1 Department of Medicine (Box 157), Addenbrooke's Hospital, Cambridge, UK and 2 Division of Medicine, Imperial College London, Hammersmith Hospital, London, UK
Correspondence and offprint requests to: Dr A. D. Booth. Department of Medicine, Box 157, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. Email: tonybooth1{at}yahoo.co.uk
Keywords: ANCA; renal; vasculitis
Introduction
The primary systemic vasculitides are a group of inflammatory diseases of unknown cause, which are usually fatal if untreated. Their classification has been harmonized over the last decade and an evidence base for treatment decisions is emerging. Current therapy saves lives, salvages organ function and reduces morbidity. However, mortality and end-stage renal failure (ESRF) rates remain high, up to 50% relapse and the consequences of treatment-related toxicity rival those of the underlying diseases. There is a need for safer, more effective therapy.
Classification
Primary systemic vasculitides are classified according to their clinical, serological and pathological features. The Chapel Hill Consensus conference defined diagnostic terminology in 1993 [1]. The largest subgroup comprises syndromes associated with circulating anti-neutrophil cytoplasm antibodies (ANCA)ANCA-associated systemic vasculitides (AASV). These include Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), Churg-Strauss angiitis and renal limited vasculitis.
Epidemiology
The annual incidence and point prevalence of renal vasculitis in Europe is 1020/million/year and 150200/million, respectively [2]. Incidence increases with age peaking in those aged 6574. Regional, geographical, ethnic and seasonal differences in disease patterns and increasing incidence have been suggested, but lack confirmation [2]. Renal vasculitis is the most common severe manifestation of AASV, occurring in over 50% at presentation, but in 7085% during the course of the disease [3]. AASV is the major cause of rapidly progressive crescentic glomerulonephritis (80%), and is responsible for 5% of patients on renal replacement therapy.
Aetiology
The aetiology of AASV remains unknown but is likely to be multi-factorial. A few reported familial cases suggest a genetic contribution to the pathogenesis, but results of major histocompatibility complex associations with vasculitis have been conflicting. ANCA-induced neutrophil activation is dependent on interaction with Fcg receptors on the neutrophil surface, which show functional polymorphism. Although no skewing was observed with the FcRIIa, Fc
RIIIa and Fc
RIIIb phenotype, the presence of homozy-gous Fc
RIIa-H/H131 alleles in combination with Fc
RIIIa-V/V158 polymorphism may be a significant risk factor for WG [4], and has been associated with stronger binding affinity to IgG3 and a reduced relapse rate. Polymorphisms within the ANCA autoantigen proteinase 3 protease inhibitor,
1 anti-trypsin, are found at increased frequency in patients with WG, but do not predict either the development of AASV or disease severity [5]. Other suggested genetic polymorphisms include CTLA-4 and cytokine polymorphisms [6]. Casecontrol studies have highlighted the environmental association of AASV with silica and this is supported by reports of a doubling in MPA incidence following the Kobe earthquake [7,8]. Certain drugs including propylthiouracil, penicillamine and hydralazine are associated with AASV.
Some reports have suggested a higher rate of AASV in the winter months, but no clear infectious link has been made. Nasal staphylococcus carriage is a risk factor for relapse in WG and the use of the antibiotic sulfamethoxazole/trimethoprim has been associated with a reduction in disease relapse [9].
Diagnosis
The specificity of ANCA has been improved by use of autoantigen-specific ELISAs for proteinase 3 (PR3) and myeloperoxidase [10]. Positive results have a sensitivity of over 70% and specificity for vasculitis of 99% depending on the clinical setting. In a patient with suspected nephritis, the sensitivity rises to 95%, rendering urgent renal histology less important. Furthermore, the combination of a positive ANCA and haematuria has positive and negative predictive values of 95 and 85%, respectively, depending on the severity of the renal dysfunction [11].
