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Newer therapies for vasculitis
Best Practice & Research Clinical Rheumatology 23 (2009) 379–389
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Newer therapies for vasculitis Thomas F. Hiemstra, MRCP, Research Fellow in Nephrology, David Jayne, MD, FRCP, Consultant in Nephrology and Vasculitis * Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK
Keywords: alemtuzumab clinical trials etanercept infliximab intravenous immunoglobulin leflunomide mycophenolic acid plasma exchange rituximab stem cell transplantation therapy tumour necrosis factor vasculitis
There is a clear unmet need in the therapy of vasculitis reflecting the toxicity and partial efficacy of conventional agents. Vasculitis is a complex area for the evaluation of newer therapies due to the heterogeneity between and within syndromes with multisystem manifestations. Much of the evidence supporting newer therapies comes from small, non-randomised trials and is insufficient to permit firm recommendations. Newer immunosuppressive drugs, including mycophenolic acid and leflunomide, are alternative second-line agents to methotrexate and azathioprine. Plasma exchange appears to have a role in severe renal vasculitis and vasculitis caused by circulating immune complexes, but evidence supporting other indications is weak. In contrast to most other therapies, intravenous immunoglobulin (Ig) does not affect infective risk and is an alternative agent for refractory disease where standard approaches are contraindicated. The role of tumour necrosis factor blockade remains unresolved with important negative studies, but the therapeutic rationale persists and positive non-randomised trials are also under way. Experience with more aggressive immunosuppression, such as, T-cell depletion or autologous stem cell transplantation has been limited to a few centres. B-cell depletion with rituximab is currently attracting most attention with good success rates in small studies of refractory disease. The treatment of vasculitis in the future will become more complex with a wider range of available treatments; their optimal combination, sequencing and tailoring to the individual clinical situation will place unique demands on those delivering vasculitis services. Ó 2009 Elsevier Ltd. All rights reserved.
* Corresponding author. Box 118, Renal Unit, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK. Tel.: þ44 1223 586 796; Fax: þ44 1223 586 506. E-mail address: [email protected] (D. Jayne). 1521-6942/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.berh.2009.01.005
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The different vasculitis syndromes Much of the experience of newer therapies has been with primary vasculitis that predominantly affects small blood vessels and is associated with anti-neutrophil cytoplasmic antibodies (ANCA). The ANCA vasculitides (AAV) include Wegener’s granulomatosis, microscopic polyangiitis (and its renallimited variant) and Churg–Strauss angiitis. This experience also reflects the stronger evidence base of standard therapies for ANCA vasculitis which permits comparisons to be made with studies of newer agents. There is considerably less study of large-vessel vasculitides and of secondary vasculitis, and by their nature, rare vasculitis syndromes are difficult to study. The extent to which results in ANCA vasculitis can be extrapolated to other vasculitis syndromes is uncertain and it cannot be assumed that success in one syndrome will be reflected in another. Vasculitis syndromes have been defined according to the nature of their pathology. An understanding of the pathogenesis of a vasculitis syndrome, such as the role of ANCA in AAV, provides a rationale for targeted therapy, for example, B-cell depletion with rituximab aimed to reduce autoantibody production [1]; however, this understanding remains limited and the actual therapeutic mechanisms may be quite different. On the other hand, the targeted nature of monoclonal-antibodybased therapies permits exploration of pathogenesis as the activity of a specific immune or inflammatory component, for example, tumour necrosis factor (TNF), is modulated. Vasculitis syndromes differ in their steroid responsiveness, in their demography and patterns of organ involvement, for example, between giant cell arteritis (which affects the elderly, reliably responds to glucocorticoids and spares the kidneys) and AAV (which affects a wider age group, requires an immunosuppressive agent and commonly causes renal vasculitis). Furthermore, there is considerable inter-patient variability in the severity and extent of disease. This heterogeneity between and within syndromes makes vasculitis a challenging scenario for the introduction of newer agents. Areas of unmet need Current therapy has dramatically changed the prognosis of vasculitis from a usually fatal condition to one that can be controlled, but is limited by both only partial efficacy and high levels of toxicity (Table 1) [2]. Despite optimal standard therapy, remission of disease is incomplete in 20–30%, and a smaller proportion progress to more severe disease. Active disease is the second most common cause of death in vasculitis patients, especially in the first year after diagnosis [3]. Remission is often slow, requiring at least 3 months of therapy, by which time irreversible damage has usually occurred. It is possible that more rapid remission induction will salvage organ function and reduce long-term organ dysfunction. By 5 years after diagnosis, 50% of patients will relapse in spite of at least 2 years of therapy, indicating a failure of current therapies to correct the underlying immunopathogenicity of vasculitis [4]. Approximately 25% will pursue a refractory course manifested by incomplete disease control or frequent relapses despite remission-maintaining therapy. The quality of life of vasculitis patients remains depressed for at least a year after diagnosis, although the causes are likely to be multifactorial,
Table 1 The areas of unmet need in vasculitis. Induction phase (0–6 months)
Maintenance phase (beyond 6 months)
Failure to control progressive disease (5–10%) Failure to induce remission (10–20%) Delay in achieving remission
Failure to prevent relapse, 50% by 5 years
Failure to prevent accrual of irreversible organ damage Drug-related toxicity (>90%) Failure to tolerate therapy Non-drug-related severe adverse events (e.g., cardiovascular events, thrombo-embolic disease)
Requirement for prolonged therapy to prevent relapse (immunosuppressive and glucocorticoid drugs) Morbidity related to irreversible organ damage Drug-related toxicity (>90%) Failure to tolerate therapy Increased risk of cardiovascular events Increased malignancy risk Depressed quality of life
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a slow response to induction therapy, on-going subclinical disease activity and relapse will contribute. Cardiovascular, and probably malignancy, risk are considerably increased in vasculitis patients; the former is likely to be influenced by the quality and rapidity of disease control because surrogates of cardiovascular disease, such as endothelial dysfunction, correlate with vasculitic activity [5]. The toxicity of current therapy causes adverse effects and limits dosing, thereby impairing its efficacy. Over 90% of patients will experience drug-related toxicity, which is severe in 25–50% [6]. Infection is the most common cause of death in the first year and is strongly associated with cyclophosphamide-induced leukopaenia [4]. A very high rate of malignancy has been reported in older regimens employing prolonged treatment with cyclophosphamide [7]. Although more recent strategies, including switching to an alternative immunosuppressive at the time of remission or using intravenous pulsed cyclophosphamide, have reduced the malignancy risk, nevertheless, it remains present [3,8]. Glucocorticoid dosing remains high, typically commencing at 1 mg kg1 per day, with inevitable consequences both in terms of glucocorticoid toxicity and, in combination with cyclophosphamide, as an important contribution to severe infection [9]. Prolonged lower-dose glucocorticoid probably helps to maintain remission at the expense of a high cumulative exposure. Approach to newer therapies Potential alternative therapies require a theoretical rationale, which may dictate the vasculitis syndromes that are likely to be responsive. Other factors that merit consideration include the phase of the disease or disease state, for example, remission induction or remission maintenance; the extent and severity of disease; the pattern of organ involvement; the requirement for concomitant medication and, finally, an understanding of the efficacy and safety end-points by which they can be judged (Table 2) [6,10]. An example is plasma exchange which aims to remove ANCA antibodies in AAV with severe renal involvement [11,12]. It is administered early in the remission-induction phase before other strategies to suppress ANCA production, such as the cytotoxic cyclophosphamide, have started to work. Efficacy can be judged by changes in circulating ANCA levels and improvements in renal function. TNF-a blockade with etanercept is ineffective at sustaining remission in Wegener’s granulomatosis, but this does not exclude the role of TNF-a blockade as a component of induction therapy [9,13,14]. Interactions between therapies not only can potentiate benefit, but also may increase the risk of toxicity. The addition of cyclophosphamide to regimens with glucocorticoids permits the achievement of remission, but significantly increases the risk of severe infection [15]. The removal of therapeutic monoclonal antibodies by plasma exchange needs to be considered if these therapies are combined. Most newer therapies in vasculitis have been previously licensed for other indications using different concomitant therapies, and safety profiles will differ and cannot be assumed to be the same. Evidence in support of newer therapies Newer anti-proliferative drugs Mycophenolic acid Mycophenolic Acid (MPA) is administered as its prodrug mycophenolate mofetil (MMF, CellceptÒ), or as mycophenolate sodium (MyforticÒ). It is a non-competitive inhibitor of inosine monophosphate Table 2 The issues in the evaluation of newer therapies in vasculitis. Phase of disease
