Renal Section, Imperial College School of Medicine, Hammersmith Hospital, Ducane Road, London, UK
Keywords: ANCA; cyclophosphamide; immunosuppression; intravenous immunoglobulin; leflunomide; mycophenolate mofetil
Introduction
Vasculitides associated with anti-neutrophil cytoplasm antibody (ANCA) are increasingly recognized. Over the last decade there has been a concerted attempt at clarifying definitions of vasculitis [1], improving diagnosis on the basis of serological testing [2], and determining disease activity by scoring systems [3]. The next major developments will be in identifying treatment strategies best suited to different disease states, and in particular those that minimize treatment toxicity. The importance of distinguishing initial acute disease from chronic phases of vasculitis has become increasingly clear, and different regimens are necessary during induction and maintenance phases of treatment. The current European multi-centre controlled trials, coordinated by the European Vasculitis Study Group (EUVAS) (due to report over the next few years), will provide more definitive answers to some of the most difficult questions with respect to the treatment of patients with ANCA-associated vasculitis [4]. However, over the last couple of years an increasing amount of data on a variety of new approaches has been made available.
Old drugs: new data
Cyclophosphamide
The combination of steroids and cyclophosphamide has been the mainstay of treatment for both microscopic polyangiitis and Wegener's granulomatosis since first reported by Fauci et al. in the 1980s [5]. This combination can induce remission in the majority of patients (7085%). However, the initial National Institutes of Health protocol used oral cyclophosphamide for many months, and subsequent studies have documented significant morbidity attributable to long-term continuation of treatment with the drug [6]. Bone marrow suppression, urothelial injury, urothelial transitional cell carcinomas and infertility are all common complications of long-term use. A number of studies have attempted to reduce the toxicity of cyclophosphamide by giving it as monthly intravenous pulses [7,8]. Results are conflicting, but suggest that the cumulative dose of cyclophosphamide is reduced with monthly pulses (rather than daily oral dosing) and that this is associated with a decrease in leukopenia and reduced incidence of serious infections. Remission of initial disease may be less likely, however, and relapses may be more common with an intermittent treatment schedule. The ongoing EUVAS CYCLOPS trial will randomize 160 patients between pulsed and daily cyclophosphamide regimens to determine their efficacy and safety during induction of remission.
The CYCAZAREM (cyclophosphamide versus azathioprine for early remission phase of vasculitis) trial examined whether azathioprine was as effective as cyclophosphamide in maintaining remission and preventing relapses in ANCA-associated systemic vasculitides, but with fewer side effects [4]. One hundred and forty-one patients with threatened vital organ function and creatinine levels <500 µmol/l were randomized after induction of remission (with oral prednisolone and daily oral cyclophosphamide) to either treatment with continued oral cyclophosphamide for 12 months, or azathioprine. Twelve relapses occurred in cyclophosphamide-treated patients (17%), 11 in those receiving azathioprine (16%), and one patient died in each group. Short-term adverse effects were distributed equally, but there was a trend towards more severe adverse effects in cyclophosphamide-treated patients. There was no significant difference in serum creatinine levels, Birmingham vasculitis activity scores (BVAS) or vasculitis damage index (VDI) scores at 18 months. Given the equal efficacy of both treatments, and the known long-term safety profile of azathioprine compared with cyclophosphamide, this trial has clearly established the superiority of azathioprine over cyclophosphamide for preventing relapse after initial induction of remission in ANCA-associated disease. The optimum duration of treatment is the subject of a separate EUVAS trial.
Plasma exchange
The place of plasma exchange in the treatment of ANCA-associated disease remains controversial. Evidence from three controlled trials and several uncontrolled studies [9] suggests that plasma exchange (in addition to steroids and cyclophosphamide) only provides benefit in patients requiring dialysis at presentation, but in this cohort may confer a significantly increased chance of renal recovery. Gaskin et al. recently reported their experience in treating >70 patients with ANCA-associated vasculitis and severe renal failure, all of whom received at least five plasma exchanges in addition to oral immunosuppression [10]. Seventy-five per cent of dialysis-dependent patients recovered renal function and 83% of respondents had independent renal function at 5 years. Anecdotal evidence supports an additional role for plasma exchange in patients with pulmonary haemorrhage. The multi-centre European MEPEX trial (methyl prednisolone versus plasma exchange as additional therapy for severe ANCA associated glomerulonephritis) has attempted to define the role of plasma exchange in patients with ANCA-associated vasculitis and an initial creatinine level of >500 µmol/l. One hundred and fifty patients have been randomized to receive either intravenous methylprednisolone or plasma exchange as initial treatment, in addition to oral cyclophosphamide and prednisolone, and results should be available in 2001.
Cyclosporin
Little new data is available on the use of cyclosporin. Haubitz et al. treated seven patients after inducing remission with 6 months of combined cyclophosphamide and steroid treatment [11]. Cyclosporin treatment was continued for 1 year and blood levels were maintained between 60 and 90 ng/ml. None of the patients suffered a relapse during the year of follow up. This is a very small and short-term study, but supports data showing low rates of relapse in patients with vasculitis receiving cyclosporin after renal transplantation.
Old drugsnew uses
Intravenous immunoglobulin
A number of studies have reported beneficial effects of intravenous immunoglobulin (IVIG) in patients with chronic grumbling vasculitis despite more conventional treatments or in patients with acute disease. Jayne et al. conducted a small controlled trial of IVIG given as a single dose of 2 g/kg body weight in patients with chronic active disease. Fourteen of 17 patients given IVIG showed improvement compared with only six of 17 given placebo [12], but the effect was often short-lived. Schoenfeld et al. used monthly IVIG (2 g/kg) given over 5 days to 13 patients with vasculitis, after other treatments had failed to control disease [13]. Eight patients had a beneficial outcome, but relapses were common. The mechanism of action is not known, but may include Fc receptor blockade, or complement regulation or an anti-idiotype effect. A major concern over IVIG preparations has been the risk of acute renal failure, which may be increased in patients with pre-existing renal disease.