Pathogenesis
The characteristic histological finding in renal AASV is a pauci-immune, necrotizing, crescentic glomerulonephritis (GN), but 1418% of biopsies have evidence of immune complex deposition, the significance of which remains unclear [12]. In addition to the neutrophil predominant infiltrate, there are increased tissue and circulating levels of inflammatory cytokines, such as tumour necrosis factor alpha (TNF), leucocyte-derived proteases and markers of endothelial activation. Furthermore, renal disease activity may be related to urinary levels of monocyte chemotactic protein-1.
In vitro studies have focused on the central pathogenic role of the ANCA-neutrophilendothelial interaction. Indeed, ANCA induces a respiratory burst from TNF primed neutrophils, and release of other cytokines and proteases, together resulting in neutrophil-mediated endothelial cell injury and apoptosis [13]. TNF
induces translocation of autoantigens to the cell surface and facilitates engagement of IgG-ANCA through increased signalling by ß2 integrins and Fc
RIIIb. The stability of neutrophil membrane expression of PR3 (mPR3) depends on the association with the integrin, Mac-1 and the soluble endothelial protein C receptor (sEPCR). Interestingly, both the large mPR3+ membrane subset and rising serum sEPCR predict disease relapse, suggesting that the ANCAPR3 interaction is not the only contribution of this autoantigen to the pathogenesis [14].
Several newer animal models support both the pivotal role played by the neutrophil in vasculitic damage and the pathogenic role of ANCA in pauci-immune glomerulonephritis [15]. Furthermore, the observed dose-dependent augmentation of the renal manifestations in TNF-treated rodents has also been abrogated by anti-TNF
therapy [16].
Outcome
Mortality
Untreated these conditions have an 80% 1 year mortality. The introduction of steroids, azathioprine and cyclophosphamide has led to a progressive reduction in fatalities. Indeed, retrospective cohort studies of renal vasculitis from the 1990s, reported a 1 and 5 year survival of 84 and 76%, respectively [17]. Predictors of death include increasing age and creatinine (Cr) at presentation, disease extent and severity at diagnosis [either measured by Birmingham Vasculitis Activity Score (BVAS) or the disease extension index] [18], and treatment-related infection.
Renal outcome
The success of current therapy is tempered by the development of ESRF in 2025% of the survivors. Histological features at diagnosis are predictive of renal outcome. Acute lesions (cellular crescents and fibrinoid necrosis) are positively correlated with renal recovery and the degree of chronicity (glomerulosclerosis, interstitial fibrosis and tubular atrophy) negatively correlated with renal outcome in patients with Cr <500 µmol/l at presentation [19]. Other predictors of renal outcome include the level of presenting Cr, proteinuria and renal relapse. Furthermore, the levels of PR3-ANCA at diagnosis predict both treatment response and renal outcome [20]. The disease variables have been integrated with histological features to produce a predictive tool for glomerular filtration rate at 18 months [21]. In prospective trials, conventional therapy arrests further deterioration and partially salvages renal function in the majority of those presenting with an elevated Cr [22].
Relapse
After control of the acute presentation, vasculitis has become a chronic disorder associated with renal and extra-renal relapse rates of 50% by 5 years and in consequence, accumulating disease-related morbidity and treatment-related toxicity [23]. Risk factors for relapse include a diagnosis of WG or PR3-ANCA at diagnosis, the persistence of, or rise in, ANCA levels during clinical remission, reduction or withdrawal of immune suppressive therapy, and nasal carriage of Staphylococcus aureus in WG [9]. Two prospective studies have shown that at least 65% of relapses are preceded by an ANCA rise and at least 60% of ANCA rises are followed by a relapse [24,25]. The low sensitivity and specificity of ANCA ELISA in this context may be improved by the capture ELISA technique [26]. Rises in ANCA should raise suspicion of a future relapse and subsequent augmentation of therapy may lead to reduced relapse rates [27].
Therapy
Current treatment
Combination therapy with cyclophosphamide and prednisolone is the current standard treatment for active renal vasculitis, although the optimal dose, route of administration, duration and adjuvant role of plasma exchange (PE) remains poorly defined. The European Vasculitis Study Group (EUVAS) has published consensus protocols and sought to harmonize therapy through randomized controlled trials [28]. In these studies patients with AASV were sub-grouped at entry, according to disease severity into those with no or minimal renal disease, moderate renal vascultis (Cr <500 µmol/l) and severe renal (Cr >500 µmol/l) disease.