Disease state Pathogenesis of vasculitis syndrome Disease extent and severity Organ involvement Concomitant therapy
Remission induction (0–6 months) Remission maintenance (6 months–>2 years) Long-term follow-up (2 years–indefinite) Flare, remission, low disease activity state and refractory e.g., ANCA-associated, giant cell arteritis, immune-complex mediated, etc. Localised, early systemic, generalised and severe e.g., ENT, renal, etc. Immunosuppression Glucocorticoids
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dehydrogenase (IMPDH) required for guanine synthesis. It has some specificity for activated lymphocytes where IMPDH activity is increased and lymphocytes, compared to other cell types, are uniquely dependant on this pathway for deoxyribonucleic acid (DNA) synthesis. For this reason, MMF inhibits proliferation of B and T lymphocytes. In addition to this ‘conventional’ mechanism of action, MMF may also inhibit the adhesion of activated lymphocytes at the site of inflammation. There is an inverse relationship between MPA exposure and renal function and renal excretion of the glucuroinde metabolite, MPAG, is reduced in renal impairment, increasing MPA gastrointestinal toxicity. The optimal dosing of MPA in autoimmune disease has not been determined, with target dosing for MMF ranging between 2 and 3 g a day, although it is clear many patients have effective blood levels at lower doses. The role of trough-level monitoring in the management of MMF has not yet been proven. A number of studies in AAV have explored the use of MPA for remission induction and maintenance therapy, as salvage therapy for refractory disease or in the face of intolerance of first-line immunosuppressive agents. One, small, randomised trial compared MMF to study of cyclophosphamide for remission induction in patients with AAV and renal involvement [16]. MMF was successful in inducing remission in 14 of 18 patients by 6 months, compared to 8 of 13 patients in the cyclophosphamide group (although three of the cyclophosphamide patients were lost to follow-up). Renal function was insignificantly better in the MMF group at 6 months, and adverse event rates were similar. This small study suggests that MMF is at least equivalent to cyclophosphamide in inducing remission. Indeed, Stassen et al. demonstrated the efficacy of MMF for remission induction in 32 patients with AAV in an uncontrolled series, achieving complete remission in 78% of patients and partial remission in 19%, with only one patient failing to achieve remission [17]. These data are further supported by results from a small study by Joy et al. of 12 patients with refractory ANCA-associated systemic vasculitis (AASV) treated with MMF, where a 60% remission rate was achieved within 6 months [18]. Although these data are promising for MMF as induction therapy, supportive evidence from adequately powered randomised controlled trials is lacking. A pilot study of MMF as remission-maintenance therapy in 11 patients with AAV following 3 months of conventional induction therapy with cyclophosphamide reported only one relapse by 14 months [19]. Two retrospective studies of 34 and 51 patients reported the use of MMF either for remissioninduction or remission-maintenance therapy. Approximately one-third of the patients failed to tolerate MMF, and one-half of those whose disease was controlled subsequently relapsed, typically when glucocorticoids were withdrawn [20]. Small numbers of patients with other forms of vasculitis, including Takayasu’s arteritis, giant cell arteritis, Henoch–Scho¨nlein purpura (HSP) and urticarial vasculitis, have been reported following good responses to MMF. In addition to the gastrointestinal toxicity and increased infection risk associated with MMF, it is teratogenic and cannot, therefore, be used by pregnant women, mothers or women attempting to conceive as MMF is present in breast milk. Leflunomide Leflunomide is a newer immunosuppressive drug licensed for rheumatoid arthritis and has been evaluated for remission-maintenance therapy in one randomised trial of Wegener’s granulomatosis [21]. This was stopped early after 54 patients had been recruited due to an excess of severe relapses in the control, methotrexate group. However, adverse events were more frequent in the leflunomide group and the reduced efficacy of methotrexate may have been related to dosing. Lefunomide was dosed at 30 mg per day and lower doses have not been evaluated. Deoxyspergualin Deoxyspergualin is a novel anti-proliferative drug derived from bacillus laterosporus that suppresses lymphocyte and macrophage function and impairs neutrophil production. Studies in refractory ANCAassociated vasculitis and crescentic glomerulonephritis have demonstrated useful efficacy and, in a murine model of spontaneous vasculitis, deoxyspergualin was superior to MMF and as effective as cyclophosphamide in the control of vasculitis [22,23]. A larger, multicentre study of deoxyspergualin in 46 patients with refractory Wegener’s granulomatosis has been recently completed [23]. This study found a response rate of 90% with almost half of the number of patients reaching a sustained full remission accompanied by significant reductions in prednisolone requirement. The improvement in disease activity was maintained after stopping deoxyspergualin during treatment with azathioprine. Deoxyspergualin has the potential to
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replace cyclophosphamide for the induction of remission in vasculitis without exposing patients to the fertility and malignancy risks of cyclophosphamide. Reversible leukopaenia was frequent with deoxyspergualin and required close monitoring of blood counts. Plasma exchange Removal of circulating immune reactants, including autoantibodies, by plasma exchange has focussed on those vasculitic syndromes where circulating pathogenetic factors have been identified. However, removal of other plasma constituents, such as coagulation factors, cytokines and chemokines, may contribute to the therapeutic effect. The renal lesion in Wegener’s granulomatosis and microscopic polyangiitis is a focal, necrotising, glomerulonephritis in association with ANCA. The pathogenicity of ANCA has been proven in in vitro and in experimental models [24]. In human disease, ANCA appears likely to contribute to pathogenesis, but other mechansims are important and ANCA is not detectable in 5% of ‘pauci-immune’ crescentic glomerulonephritis. Plasmapheresis reduces levels of circulating ANCA and adhesion molecules in vasculitis, but has little effect on the high cytokine levels. Randomised controlled trials have evaluated the efficacy of plasmapheresis as an adjunct to immunosuppressive therapy in patients with pauci-immune glomerulonephritis, and varying degrees of renal failure – mostly recruiting prior to the availability of ANCA testing – and found varying results. Non-randomised, controlled studies and other case series have indicated a recovery rate of 75% in those presenting with renal failure, (creatinine > 500 mmol l1); this rate appears superior to that reported in series not using plasmapheresis where recovery rates of 40–50% have been seen. A recent study focussed on 137 AAV patients presenting with creatinine >500 mmol l1 who were randomised to either seven plasmapheresis sessions of 60 ml kg1 within 14 days or three once-daily infusions of 1000 mg of methyl prednisolone [11]. All patients received oral cyclophosphamide and the same oral corticosteroid regimen. Renal recovery occurred in 69% of the pheresis group and 49% of the control group. Risk of progression to end-stage renal disease was reduced by 24% in the pheresis group. In a multivariate analysis studying predictive factors for renal recovery in this subgroup, the use of plasmapheresis remained associated with a good outcome even in the presence of severe histological features [25]. Uncertainty remains as to the role of plasmapheresis in AAV with renal involvement and serum creatinine <500 mmol l1. The number of plasmaphereses varied between studies, and an appropriate measure by which to judge how many sessions are needed has not been established. There is no evidence to support or refute using ANCA levels in this setting. However, persistence of ANCA, lack of renal improvement – as judged by urine output and serum creatinine – and activity of extrarenal vasculitis indicate that prolonged plasmapheresis may be required. Pulmonary haemorrhage occurring with glomerulonephritis is termed the ‘pulmonary renal syndrome’. AAV is the cause in 80% of cases, and it has been suggested that the pathogenesis of alveolar capillaritis is similar to that occurring in the glomeruli. Lung haemorrhage can be life threatening and plasmapheresis is frequently used for this indication, but no randomised trials have addressed this presentation [26]. Whether plasmapheresis has a role for the treatment of other, severe, extrarenal manifestations of vasculitis is unknown, with inconclusive randomised trials providing conflicting evidence (Table 3). Table 3 The current roles of plasma exchange in vasculitis. Indication