Methotrexate
Methotrexate has been used in patients with extra-renal vasculitis in particular because of concerns over correct dosing in patients with renal impairment. It is usually given at 0.3 g/kg/week (20 mg/week) and can induce remission in 70% of patients [14]. Relapses, however, are common during therapy (58% of patients in one study). Adverse effects include leukopenia, minor abnormalities in liver function tests and pneumonitis. EUVAS are currently enrolling patients into a controlled trial of methotrexate compared with cyclophosphamide as induction therapy in (non-renal) vasculitis (NORAM trial; Non-renal Wegener's alternatively treated with methotrexate).
New drugsnew uses
Mycophenolate (MMF)
MMF has been used to treat patients with a variety of immune-mediated nephritides, including lupus nephritis, other proliferative glomerulonephritides and ANCA-associated vasculitis. Nowack et al. treated 11 patients with severe vasculitis with MMF, after induction of remission with cyclophosphamide and prednisolone [15]. All but one patient remained in remission without relapse for 15 months. Nachman et al. reported the use of MMF in 12 patients with persistent or relapsing non-life-threatening vasculitis. All but one had an improvement in clinical vasculitis score (BVAS), six achieved a remission, but four subsequently relapsed [16]. Finally, Stegeman et al. have used MMF for induction of remission in patients with active Wegener's granulomatosis who were intolerant of cyclophosphamide [17]. Eleven achieved complete remission, two partial remission, and three subsequently relapsed. Side effects include leukopenia, anaemia, abdominal pain and diarrhoea, and are often dose-related. MMF could therefore have a place in the treatment of vasculitis in remission (although it is much more expensive than azathioprine and there is no data suggesting superior efficacy), or more importantly in patients with chronic active disease unresponsive to cyclophosphamide, or in whom further courses of cyclophosphamide would be inappropriate.
Deoxyspergualin (DSG)
The mechanism of action of DSG is not entirely clear, but includes inhibition of IL1 synthesis and anti-proliferative effects. Studies in transplant recipients have shown its efficacy in treating steroid-resistant acute rejection. Birck et al. treated 20 patients with relapsed vasculitis who could not receive a further course of cyclophosphamide, using subcutaneous DSG [18]. Treatment was continued for 1419 days or until the white cell count reached 3x109/l, and then withheld for the next 2 weeks. Complete remission was attained and maintained in five patients, partial remission in seven, and disease progressed in five patients. Adverse effects include leukopenia, thrombocytopenia, hot flushes and infections. DSG may increasingly be used for resistant vasculitis, but the mode of administration and leukopenia are potential drawbacks.
Leflunomide
Leflunomide inhibits pyrimidine nucleotide synthesis, inhibits proliferation of activated lymphocytes, and reduces IL2, TGF and antibody production. Only a single report has documented the use of leflunomide in patients with vasculitis. Fourteen patients were treated after induction of remission with cyclophosphamide and prednisolone, and none relapsed during 12 months of follow up. There is an increasing amount of literature on the use of leflunomide in rheumatoid arthritis, including at least two large randomized trials in which leflunomide was as efficacious as conventional disease-modifying drugs. Adverse effects include diarrhoea, nausea, alopecia, transient abnormalities in liver function tests, infections and pancytopenia.
Entirely new approaches
Lymphocyte depletion using monoclonal antibodies (for example CAMPATH 1Hanti-CD52 pan lymphocyte antigen, or anti-CD4) has been reported in a handful of patients with relapsing or persistent disease [19]. Anti-thymocyte globulin (ATG) has been used in at least 10 patients with refractory disease with limited success (one complete remission, eight partial remissions, four patients relapsed after 12 months) [20], and is the subject of another EUVAS trial. At least five patients have been treated with an anti-CD18 monoclonal antibody (against a ß2 integrin adhesion molecule) with clinical improvement in four [21]. More specific approaches include co-stimulation blockade (with anti-CD40 ligand for example) to prevent antigen-driven immune responses, and anti-TNF antibody therapy (as currently used in rheumatoid arthritis and Crohn's disease). In view of the importance of ANCAs themselves in the pathogenesis of vasculitis, semi-specific removal of these antibodies has been attempted using L-tryptophan immunoadsorption [22], and more specifically with myeloperoxidase (MPO)-bound immunosorbent columns to remove anti-MPO ANCAs [23]. Finally, a few patients with severe disease have received immunoablation with autologous bone marrow stem cell transplant, with only short-term benefit.
Conclusion
Treatment of ANCA-associated vasculitis remains a challenge. Current treatments can be very successful in inducing remission, but with significant risk of infective complications in particular. Long-term treatment is necessary to maintain remission and prevent relapses, and here the balance must be struck between disease suppression and treatment toxicity. The vasculitides are relatively rare, with an incidence of 20 new cases per million population per year, and are heterogeneous in their presentation; hence the importance of well conducted, multi-centre collaborative trials to identify promising new therapies, and to maximize the benefit of existing treatment regimens. The EUVAS trials should provide some definitive answers.
Notes
Correspondence and offprint requests to: Jeremy Levy, Renal Section, Imperial College School of Medicine, Hammersmith Hospital, Ducane Road, London W12 ONN, UK.
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