Remission induction
Retrospective series have reported remission rates of over 85% in patients with renal vasculitis, using prednisolone and daily, oral cyclophosphamide. Using this regimen, the recently reported prospective randomized control trial CYCAZAREM (n = 144, mean presenting Cr = 212 µmol/l) demonstrated a remission rate of 93% and mortality of 7% at 6 months. There were no primary treatment failures [22].
The toxicity associated with cyclophosphamide administration has prompted studies of alternative immunosuppression, such as methotrexate (MTX) as therapy for patients with early or no renal disease. A randomized trial from the EUVAS group reported similar efficacy between MTX and cyclophosphamide for remission induction in those with no or minimal renal vasculitis. However, after treatment withdrawal, relapse was more frequent in the MTX group.
In a further effort to lower the burden of cyclophosphamide exposure and associated toxicity, the use of pulsed rather than continuous administration has been proposed. Four randomized trials have tried to address whether pulse intravenous cyclophosphamide might be superior to daily oral for the induction of sustained remission [2932]. None of the trials were sufficiently powered to detect differences in efficacy between the treatments. However, a recent meta-analysis suggested that intravenous pulsed cyclophosphamide is as effective and associated with fewer severe infections, but at the expense of a higher relapse rate [33]. An ongoing multi-centre EUVAS trial of pulsed versus oral cyclophosphamide (CYCLOPS) is due to report shortly [34].
Remission maintenance
The high relapse rates (3050%) argue for prolonged treatment with a safer immunosuppressive agent, such as azathioprine or MTX. The CYCAZAREM trial compared azathioprine from 3 months to continued cyclophosphamide and found no difference in relapse rate (1415%) between the two groups at 18 months [22]. Uncontrolled studies have produced conflicting results as to the efficacy of MTX in preventing the development of renal disease [35,36].
Severe renal disease
Patients presenting with severe renal disease (Cr >500 µmol/l) have a particularly poor outcome and early additional intervention may reverse renal inflammation, minimize damage and improve prognosis. The addition of pulsed intravenous methyl prednisolone and PE has been reported to improve the chances of renal recovery [37]. A preliminary report of a randomized trial by the EUVAS Group in those presenting with a serum Cr >500 µmol/l found a higher rate of sustained renal recovery after seven PEs as compared to 3 g of methyl prednisolone [34].
Adverse events
Treatment-related toxicity directly alters outcome. Indeed, the frequency of adverse events is associated with severity of the presentation, in particular to renal impairment, age, cyclophosphamide-induced leucopaenia and the level of concurrent steroid exposure. In addition, the high relapse rate increases the potential for disease scarring and toxicity of treatment.
Immunotherapy in renal vasculitis
The need for safer treatments and to optimize renal recovery in those presenting with advanced renal failure has inspired the evaluation of alternative agents. Preliminary studies suggest the addition of anti-TNF therapy to conventional agents may improve efficacy and reduce steroid requirements [38]. T-cell depletion with CAMPATH-1H or anti-thymocyte globulin and B-cell depletion using rituximab, an anti-CD20 antibody, has been safely and successfully administered to patients with relapsing disease [39,40]. The role of these and alternative immunosuppressive drugs, such as mycophenolate mofetil and deoxyspergualin [41] await confirmation in large randomized trials.
Summary
Patient survival and risk of ESRF are closely related to Cr at diagnosis, and indirectly, to diagnostic delay. There is now widespread agreement on classification and terminology in vasculitis and together with the ANCA test, these are facilitating earlier diagnosis. Treatment is entering a transitional phase with harmonization of traditional immunosuppressive and steroid regimens, at the same time as the introduction of novel, more focused, agents. Clinical trial methodology in vasculitis has been developed and is being refined to permit the more rapid introduction of better therapies into routine practice. Early referral and institution of appropriate therapy remain the most important elements in achieving a good outcome.
Conflict of interest statement. None declared.
References