Mechanism
Consensus recommendations
ANCA-associated renal vasculitis with severe renal disease (creatinine >500 umol l1) ANCA-associated vasculitis with: lung haemorrhage, creatinine <500 umol l1, other severe organ manifestation Henoch–Scho¨nlein purpura
? Removal of ANCA, cytokines and coagulation factors ? Removal of ANCA, cytokines and coagulation factors
Recommended
? Removal of IgA immune complexes, cytokines and coagulation factors Removal of circulating immune complexes, cytokines and coagulation factors
May be considered
Cryoglobulinaemia
May be considered
Recommended in severe cases
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HSP is a systemic vasculitis characterised by the production of aberrantly glycosylated immunoglobulin A1 (IgA1), circulating IgA rheumatoid factors and IgA-containing immune complexes and mesangial deposition of IgA. A rationale exists for the use of plamapheresis to remove circulating IgA, and existing data are supportive but not conclusive. Thirty-one percent of adults with HSP have a rapidly progressive course with glomerular necrosis, crescents and deteriorating renal function and extrarenal features of systemic vasculitis. Plasmapheresis has been employed in this setting in small case series, where – in combination with other therapies – it contributed to the reversal of histological activity and prevented the development of chronic changes. Mixed cryoglobulinaemia reflecting immune complexes, containing monoclonal IgM rheumatoid factor and polyclonal IgG and type II croglobulinaemia, precipitate within the glomerular capillary lumen andinduce a proliferative or membranoproliferative glomerulonephritis with a variable, but sometimes rapidly progressive, course. Majority of cases of type II cryoglobulinaemia occur in assocation with chronic hepatitis C virus infection. Because cryoglobulins are restricted to the plasma compartment, their levels are rapidly and predictably reduced by plasmapheresis which has been used to treat cryoglobulinaemia for 30 years without being subjected to a prospective randomised controlled clinical trial. Intravenous immunoglobulin A therapeutic rationale for high-dose intravenous Ig (IVIg) arose from its ability to reverse cytokine-driven endothelial activation and arterial damage in Kawasaki disease and the presence of anti-idiotype antibodies capable of neutralising ANCA from the sera of patients with AAV [27]. However, IVIg has a wide range of effects mediated through V or Fc region interactions, and other mechanisms relevant to vasculitis include reductions in cytokine production and modulation of Fcreceptor function. A double-blind, placebo-controlled trial in refractory vasculitis demonstrated the ability of a course of IVIg (2 g kg1) to suppress disease activity in AAV for up to 3 months [28]. Subsequent observational studies have indicated potential roles for remission induction as a sole agent and as a remission-maintaining therapy in relapsing vasculitis. A recent prospective study indicated that IVIg could maintain remission in frequently relapsing patient with AAV [29]. IVIg has also been shown to enhance immune-complex clearance from the circulation and to solubilise tissue-deposited immune complexes, and this has led to preliminary data suggesting a role in HSP. Uncontrolled data have also reported benefit with IVIg in Churg–Strauss angiitis, cutaneous polyarteritis nodosa, paediatric polyarteritis and urticarial vasculitis. IVIg use in vasculitis has been occasionally complicated by infusion reactions, which have included meningitis, and by acute renal failure, linked to the use of sucrose in earlier IVIg preparations. The expense and potential shortage of IVIg have led health-care systems to restrict its use. In situations where glucocorticoids and immunosuppressives are contraindicated or represent an unacceptably high infection risk, IVIg may be considered; these include the presence of sepsis, a patient in the intensive care unit or in pregnancy. Autologous stem cell transplantation There is limited experience of stem cell transplantation in vasculitis; of the 15 cases reported to the European Group of Blood and Marrow Transplantation (EBMT), there was a response rate of over 90%, but relapses were reported in one-third which required further transplantation procedures [30]. Vasculitis patients are at higher risk of complications of severe neutropaenia due to previous drug exposure and end-organ damage; however, only one fatality occurred in this series following a secondary allogenic transplant. Appropriate patient selection appears crucial to the success of this procedure, avoiding patients with excessive previous cyclophosphamide exposure and those with irreversible vital organ dysfunction. Of particular interest has been a report of allogeneic stem cell transplantation in a patient with Wegener’s granulomatosis who developed acute myeloid leukaemia. Following successful transplantation, PR3-ANCA and evidence of vasculitis recurred, but then subsided spontaneously and the patient remains well [31].
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Biological agents Tumour necrosis factor blockade A rationale for TNF blockade in the treatment of AAV has been based on the need for TNF priming before ANCA induces neutrophil activation, on the presence of TNF and TNF-receptor hyperexpression at sites of vasculitis, on the role of TNF in activating endothelial cells permitting leucocyte adhesion and on the triggering role of infection on vasculitic activity. Blockade of TNF has led to resistance to vasculitis in animal models. Several uncontrolled studies pointed to a useful therapeutic effect of TNF blockade in giant cell arteritis, Takayasu’s arteritis and ANCA-associated vasculitis [32,33]. A study with the 75-kD soluble receptor, etanercept, was unsuccessful in preventing flares or reducing glucocorticoid requirements in Wegener’s granulomatosis in a large, placebo-controlled trial [9]. This study found an unexpected association of etanercept with malignancy, the significance of which remains unclear [34]. A smaller open-label trial of infliximab suggested some short-term efficacy in both new and relapsing ANCA-associated vasculitis, but longer exposure was associated with increased infection risk and disease relapse [32]. Whether TNF blockade has a role in induction regimens or in refractory AAV disease has not been resolved, and the current data argue against its routine use. It is also possible that different TNF-blocking drugs have different potential in vasculitis [14]. Perhaps of more concern has been the recent reports of a secondary vasculitis developing in patients with rheumatoid arthritis receiving TNFblocking drugs. In addition, the different biological functions of TNF receptors suggests that blocking all TNF may well have negative as well as positive effects and more specific TNF-receptor blockers might be safer and more useful. Lymphocyte depletion Lymphocyte depletion with anti-thymocyte globulin or alemtuzumab (CAMPATH 1-H) has induced remission in over 80% of patients with refractory AAV, but has been associated with a high rate of infections, most common in those critically ill or over 60 years of age [35,36]. However, their use in patients with refractory vasculitis has led to sustained remissions and permitted the withdrawal of immunosuppressive and glucocorticoid drugs. Re-treatment with alemtuzumab at the time of relapse appears safe and has led to further periods of sustained remission. B-cell depletion B cells are present at sites of vasculitic inflammation along with autoantigen (ANCA)-specific B cells and plasmoblasts [37]. The B-cell depletion with rituximab has led to clinical remissions in small series of patients with refractory vasculitis, mainly Wegener’s granulomatosis (Table 4) [38]. Those with AAV and renal involvement have shown reductions in serum creatinine and predictable falls in ANCA-binding level [39]. The duration of response has been variable, with relapses occurring after an average of 10–13 months, but some patients enjoyed prolonged remission for several years [40,41]. Re-treatment at the time of relapse has been effective and protocol re-treatment at 4- or Table 4 The clinical trials of rituximab in refractory ANCA-associated vasculitis. Study
Patients (nephritis)
Concomitant treatments
Remission (nephritis)
Serology changea
Relapse
Keogh (2005) Keogh (2006) Smith (2006) Stasi (2006)
11 (4) 10 (7) 11 (6) 10 (6)
GC, PLEX GC GC, MMF GC
10/11 CR, 1/11PR (4/4) 10/10 CR (7/7) 9/11 CR, 1/11 PR (6/6) 9/10 CR, 1/10 PR (6/6)
8/11 negative all decreased 6/10 negative all decreased 6/10 negative all decreased 8/10 negative all decreased
2 (7, 12 months) 1 (9 months) 6/10 (median 16.5 months) 3/10 (12, 16 and 24 months)
a ANCA for ANCA vasculitis; CR ¼ complete remission; PR ¼ partial remission; NR ¼ not reported; ANCA ¼ anti-neutrophil cytoplasmic antibody; AZA ¼ azathioprine; CYC ¼ cyclophosphamide; GC ¼ glucocorticoids; MMF ¼ mycophenolate mofetil; MTX ¼ methotrexate; PLEX ¼ plasma exchange.
