1 Ipswich Hospital, Ipswich,
2 School of Health, University of East Anglia, Norwich,
3 Norfolk & Norwich Hospital, Norwich,
4 Imperial College School of Medicine, London and
5 Cambridge University School of Medicine, Cambridge, UK
The vasculitides are a heterogeneous group of uncommon conditions characterized by inflammation and necrosis of blood vessels. The clinical features are determined to a large extent by the size and distribution of the vessels involved. There have over the past few years been important advances in our understanding of the aetiology, assessment, classification and treatment of vasculitis and these should hopefully lead to the more appropriate use of specific targeted therapies in our patients.
In common with other systemic disease, the aims of therapy fall into three categories: (i) induction of remission; (ii) maintenance of remission; and (iii) prevention of relapse, all of which should be undertaken with minimal mortality and morbidity either from the disease itself or the therapy. Accurate assessment of specific organ involvement and disease severity is vital if we are going to tailor appropriate therapy to the appropriate patient.
The introduction of prednisolone and cyclophosphamide in the 1970s dramatically improved survival. The natural history of untreated primary systemic vasculitis (i.e. Wegener's granulomatosis, ChurgStrauss syndrome, microscopic polyangiitis and polyarteritis nodosa) is of a rapidly progressive, usually fatal disease with a 5-yr survival of only 10% [1]. The problem of interpreting the early literature is that most vasculitides were called polyarteritis nodosa and modern classifications separating the different diseases are relatively new. Corticosteroids improved the 5-yr survival rate to 55%. This 5-yr survival was further improved, following the introduction of cyclophosphamide, to 82% [2]. In most modern series, over 80% of patients with Wegener's granulomatosis and classical polyarteritis nodosa survive for over 5 yr and 75% of Wegener's granulomatosis patients survive for 10 yr [3]. The outcome for microscopic polyangiitis is less good with a 5080% 5-yr survival [3]. Relapse occurs in most cases of primary systemic vasculitis and can occur during maintenance therapy or after withdrawal of treatment. The clinical features of relapse may differ from those at presentation with new organ involvement. There is a continual relapse rate which does not decrease with time, unlike mortality. The highest mortality is seen early but there is relatively little mortality directly attributable to active vasculitis after 4 yr [3].
The improved survival has changed our perception of the vasculitides from acute systemic disease with a high mortality to chronic diseases which relapse and remit. We are now seeing the long-term consequences arising from relapsing disease with organ damage and side-effects of therapy (e.g. malignancy, sterility). Current treatment protocols and trials are designed to establish whether lower doses of cytotoxic agents are as effective at inducing and maintaining remission as more traditional long-term cytotoxic therapy.
The accurate assessment of patients is vital to successful management; this includes the detection of specific organ involvement, assessment of the severity of the inflammatory response and assessment of damage as a consequence of vasculitis. Organ involvement can be determined by simple measures such as clinical examination, urinalysis, chest and sinus radiography. In all cases it is essential to exclude other possible diseases which can mimic vasculitis, especially infection. More recently, radiolabelled white cell scanning techniques have been developed which enable detection of active disease in otherwise unsuspected places, for example detecting nasal inflammation in patients with Wegener's granulomatosis [4]. Techniques to monitor endothelial cell function using probes attached to cellular adhesion molecules are being developed but remain a research tool [5].
The measurement of the severity of the inflammatory response is usually assessed by non-specific means such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). The acute phase response may be raised by concurrent infections or by other systemic diseases (e.g. rheumatoid arthritis).
Following the discovery of antineutrophil cytoplasmic antibodies (ANCA) and their association with systemic vasculitis [6], there has been much interest in the use of ANCA to detect relapse, with conflicting reports. Cohen Tervaert et al. [7] performed a meta-analysis of studies on ANCA with relapse and found a sensitivity of 48% (94 of 197 increases in ANCA were followed by a relapse) and specificity of 52% (81 of 157 relapses were preceded by an increase in ANCA titre). The pragmatic conclusion is that a rising ANCA titre may herald a flare and should serve to heighten vigilance, but therapy ought not to be escalated solely on the basis of a change in ANCA titre.
The accurate assessment of disease activity and damage resulting from disease or therapy has been considerably improved by the development of validated scoring systems such as the Birmingham Vasculitis Activity Score (BVAS) [8]. Disease attributable to active vasculitis must be distinguished from damage caused by previously active disease. Damage occurs early and is associated with a poor outcome [9]. Significant pulmonary involvement, especially haemorrhage, and evidence of multiple system involvement are also indicators of poor outcome. The vasculitis damage index has been designed to measure the impact of scars from previous disease or treatment [10]. The BVAS has recently been incorporated into the VITAL score (vasculitis integrated assessment log) which has three componentsactivity, damage and function [11]. The third component of this score is the SF-36 instrument which is a generic assessment of function which has also been validated for use in vasculitis patients. These scoring systems have been carefully validated for both inter- and intra-observer error and are suitable for use by most clinicians after some initial training.
