanent infertility is high should be considered for RTX as first-line treatment, as RTX is not known to be associated with infertility. The rates of infection are generally low in RTX-treated patients and therefore RTX is also justified first-line in patients at high risk of infection.
49 Other biologics
The anti-tumour necrosis factor (TNF) agent etanercept was not effective in preventing relapse in GPA in a placebo-controlled trial (WGET – Wegener’s Granulomatosis Etanercept Trial)
and its use for remission maintenance is not recommended. Other anti-TNF agents, infliximab and adalimumab, offer a steroid-sparing effect when added to induction regimens for renal vasculitis. Historic, preliminary, studies of T-cell depletion with antithymocyte globulin and alemtuzumab have demonstrated efficacy in refractory disease but severe infections were common. 50
In summary, the role of anti-TNF agents in remission induction is uncertain as the data supporting their use is only from uncontrolled studies. Randomised controlled trials are needed to establish the role of TNF blockers in remission induction. The incidence of adverse effects such as infections, malignancy, autoimmunity and thromboembolic complications are a concern and need to be evaluated further in refractory patients with significant previous exposure to cytotoxic drugs.
Prevention of adverse effects
Despite the developments outlined above, treatment is still associated with significant potential morbidity. Patients receiving CYC should receive co-trimoxazole as prophylaxis against
Pneumocystis jirovecii infection and mesna to reduce the potential risk of haemorrhagic cystitis and bladder cancer. Prophylaxis against osteoporosis should be given where appropriate. Conclusion
ANCA-associated vasculitides are rare diseases, still of unknown aetiology, although since the discovery of ANCA there has been considerable progress towards understanding their pathogenesis. The introduction of immunosuppressant therapy with cyclophosphamide and corticosteroids has dramatically improved the prognosis from conditions with high mortality to chronic diseases with a relapsing and remitting course. These treatment regimens are associated with substantial toxicity and one of the main thrusts of current research is to devise therapies that are substantially less toxic. Rituximab has a role in the treatment of refractory disease; its place in the treatment of new disease and remission maintenance remains to be established.
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