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6-month intervals is under evaluation. A near-universal finding has been the achievement of peripheral B-cell (CD19- or CD20-positive lymphocytes) depletion below 1 106 l1 after rituximab, and failure to achieve depletion is correlated with poor or no clinical response. B-cell recovery is detectable after 6–9 months, and although prolonged B-cell depletion is associated with a prolonged clinical response, B-cell return is not closely associated with disease activity and relapses have occurred before B-cell return. In the minority of refractory vasculitis patients positive for ANCA at the time of rituximab therapy, changes in ANCA levels have reflected changes in disease activity; however, in general, ANCA levels are not predictive of relapse [40]. Rituximab dosing has copied that used in lymphoma, 375 mg m2 per week 4, or rheumatoid arthritis regimens, 1000 mg repeated after 2 weeks, although superficially the responses appear similar, these regimens have not been directly compared. The role of concomitant immunosuppressive therapy with rituximab, or for relapse prevention following treatment with rituximab, is controversial. In rheumatoid arthritis, there is a synergistic effect of methotrexate and rituximab, possibly due to a direct reduction of synovitis by methotrexate [42]. Immunosuppressive drugs do not appear to contribute to the duration of B-cell depletion, and there are no major differences in the duration of response between those studies continuing immunosuppression after rituximab and those that do not. The development of anti-chimaeric antibodies to rituximab (HACA) is found in up to 30%, and although they appear to have no clinical effect in the majority of cases, failure to induce depletion with repeat dosing has occurred [40]. Infusion reactions to rituximab occur in 20–40% of cases and are mostly mild, although severe reactions including meningism, anaphlyaxis and serum sickness have been reported. It is unclear whether the frequency of infections reported in current studies with rituximab in vasculitis represents any increase on what would be expected from concomitant therapy; this is an important aim of ongoing randomised trials. Late-onset neutropaenia is a transient phenomenon after treatment with rituximab that may be more common in those previously exposed to cytotoxic drugs. Occasionally, patients have developed hypogammaglobulinaemia and recurrent infection requiring IgG replacement. Thus, IgG levels should be monitored and falling levels should influence a decision to repeat treatment with rituximab. Cases of rituximab failure have been associated with lower rituximab doses and retro-orbital granulomata [43]. Paediatric practice There is limited experience of newer therapies in paediatric vasculitis. Important differences in the phenotype of paediatric vasculitis and an increased role of infection in their aetiology influence therapeutic decisions [44]. The role of MMF for remission induction of AAV is currently being explored, and rituximab and TNF-a blockade have been used in small numbers of patients. Current roles of newer therapies While the role of conventional agents is now well established following several randomised controlled trials, the place of newer therapies in routine vasculitis therapy remains to be determined. MMF and leflunomide can both be recommended as second-line alternatives to azathioprine and methotrexate for remission-maintenance regimens and remission induction in mild presentations. Plasma exchange increases the recovery of renal function in severe renal presentations, but it is unclear whether this provides a lasting benefit in terms of patient or renal survival. Plasma exchange is also considered in other severe presentations, such as lung haemorrhage without a good evidence base (Table 3). IVIg cannot be recommended for routine use in AAV, but can be considered where conventional agents are ineffective or contraindicated. Blockade of TNF-a has suffered from negative randomised trials for remission maintenance in AAV and giant cell arteritis, but a role in induction therapy and in refractory disease remains incompletely explored. T-cell depletion with anti-thymocyte globulin is complicated by the inability to re-use this drug in patients with a chronic relapsing disease; alemtuzumab can be considered in refractory vasculitis, but is a potent immunosuppressive agent which considerably increases the risk of severe infection (Table 5).
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Table 5 The current roles of biological agents in vasculitis. Agent
Indication
T-cell depletion with: Anti-thymocyte globulin Anti-CD52 (CAMPATH, alemtuzumab) B-cell depletion with: Rituximab Tumour necrosis factor blockade with: Etanercept Infliximab Aadalimumab
Consider in refractory AAV, little data in other vasculitis syndromes Consider in refractory AAV, little data in other vasculitis syndromes
Consider in refractory AAV, giant cell arteritis and Takayasu’s arteritis Potential alternative to infliximab
AAV ¼ ANCA-associated vasculitis.
Perhaps surprisingly, B-cell depletion with rituximab is now the most strongly supported newer biological therapy and its combination of apparently high efficacy rates in refractory disease and low drug-related toxicity makes it an attractive option. Rituximab cannot be recommended for routine induction therapy based on existing data, but it should be seriously considered in refractory disease in view of the lack of safe alternatives. However, the short duration of experience with rituximab, relatively small numbers of patients treated and lack of randomised trial information should indicate caution. Looking to the future In view of the small market size, vasculitis ‘borrows’ drugs developed for more common autoimmune indications. Current candidates for evaluation in vasculitis include co-stimulatory blockade with abatacept, blockade of interleukin 6 (IL6) with the anti-IL6 receptor monoclonal antibody tocilizumab, and alternative B-cell-modulating agents including anti-B-cell-stimulating factor monoclonal antibodies and anti-CD20 and Cd22 B-cell-depleting antibodies. For Churg–Strauss syndrome, modulation of eosinophils with interferon-a or blockade of IL5 is being investigated.
Practice points Mycophenolic acid and leflunomide are alternatives to methotrexate and azathioprine for remission-maintenance therapy or remission induction of early-systemic vasculitis Plasma exchange and intravenous immunoglobulin are adjunctive therapies that have been evaluated in many different vasculitis scenarios and provide options when vasculitis is severe or refractory or standard agents are contraindicated Biological agents cannot be currently recommended in the routine management of vasculitis, but they have potential roles and should be considered in refractory vasculitis Rituximab is the most promising biological for ANCA associated vasculitis in terms of its efficacy and safety, but current evidence is weak
Research agenda Evaluation of plasma exchange for renal vasculitis, creatinine <500 umol l1 and lung haemorrhage Evaluation of rituximab as routine remission-maintenance and refractory vasculitis therapy Evaluation of cytokine blockade (TNF-a and IL-6) as a component of induction therapy to permit steroid reduction and faster remissions Evaluation of the ability of alemtuzumab or stem cell transplantation to induce sustained, treatment-free remissions in refractory disease Development of biomarkers to assess vasculitis activity
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Acknowledgement This work was supported by the Cambridge Biomedical Research Centre.
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The treatment of Wegener’s granulomatosis with glucocorticoids and methotrexate. Arthritis Rheum 1992;35:1322. [8] de Groot K, Adu D, Savage CO. The value of pulse cyclophosphamide in ANCA-associated vasculitis: meta-analysis and critical review. Nephrol Dial Transplant 2001;16:2018. *[9] Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med 2005;352:351. [10] Hellmich B, Flossmann O, Gross WL, et al. EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis: focus on anti-neutrophil cytoplasm antibody-associated vasculitis. Ann Rheum Dis 2007;66:605. [11] Jayne DR, Gaskin G, Rasmussen N, et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol 2007;18:2180. [12] Lockwood CM, Pinching AJ, Sweny P, et al. Plasma-exchange and immunosuppression in the treatment of fulminating immune-complex crescentic nephritis. Lancet 1977;1:63. [13] Booth A, Harper L, Hammad T, et al. Prospective study of TNFalpha blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol 2004;15:717. [14] Mitoma H, Horiuchi T, Tsukamoto H, et al. Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor alpha-expressing cells: comparison among infliximab, etanercept, and adalimumab. Arthritis Rheum 2008;58:1248. *[15] Guillevin L, Jarrousse B, Lok C, et al. Longterm followup after treatment of polyarteritis nodosa and Churg-Strauss angiitis with comparison of steroids, plasma exchange and cyclophosphamide to steroids and plasma exchange. A prospective randomized trial of 71 patients. The Cooperative Study Group for Polyarteritis Nodosa. J Rheumatol 1991;18:567. [16] Hu W, Liu C, Xie H, et al. Mycophenolate mofetil versus cyclophosphamide for inducing remission of ANCA vasculitis with moderate renal involvement. Nephrol Dial Transplant 2008;23:1307. [17] Stassen PM, Cohen Tervaert JW, Stegeman CA. Induction of remission in active anti-neutrophil cytoplasmic antibodyassociated vasculitis with mycophenolate mofetil in patients who cannot be treated with cyclophosphamide. Ann Rheum Dis 2007;66:798. [18] Joy MS, Hogan SL, Jennette JC, et al. A pilot study using mycophenolate mofetil in relapsing or resistant ANCA small vessel vasculitis. Nephrol Dial Transplant 2005;20:2725. [19] Nowack R, Gobel U, Klooker P, et al. Mycophenolate mofetil for maintenance therapy of Wegener’s granulomatosis and microscopic polyangiitis: a pilot study in 11 patients with renal involvement. J Am Soc Nephrol 1999;10:1965. [20] Koukoulaki M, Jayne DR. Mycophenolate mofetil in anti-neutrophil cytoplasm antibodies-associated systemic vasculitis. Nephron Clin Pract 2006;102:c100. [21] Metzler C, Miehle N, Manger K, et al. Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener’s granulomatosis. Rheumatology (Oxford) 2007;46:1087. [22] Birck R, Newman M, Braun C, et al. 15-Deoxyspergualin and cyclophosphamide, but not mycophenolate mofetil, prolong survival and attenuate renal disease in a murine model of ANCA-associated crescentic nephritis. Nephrol Dial Transplant 2006;21:58. *[23] Flossmann O, Baslund B, Bruchfeld A, et al. Deoxyspergualin in relapsing and refractory Wegener’s granulomatosis. Ann Rheum Dis 2008. [24] Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 2002;110:955. [25] de Lind van Wijngaarden RA, Hauer HA, Wolterbeek R, et al. Chances of renal recovery for dialysis-dependent ANCAassociated glomerulonephritis. J Am Soc Nephrol 2007;18:2189. [26] Specks U. Diffuse alveolar hemorrhage syndromes. Curr Opin Rheumatol 2001;13:12. [27] Rossi F, Jayne DR, Lockwood CM, Kazatchkine MD. Anti-idiotypes against anti-neutrophil cytoplasmic antigen autoantibodies in normal human polyspecific IgG for therapeutic use and in the remission sera of patients with systemic vasculitis. Clin Exp Immunol 1991;83:298. [28] Jayne DR, Chapel H, Adu D, et al. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. QJM 2000;93:433. *[29] Martinez V, Cohen P, Pagnoux C, et al. Intravenous immunoglobulins for relapses of systemic vasculitides associated with antineutrophil cytoplasmic autoantibodies: results of a multicenter, prospective, open-label study of twenty-two patients. Arthritis Rheum 2008;58:308. [30] Kotter I, Daikeler T, Amberger C, et al. Autologous stem cell transplantation of treatment-resistant systemic vasculitis– a single center experience and review of the literature. Clin Nephrol 2005;64:485.