Progress in the standardization of assessment has permitted the development of multicentre trials with agreed systems of objective assessment. Before these could successfully be established it has been necessary to agree on a system for diagnosis and classification. The classification of vasculitis either by vessel size [12] or association with ANCA continues to cause much debate amongst interested physicians, unfortunately much of this is sterile and resembles mediaeval theologians debating how many angels could dance on the head of a pin! The American College of Rheumatology (ACR) 1990 classification criteria [13] and the Chapel Hill Consensus Conference 1994 (CHCC) [14] definitions, whilst not perfect, have at least produced some degree of uniformity so that groups around the world can compare patients easily. Using these criteria/definitions in practice is less easy as the ACR criteria were developed by comparing patients with different types of systemic vasculitis and have not been adequately tested in patients without confirmed vasculitis where they do not appear to perform so well [15]. The CHCC definitions were not supposed to be used for classification, but in practice are, as there is no alternative definition for microscopic polyangiitis. A challenge to the vasculitis community is to produce classification criteria which are validated against unselected vasculitis patients. Current classification may in the future appear naive when there is better understanding of the true aetiopathogenesis of these conditions.
The elements are now in place for progress in treatment. Prednisolone and cyclophosphamide were clearly a major advance, but the improvement in survival has been achieved with significant treatment-related morbidity. Much of this is related to the doses of prednisolone and cyclophosphamide used to induce and maintain remission. Regimens have been developed to reduce the total dose of cyclophosphamide, either by reducing the duration of therapy [as in the recently completed European Union (EU)-sponsored trial Cycazarem] or by using intermittent pulse therapy. Pulse intravenous cyclophosphamide is probably equally effective as oral cyclophosphamide at inducing remission and both regimens are associated with a 1-yr survival of 84% [16]. Pulse therapy may be associated with more relapses (usually mild) but is also associated with less toxicity, probably due to the lower total dose of cyclophosphamide administered. Remission is usually maintained by continuing cyclophosphamide for 36 months before changing to a combination of azathioprine and low-dose prednisolone as maintenance therapy. More prolonged use of continuous oral cyclophosphamide leads to an unacceptable level of side-effects, particularly haemorrhagic cystitis and bladder malignancy. During the maintenance phase the doses of azathioprine and prednisolone are gradually reduced depending on the clinical condition. Vigilance must be maintained as relapse may occur at any time. At present, cyclophosphamide combined with corticosteroids remains the treatment of choice for the majority of patients with active systemic vasculitis.
Weekly low-dose methotrexate has been used by several groups to control non-life- or organ-threatening disease in Wegener's granulomatosis. De Groot et al. [17] have shown that methotrexate is effective in preventing relapse with or without the concomitant use of prednisolone, and in open studies 6071% of patients achieved remission when methotrexate was used as initial therapy [18, 19]. Hoffman et al. [20] have also reported that methotrexate is effective at inducing remission and minimizing corticosteroid toxicity in Takayasu arteritis. Methotrexate may therefore be considered as an acceptable alternative to azathioprine for the maintenance of remission but whether it is as effective as cyclophosphamide in inducing remission is unknown.
Other less immunosuppressive and less aggressive treatments have been used, especially in Wegener's granulomatosis involving the upper and lower respiratory tracts. Chronic nasal carriage of Staphylococcos aureus in these patients has been associated with relapse leading to the use of antibiotics such as trimethoprim/sulphamethoxazole (co-trimoxazole) as treatment [21]. Stegeman et al. [22] reported that the addition of co-trimoxazole to therapy with cyclophosphamide and prednisolone reduced the relapse rate. Co-trimoxazole alone or combined with prednisolone only is not effective at preventing relapses in patients in remission [17].
Intravenous immunoglobulin (IVIg), in combination with other immunosuppression, has been used to treat patients with refractory disease. Remission at 2 months has been described in 50% of patients and has been maintained for 1 yr [23]. In six patients with previously untreated disease, IVIg successfully induced remission which was maintained for 1 yr [24]. Plasma exchange may also have a place in the treatment of severe disease, especially advanced renal failure. One trial showed that patients on dialysis at the start of treatment were more likely to regain renal function if treated with plasma exchange in addition to prednisolone and cyclophosphamide [25].
Humanized monoclonal antibodies have been used to treat patients with refractory Wegener's granulomatosis [26]. In 17 patients, antibodies against the lymphocyte surface molecules CD52 and CD4 were used, in 16 remission (programmed withdrawal of drug therapy without return of refractory disease) was achieved. Nine patients relapsed, but this was controlled by a further course of monoclonal antibody therapy. More recently the use of monoclonal antibodies has been combined with semi-specific immunoabsorption using L-tryptophan to remove circulating ANCA. Three of four patients so treated responded with clinical improvement and depletion of circulating ANCA [27].
The relative rarity of the primary systemic vasculitides (overall incidence 20/million [28]) means only large multicentre studies can hope to address the therapeutic problems posed above. Within Europe we are fortunate to have a series of trials sponsored by the EU addressing these issues [29]. The current trials include comparison of oral vs intravenous cyclophosphamide, methotrexate vs cyclophosphamide in early mild disease and additional methylprednisolone or plasma exchange in severe renal disease. It behoves us as clinicians to enter as many patients as possible into these trials to permit rapid establishment of a sound evidence base on which to treat our patients.
The systemic vasculitides continue to pose a challenge to clinicians. Over the past few years there have been significant advances in our understanding of pathogenesis and treatment. These advances will hopefully in the next few years lead to more specific and targeted treatments, with consequent improvements in clinical outcomes. The recent symposium VasculitisAims of Treatment addressed many of the most exciting recent developments. Over subsequent months, starting in this issue, we will be publishing a series of educational review articles covering some of the more important aspects of disease management and assessment.
Notes
Correspondence to: R. A. Watts, Department of Rheumatology, Ipswich Hospital, Heath Road, Ipswich IP4 5PD, UK.
References