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[31] Kunitomi A, Ishikawa T, Tajima K, et al. Bone marrow transplantation with a reduced-intensity conditioning regimen in a patient with Wegener granulomatosis and therapy-related leukemia. Int J Hematol 2006;83:262. [32] Booth AD, Jefferson HJ, Ayliffe W, et al. Safety and efficacy of TNFalpha blockade in relapsing vasculitis. Ann Rheum Dis 2002;61:559. [33] Josselin L, Mahr A, Cohen P, et al. Infliximab efficacy and safety against refractory systemic necrotising vasculitides: longterm follow-up of 15 patients. Ann Rheum Dis 2008;67:1343. [34] Stone JH, Holbrook JT, Marriott MA, et al. Solid malignancies among patients in the Wegener’s Granulomatosis Etanercept Trial. Arthritis Rheum 2006;54:1608. [35] Walsh M, Chaudhry A, Jayne DR. Long-term follow-up of relapsing/refractory ANCA associated vasculitis treated with the lymphocyte depleting antibody alemtuzumab (CAMPATH-1H). Ann Rheum Dis 2007. [36] Schmitt WH, Hagen EC, Neumann I, et al. Treatment of refractory Wegener’s granulomatosis with antithymocyte globulin (ATG): an open study in 15 patients. Kidney Int 2004;65:1440. *[37] Voswinkel J, Mueller A, Kraemer JA, et al. B lymphocyte maturation in Wegener’s granulomatosis: a comparative analysis of VH genes from endonasal lesions. Ann Rheum Dis 2006;65:859. [38] Walsh M, Jayne D. Rituximab in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis and systemic lupus erythematosus: past, present and future. Kidney Int 2007;72:676. [39] Keogh KA, Wylam ME, Stone JH, Specks U. Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2005;52:262. [40] Smith KG, Jones RB, Burns SM, Jayne DR. Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: remission, relapse, and re-treatment. Arthritis Rheum 2006;54:2970. [41] Ng KP, Cambridge G, Leandro MJ, et al. B cell depletion therapy in systemic lupus erythematosus: long-term follow-up and predictors of response. Ann Rheum Dis 2007;66:1259. [42] Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572. *[43] Aries PM, Hellmich B, Voswinkel J, et al. Lack of efficacy of rituximab in Wegener’s granulomatosis with refractory granulomatous manifestations. Ann Rheum Dis 2006;65:853. [44] Dillon MJ, Ozen S. A new international classification of childhood vasculitis. Pediatr Nephrol 2006;21:1219.
Contents lists available at ScienceDirect
Best Practice & Research Clinical Rheumatology journal homepage: www.elsevierhealth.com/berh
6
Newer therapies for vasculitis Thomas F. Hiemstra, MRCP, Research Fellow in Nephrology, David Jayne, MD, FRCP, Consultant in Nephrology and Vasculitis * Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK
Keywords: alemtuzumab clinical trials etanercept infliximab intravenous immunoglobulin leflunomide mycophenolic acid plasma exchange rituximab stem cell transplantation therapy tumour necrosis factor vasculitis
There is a clear unmet need in the therapy of vasculitis reflecting the toxicity and partial efficacy of conventional agents. Vasculitis is a complex area for the evaluation of newer therapies due to the heterogeneity between and within syndromes with multisystem manifestations. Much of the evidence supporting newer therapies comes from small, non-randomised trials and is insufficient to permit firm recommendations. Newer immunosuppressive drugs, including mycophenolic acid and leflunomide, are alternative second-line agents to methotrexate and azathioprine. Plasma exchange appears to have a role in severe renal vasculitis and vasculitis caused by circulating immune complexes, but evidence supporting other indications is weak. In contrast to most other therapies, intravenous immunoglobulin (Ig) does not affect infective risk and is an alternative agent for refractory disease where standard approaches are contraindicated. The role of tumour necrosis factor blockade remains unresolved with important negative studies, but the therapeutic rationale persists and positive non-randomised trials are also under way. Experience with more aggressive immunosuppression, such as, T-cell depletion or autologous stem cell transplantation has been limited to a few centres. B-cell depletion with rituximab is currently attracting most attention with good success rates in small studies of refractory disease. The treatment of vasculitis in the future will become more complex with a wider range of available treatments; their optimal combination, sequencing and tailoring to the individual clinical situation will place unique demands on those delivering vasculitis services. Ó 2009 Elsevier Ltd. All rights reserved.
* Corresponding author. Box 118, Renal Unit, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK. Tel.: þ44 1223 586 796; Fax: þ44 1223 586 506. E-mail address: [email protected] (D. Jayne). 1521-6942/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.berh.2009.01.005
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The different vasculitis syndromes Much of the experience of newer therapies has been with primary vasculitis that predominantly affects small blood vessels and is associated with anti-neutrophil cytoplasmic antibodies (ANCA). The ANCA vasculitides (AAV) include Wegener’s granulomatosis, microscopic polyangiitis (and its renallimited variant) and Churg–Strauss angiitis. This experience also reflects the stronger evidence base of standard therapies for ANCA vasculitis which permits comparisons to be made with studies of newer agents. There is considerably less study of large-vessel vasculitides and of secondary vasculitis, and by their nature, rare vasculitis syndromes are difficult to study. The extent to which results in ANCA vasculitis can be extrapolated to other vasculitis syndromes is uncertain and it cannot be assumed that success in one syndrome will be reflected in another. Vasculitis syndromes have been defined according to the nature of their pathology. An understanding of the pathogenesis of a vasculitis syndrome, such as the role of ANCA in AAV, provides a rationale for targeted therapy, for example, B-cell depletion with rituximab aimed to reduce autoantibody production [1]; however, this understanding remains limited and the actual therapeutic mechanisms may be quite different. On the other hand, the targeted nature of monoclonal-antibodybased therapies permits exploration of pathogenesis as the activity of a specific immune or inflammatory component, for example, tumour necrosis factor (TNF), is modulated. Vasculitis syndromes differ in their steroid responsiveness, in their demography and patterns of organ involvement, for example, between giant cell arteritis (which affects the elderly, reliably responds to glucocorticoids and spares the kidneys) and AAV (which affects a wider age group, requires an immunosuppressive agent and commonly causes renal vasculitis). Furthermore, there is considerable inter-patient variability in the severity and extent of disease. This heterogeneity between and within syndromes makes vasculitis a challenging scenario for the introduction of newer agents. Areas of unmet need Current therapy has dramatically changed the prognosis of vasculitis from a usually fatal condition to one that can be controlled, but is limited by both only partial efficacy and high levels of toxicity (Table 1) [2]. Despite optimal standard therapy, remission of disease is incomplete in 20–30%, and a smaller proportion progress to more severe disease. Active disease is the second most common cause of death in vasculitis patients, especially in the first year after diagnosis [3]. Remission is often slow, requiring at least 3 months of therapy, by which time irreversible damage has usually occurred. It is possible that more rapid remission induction will salvage organ function and reduce long-term organ dysfunction. By 5 years after diagnosis, 50% of patients will relapse in spite of at least 2 years of therapy, indicating a failure of current therapies to correct the underlying immunopathogenicity of vasculitis [4]. Approximately 25% will pursue a refractory course manifested by incomplete disease control or frequent relapses despite remission-maintaining therapy. The quality of life of vasculitis patients remains depressed for at least a year after diagnosis, although the causes are likely to be multifactorial,
Table 1 The areas of unmet need in vasculitis. Induction phase (0–6 months)
Maintenance phase (beyond 6 months)
Failure to control progressive disease (5–10%) Failure to induce remission (10–20%) Delay in achieving remission
Failure to prevent relapse, 50% by 5 years
Failure to prevent accrual of irreversible organ damage Drug-related toxicity (>90%) Failure to tolerate therapy Non-drug-related severe adverse events (e.g., cardiovascular events, thrombo-embolic disease)
Requirement for prolonged therapy to prevent relapse (immunosuppressive and glucocorticoid drugs) Morbidity related to irreversible organ damage Drug-related toxicity (>90%) Failure to tolerate therapy Increased risk of cardiovascular events Increased malignancy risk Depressed quality of life
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a slow response to induction therapy, on-going subclinical disease activity and relapse will contribute. Cardiovascular, and probably malignancy, risk are considerably increased in vasculitis patients; the former is likely to be influenced by the quality and rapidity of disease control because surrogates of cardiovascular disease, such as endothelial dysfunction, correlate with vasculitic activity [5]. The toxicity of current therapy causes adverse effects and limits dosing, thereby impairing its efficacy. Over 90% of patients will experience drug-related toxicity, which is severe in 25–50% [6]. Infection is the most common cause of death in the first year and is strongly associated with cyclophosphamide-induced leukopaenia [4]. A very high rate of malignancy has been reported in older regimens employing prolonged treatment with cyclophosphamide [7]. Although more recent strategies, including switching to an alternative immunosuppressive at the time of remission or using intravenous pulsed cyclophosphamide, have reduced the malignancy risk, nevertheless, it remains present [3,8]. Glucocorticoid dosing remains high, typically commencing at 1 mg kg1 per day, with inevitable consequences both in terms of glucocorticoid toxicity and, in combination with cyclophosphamide, as an important contribution to severe infection [9]. Prolonged lower-dose glucocorticoid probably helps to maintain remission at the expense of a high cumulative exposure. Approach to newer therapies Potential alternative therapies require a theoretical rationale, which may dictate the vasculitis syndromes that are likely to be responsive. Other factors that merit consideration include the phase of the disease or disease state, for example, remission induction or remission maintenance; the extent and severity of disease; the pattern of organ involvement; the requirement for concomitant medication and, finally, an understanding of the efficacy and safety end-points by which they can be judged (Table 2) [6,10]. An example is plasma exchange which aims to remove ANCA antibodies in AAV with severe renal involvement [11,12]. It is administered early in the remission-induction phase before other strategies to suppress ANCA production, such as the cytotoxic cyclophosphamide, have started to work. Efficacy can be judged by changes in circulating ANCA levels and improvements in renal function. TNF-a blockade with etanercept is ineffective at sustaining remission in Wegener’s granulomatosis, but this does not exclude the role of TNF-a blockade as a component of induction therapy [9,13,14]. Interactions between therapies not only can potentiate benefit, but also may increase the risk of toxicity. The addition of cyclophosphamide to regimens with glucocorticoids permits the achievement of remission, but significantly increases the risk of severe infection [15]. The removal of therapeutic monoclonal antibodies by plasma exchange needs to be considered if these therapies are combined. Most newer therapies in vasculitis have been previously licensed for other indications using different concomitant therapies, and safety profiles will differ and cannot be assumed to be the same. Evidence in support of newer therapies Newer anti-proliferative drugs Mycophenolic acid Mycophenolic Acid (MPA) is administered as its prodrug mycophenolate mofetil (MMF, CellceptÒ), or as mycophenolate sodium (MyforticÒ). It is a non-competitive inhibitor of inosine monophosphate Table 2 The issues in the evaluation of newer therapies in vasculitis. Phase of disease
Disease state Pathogenesis of vasculitis syndrome Disease extent and severity Organ involvement Concomitant therapy
Remission induction (0–6 months) Remission maintenance (6 months–>2 years) Long-term follow-up (2 years–indefinite) Flare, remission, low disease activity state and refractory e.g., ANCA-associated, giant cell arteritis, immune-complex mediated, etc. Localised, early systemic, generalised and severe e.g., ENT, renal, etc. Immunosuppression Glucocorticoids
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dehydrogenase (IMPDH) required for guanine synthesis. It has some specificity for activated lymphocytes where IMPDH activity is increased and lymphocytes, compared to other cell types, are uniquely dependant on this pathway for deoxyribonucleic acid (DNA) synthesis. For this reason, MMF inhibits proliferation of B and T lymphocytes. In addition to this ‘conventional’ mechanism of action, MMF may also inhibit the adhesion of activated lymphocytes at the site of inflammation. There is an inverse relationship between MPA exposure and renal function and renal excretion of the glucuroinde metabolite, MPAG, is reduced in renal impairment, increasing MPA gastrointestinal toxicity. The optimal dosing of MPA in autoimmune disease has not been determined, with target dosing for MMF ranging between 2 and 3 g a day, although it is clear many patients have effective blood levels at lower doses. The role of trough-level monitoring in the management of MMF has not yet been proven. A number of studies in AAV have explored the use of MPA for remission induction and maintenance therapy, as salvage therapy for refractory disease or in the face of intolerance of first-line immunosuppressive agents. One, small, randomised trial compared MMF to study of cyclophosphamide for remission induction in patients with AAV and renal involvement [16]. MMF was successful in inducing remission in 14 of 18 patients by 6 months, compared to 8 of 13 patients in the cyclophosphamide group (although three of the cyclophosphamide patients were lost to follow-up). Renal function was insignificantly better in the MMF group at 6 months, and adverse event rates were similar. This small study suggests that MMF is at least equivalent to cyclophosphamide in inducing remission. Indeed, Stassen et al. demonstrated the efficacy of MMF for remission induction in 32 patients with AAV in an uncontrolled series, achieving complete remission in 78% of patients and partial remission in 19%, with only one patient failing to achieve remission [17]. These data are further supported by results from a small study by Joy et al. of 12 patients with refractory ANCA-associated systemic vasculitis (AASV) treated with MMF, where a 60% remission rate was achieved within 6 months [18]. Although these data are promising for MMF as induction therapy, supportive evidence from adequately powered randomised controlled trials is lacking. A pilot study of MMF as remission-maintenance therapy in 11 patients with AAV following 3 months of conventional induction therapy with cyclophosphamide reported only one relapse by 14 months [19]. Two retrospective studies of 34 and 51 patients reported the use of MMF either for remissioninduction or remission-maintenance therapy. Approximately one-third of the patients failed to tolerate MMF, and one-half of those whose disease was controlled subsequently relapsed, typically when glucocorticoids were withdrawn [20]. Small numbers of patients with other forms of vasculitis, including Takayasu’s arteritis, giant cell arteritis, Henoch–Scho¨nlein purpura (HSP) and urticarial vasculitis, have been reported following good responses to MMF. In addition to the gastrointestinal toxicity and increased infection risk associated with MMF, it is teratogenic and cannot, therefore, be used by pregnant women, mothers or women attempting to conceive as MMF is present in breast milk. Leflunomide Leflunomide is a newer immunosuppressive drug licensed for rheumatoid arthritis and has been evaluated for remission-maintenance therapy in one randomised trial of Wegener’s granulomatosis [21]. This was stopped early after 54 patients had been recruited due to an excess of severe relapses in the control, methotrexate group. However, adverse events were more frequent in the leflunomide group and the reduced efficacy of methotrexate may have been related to dosing. Lefunomide was dosed at 30 mg per day and lower doses have not been evaluated. Deoxyspergualin Deoxyspergualin is a novel anti-proliferative drug derived from bacillus laterosporus that suppresses lymphocyte and macrophage function and impairs neutrophil production. Studies in refractory ANCAassociated vasculitis and crescentic glomerulonephritis have demonstrated useful efficacy and, in a murine model of spontaneous vasculitis, deoxyspergualin was superior to MMF and as effective as cyclophosphamide in the control of vasculitis [22,23]. A larger, multicentre study of deoxyspergualin in 46 patients with refractory Wegener’s granulomatosis has been recently completed [23]. This study found a response rate of 90% with almost half of the number of patients reaching a sustained full remission accompanied by significant reductions in prednisolone requirement. The improvement in disease activity was maintained after stopping deoxyspergualin during treatment with azathioprine. Deoxyspergualin has the potential to
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replace cyclophosphamide for the induction of remission in vasculitis without exposing patients to the fertility and malignancy risks of cyclophosphamide. Reversible leukopaenia was frequent with deoxyspergualin and required close monitoring of blood counts. Plasma exchange Removal of circulating immune reactants, including autoantibodies, by plasma exchange has focussed on those vasculitic syndromes where circulating pathogenetic factors have been identified. However, removal of other plasma constituents, such as coagulation factors, cytokines and chemokines, may contribute to the therapeutic effect. The renal lesion in Wegener’s granulomatosis and microscopic polyangiitis is a focal, necrotising, glomerulonephritis in association with ANCA. The pathogenicity of ANCA has been proven in in vitro and in experimental models [24]. In human disease, ANCA appears likely to contribute to pathogenesis, but other mechansims are important and ANCA is not detectable in 5% of ‘pauci-immune’ crescentic glomerulonephritis. Plasmapheresis reduces levels of circulating ANCA and adhesion molecules in vasculitis, but has little effect on the high cytokine levels. Randomised controlled trials have evaluated the efficacy of plasmapheresis as an adjunct to immunosuppressive therapy in patients with pauci-immune glomerulonephritis, and varying degrees of renal failure – mostly recruiting prior to the availability of ANCA testing – and found varying results. Non-randomised, controlled studies and other case series have indicated a recovery rate of 75% in those presenting with renal failure, (creatinine > 500 mmol l1); this rate appears superior to that reported in series not using plasmapheresis where recovery rates of 40–50% have been seen. A recent study focussed on 137 AAV patients presenting with creatinine >500 mmol l1 who were randomised to either seven plasmapheresis sessions of 60 ml kg1 within 14 days or three once-daily infusions of 1000 mg of methyl prednisolone [11]. All patients received oral cyclophosphamide and the same oral corticosteroid regimen. Renal recovery occurred in 69% of the pheresis group and 49% of the control group. Risk of progression to end-stage renal disease was reduced by 24% in the pheresis group. In a multivariate analysis studying predictive factors for renal recovery in this subgroup, the use of plasmapheresis remained associated with a good outcome even in the presence of severe histological features [25]. Uncertainty remains as to the role of plasmapheresis in AAV with renal involvement and serum creatinine <500 mmol l1. The number of plasmaphereses varied between studies, and an appropriate measure by which to judge how many sessions are needed has not been established. There is no evidence to support or refute using ANCA levels in this setting. However, persistence of ANCA, lack of renal improvement – as judged by urine output and serum creatinine – and activity of extrarenal vasculitis indicate that prolonged plasmapheresis may be required. Pulmonary haemorrhage occurring with glomerulonephritis is termed the ‘pulmonary renal syndrome’. AAV is the cause in 80% of cases, and it has been suggested that the pathogenesis of alveolar capillaritis is similar to that occurring in the glomeruli. Lung haemorrhage can be life threatening and plasmapheresis is frequently used for this indication, but no randomised trials have addressed this presentation [26]. Whether plasmapheresis has a role for the treatment of other, severe, extrarenal manifestations of vasculitis is unknown, with inconclusive randomised trials providing conflicting evidence (Table 3). Table 3 The current roles of plasma exchange in vasculitis. Indication
Mechanism
Consensus recommendations
ANCA-associated renal vasculitis with severe renal disease (creatinine >500 umol l1) ANCA-associated vasculitis with: lung haemorrhage, creatinine <500 umol l1, other severe organ manifestation Henoch–Scho¨nlein purpura
? Removal of ANCA, cytokines and coagulation factors ? Removal of ANCA, cytokines and coagulation factors
Recommended
? Removal of IgA immune complexes, cytokines and coagulation factors Removal of circulating immune complexes, cytokines and coagulation factors
May be considered
Cryoglobulinaemia
May be considered
Recommended in severe cases
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HSP is a systemic vasculitis characterised by the production of aberrantly glycosylated immunoglobulin A1 (IgA1), circulating IgA rheumatoid factors and IgA-containing immune complexes and mesangial deposition of IgA. A rationale exists for the use of plamapheresis to remove circulating IgA, and existing data are supportive but not conclusive. Thirty-one percent of adults with HSP have a rapidly progressive course with glomerular necrosis, crescents and deteriorating renal function and extrarenal features of systemic vasculitis. Plasmapheresis has been employed in this setting in small case series, where – in combination with other therapies – it contributed to the reversal of histological activity and prevented the development of chronic changes. Mixed cryoglobulinaemia reflecting immune complexes, containing monoclonal IgM rheumatoid factor and polyclonal IgG and type II croglobulinaemia, precipitate within the glomerular capillary lumen andinduce a proliferative or membranoproliferative glomerulonephritis with a variable, but sometimes rapidly progressive, course. Majority of cases of type II cryoglobulinaemia occur in assocation with chronic hepatitis C virus infection. Because cryoglobulins are restricted to the plasma compartment, their levels are rapidly and predictably reduced by plasmapheresis which has been used to treat cryoglobulinaemia for 30 years without being subjected to a prospective randomised controlled clinical trial. Intravenous immunoglobulin A therapeutic rationale for high-dose intravenous Ig (IVIg) arose from its ability to reverse cytokine-driven endothelial activation and arterial damage in Kawasaki disease and the presence of anti-idiotype antibodies capable of neutralising ANCA from the sera of patients with AAV [27]. However, IVIg has a wide range of effects mediated through V or Fc region interactions, and other mechanisms relevant to vasculitis include reductions in cytokine production and modulation of Fcreceptor function. A double-blind, placebo-controlled trial in refractory vasculitis demonstrated the ability of a course of IVIg (2 g kg1) to suppress disease activity in AAV for up to 3 months [28]. Subsequent observational studies have indicated potential roles for remission induction as a sole agent and as a remission-maintaining therapy in relapsing vasculitis. A recent prospective study indicated that IVIg could maintain remission in frequently relapsing patient with AAV [29]. IVIg has also been shown to enhance immune-complex clearance from the circulation and to solubilise tissue-deposited immune complexes, and this has led to preliminary data suggesting a role in HSP. Uncontrolled data have also reported benefit with IVIg in Churg–Strauss angiitis, cutaneous polyarteritis nodosa, paediatric polyarteritis and urticarial vasculitis. IVIg use in vasculitis has been occasionally complicated by infusion reactions, which have included meningitis, and by acute renal failure, linked to the use of sucrose in earlier IVIg preparations. The expense and potential shortage of IVIg have led health-care systems to restrict its use. In situations where glucocorticoids and immunosuppressives are contraindicated or represent an unacceptably high infection risk, IVIg may be considered; these include the presence of sepsis, a patient in the intensive care unit or in pregnancy. Autologous stem cell transplantation There is limited experience of stem cell transplantation in vasculitis; of the 15 cases reported to the European Group of Blood and Marrow Transplantation (EBMT), there was a response rate of over 90%, but relapses were reported in one-third which required further transplantation procedures [30]. Vasculitis patients are at higher risk of complications of severe neutropaenia due to previous drug exposure and end-organ damage; however, only one fatality occurred in this series following a secondary allogenic transplant. Appropriate patient selection appears crucial to the success of this procedure, avoiding patients with excessive previous cyclophosphamide exposure and those with irreversible vital organ dysfunction. Of particular interest has been a report of allogeneic stem cell transplantation in a patient with Wegener’s granulomatosis who developed acute myeloid leukaemia. Following successful transplantation, PR3-ANCA and evidence of vasculitis recurred, but then subsided spontaneously and the patient remains well [31].
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Biological agents Tumour necrosis factor blockade A rationale for TNF blockade in the treatment of AAV has been based on the need for TNF priming before ANCA induces neutrophil activation, on the presence of TNF and TNF-receptor hyperexpression at sites of vasculitis, on the role of TNF in activating endothelial cells permitting leucocyte adhesion and on the triggering role of infection on vasculitic activity. Blockade of TNF has led to resistance to vasculitis in animal models. Several uncontrolled studies pointed to a useful therapeutic effect of TNF blockade in giant cell arteritis, Takayasu’s arteritis and ANCA-associated vasculitis [32,33]. A study with the 75-kD soluble receptor, etanercept, was unsuccessful in preventing flares or reducing glucocorticoid requirements in Wegener’s granulomatosis in a large, placebo-controlled trial [9]. This study found an unexpected association of etanercept with malignancy, the significance of which remains unclear [34]. A smaller open-label trial of infliximab suggested some short-term efficacy in both new and relapsing ANCA-associated vasculitis, but longer exposure was associated with increased infection risk and disease relapse [32]. Whether TNF blockade has a role in induction regimens or in refractory AAV disease has not been resolved, and the current data argue against its routine use. It is also possible that different TNF-blocking drugs have different potential in vasculitis [14]. Perhaps of more concern has been the recent reports of a secondary vasculitis developing in patients with rheumatoid arthritis receiving TNFblocking drugs. In addition, the different biological functions of TNF receptors suggests that blocking all TNF may well have negative as well as positive effects and more specific TNF-receptor blockers might be safer and more useful. Lymphocyte depletion Lymphocyte depletion with anti-thymocyte globulin or alemtuzumab (CAMPATH 1-H) has induced remission in over 80% of patients with refractory AAV, but has been associated with a high rate of infections, most common in those critically ill or over 60 years of age [35,36]. However, their use in patients with refractory vasculitis has led to sustained remissions and permitted the withdrawal of immunosuppressive and glucocorticoid drugs. Re-treatment with alemtuzumab at the time of relapse appears safe and has led to further periods of sustained remission. B-cell depletion B cells are present at sites of vasculitic inflammation along with autoantigen (ANCA)-specific B cells and plasmoblasts [37]. The B-cell depletion with rituximab has led to clinical remissions in small series of patients with refractory vasculitis, mainly Wegener’s granulomatosis (Table 4) [38]. Those with AAV and renal involvement have shown reductions in serum creatinine and predictable falls in ANCA-binding level [39]. The duration of response has been variable, with relapses occurring after an average of 10–13 months, but some patients enjoyed prolonged remission for several years [40,41]. Re-treatment at the time of relapse has been effective and protocol re-treatment at 4- or Table 4 The clinical trials of rituximab in refractory ANCA-associated vasculitis. Study
Patients (nephritis)
Concomitant treatments
Remission (nephritis)
Serology changea
Relapse
Keogh (2005) Keogh (2006) Smith (2006) Stasi (2006)
11 (4) 10 (7) 11 (6) 10 (6)
GC, PLEX GC GC, MMF GC
10/11 CR, 1/11PR (4/4) 10/10 CR (7/7) 9/11 CR, 1/11 PR (6/6) 9/10 CR, 1/10 PR (6/6)
8/11 negative all decreased 6/10 negative all decreased 6/10 negative all decreased 8/10 negative all decreased
2 (7, 12 months) 1 (9 months) 6/10 (median 16.5 months) 3/10 (12, 16 and 24 months)
a ANCA for ANCA vasculitis; CR ¼ complete remission; PR ¼ partial remission; NR ¼ not reported; ANCA ¼ anti-neutrophil cytoplasmic antibody; AZA ¼ azathioprine; CYC ¼ cyclophosphamide; GC ¼ glucocorticoids; MMF ¼ mycophenolate mofetil; MTX ¼ methotrexate; PLEX ¼ plasma exchange.
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6-month intervals is under evaluation. A near-universal finding has been the achievement of peripheral B-cell (CD19- or CD20-positive lymphocytes) depletion below 1 106 l1 after rituximab, and failure to achieve depletion is correlated with poor or no clinical response. B-cell recovery is detectable after 6–9 months, and although prolonged B-cell depletion is associated with a prolonged clinical response, B-cell return is not closely associated with disease activity and relapses have occurred before B-cell return. In the minority of refractory vasculitis patients positive for ANCA at the time of rituximab therapy, changes in ANCA levels have reflected changes in disease activity; however, in general, ANCA levels are not predictive of relapse [40]. Rituximab dosing has copied that used in lymphoma, 375 mg m2 per week 4, or rheumatoid arthritis regimens, 1000 mg repeated after 2 weeks, although superficially the responses appear similar, these regimens have not been directly compared. The role of concomitant immunosuppressive therapy with rituximab, or for relapse prevention following treatment with rituximab, is controversial. In rheumatoid arthritis, there is a synergistic effect of methotrexate and rituximab, possibly due to a direct reduction of synovitis by methotrexate [42]. Immunosuppressive drugs do not appear to contribute to the duration of B-cell depletion, and there are no major differences in the duration of response between those studies continuing immunosuppression after rituximab and those that do not. The development of anti-chimaeric antibodies to rituximab (HACA) is found in up to 30%, and although they appear to have no clinical effect in the majority of cases, failure to induce depletion with repeat dosing has occurred [40]. Infusion reactions to rituximab occur in 20–40% of cases and are mostly mild, although severe reactions including meningism, anaphlyaxis and serum sickness have been reported. It is unclear whether the frequency of infections reported in current studies with rituximab in vasculitis represents any increase on what would be expected from concomitant therapy; this is an important aim of ongoing randomised trials. Late-onset neutropaenia is a transient phenomenon after treatment with rituximab that may be more common in those previously exposed to cytotoxic drugs. Occasionally, patients have developed hypogammaglobulinaemia and recurrent infection requiring IgG replacement. Thus, IgG levels should be monitored and falling levels should influence a decision to repeat treatment with rituximab. Cases of rituximab failure have been associated with lower rituximab doses and retro-orbital granulomata [43]. Paediatric practice There is limited experience of newer therapies in paediatric vasculitis. Important differences in the phenotype of paediatric vasculitis and an increased role of infection in their aetiology influence therapeutic decisions [44]. The role of MMF for remission induction of AAV is currently being explored, and rituximab and TNF-a blockade have been used in small numbers of patients. Current roles of newer therapies While the role of conventional agents is now well established following several randomised controlled trials, the place of newer therapies in routine vasculitis therapy remains to be determined. MMF and leflunomide can both be recommended as second-line alternatives to azathioprine and methotrexate for remission-maintenance regimens and remission induction in mild presentations. Plasma exchange increases the recovery of renal function in severe renal presentations, but it is unclear whether this provides a lasting benefit in terms of patient or renal survival. Plasma exchange is also considered in other severe presentations, such as lung haemorrhage without a good evidence base (Table 3). IVIg cannot be recommended for routine use in AAV, but can be considered where conventional agents are ineffective or contraindicated. Blockade of TNF-a has suffered from negative randomised trials for remission maintenance in AAV and giant cell arteritis, but a role in induction therapy and in refractory disease remains incompletely explored. T-cell depletion with anti-thymocyte globulin is complicated by the inability to re-use this drug in patients with a chronic relapsing disease; alemtuzumab can be considered in refractory vasculitis, but is a potent immunosuppressive agent which considerably increases the risk of severe infection (Table 5).
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Table 5 The current roles of biological agents in vasculitis. Agent
Indication
T-cell depletion with: Anti-thymocyte globulin Anti-CD52 (CAMPATH, alemtuzumab) B-cell depletion with: Rituximab Tumour necrosis factor blockade with: Etanercept Infliximab Aadalimumab
Consider in refractory AAV, little data in other vasculitis syndromes Consider in refractory AAV, little data in other vasculitis syndromes
Consider in refractory AAV, giant cell arteritis and Takayasu’s arteritis Potential alternative to infliximab
AAV ¼ ANCA-associated vasculitis.
Perhaps surprisingly, B-cell depletion with rituximab is now the most strongly supported newer biological therapy and its combination of apparently high efficacy rates in refractory disease and low drug-related toxicity makes it an attractive option. Rituximab cannot be recommended for routine induction therapy based on existing data, but it should be seriously considered in refractory disease in view of the lack of safe alternatives. However, the short duration of experience with rituximab, relatively small numbers of patients treated and lack of randomised trial information should indicate caution. Looking to the future In view of the small market size, vasculitis ‘borrows’ drugs developed for more common autoimmune indications. Current candidates for evaluation in vasculitis include co-stimulatory blockade with abatacept, blockade of interleukin 6 (IL6) with the anti-IL6 receptor monoclonal antibody tocilizumab, and alternative B-cell-modulating agents including anti-B-cell-stimulating factor monoclonal antibodies and anti-CD20 and Cd22 B-cell-depleting antibodies. For Churg–Strauss syndrome, modulation of eosinophils with interferon-a or blockade of IL5 is being investigated.
Practice points Mycophenolic acid and leflunomide are alternatives to methotrexate and azathioprine for remission-maintenance therapy or remission induction of early-systemic vasculitis Plasma exchange and intravenous immunoglobulin are adjunctive therapies that have been evaluated in many different vasculitis scenarios and provide options when vasculitis is severe or refractory or standard agents are contraindicated Biological agents cannot be currently recommended in the routine management of vasculitis, but they have potential roles and should be considered in refractory vasculitis Rituximab is the most promising biological for ANCA associated vasculitis in terms of its efficacy and safety, but current evidence is weak
Research agenda Evaluation of plasma exchange for renal vasculitis, creatinine <500 umol l1 and lung haemorrhage Evaluation of rituximab as routine remission-maintenance and refractory vasculitis therapy Evaluation of cytokine blockade (TNF-a and IL-6) as a component of induction therapy to permit steroid reduction and faster remissions Evaluation of the ability of alemtuzumab or stem cell transplantation to induce sustained, treatment-free remissions in refractory disease Development of biomarkers to assess vasculitis activity
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Acknowledgement This work was supported by the Cambridge Biomedical Research Centre.
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