The role of biologics in treatment of ANCA-associated vasculitis

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1 Mod Rheumatol (2012) 22: DOI /s y REVIEW ARTICLE The role of biologics in treatment of ANCA-associated vasculitis Chethana Dharmapalaiah Richard A. Watts Received: 29 July 2011 / Accepted: 4 October 2011 / Published online: 29 October 2011 Ó Japan College of Rheumatology 2011 Abstract The vast majority of patients with anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV) who receive conventional treatment with glucocorticoids and cyclophosphamide experience frequent relapses and treatment-related side-effects. Increasing knowledge of the pathogenesis of AAV has permitted the development of targeted therapies against tumour necrosis factor (TNF)-a and T and B lymphocytes. Therapy with TNF-a blocking drugs has so far proved disappointing, and this approach is not recommended. B cell depletion using rituximab is effective for remission induction, especially in refractory patients. The long-term side-effects and the best method of using rituximab to maintain remission are still to be determined. Keywords Vasculitis Rituximab Infliximab Etanercept Treatment Introduction The anti-neutrophil cytoplasmic autoantibody (ANCA)- associated vasculitides (AAV) comprising granulomatosis with polyangiitis (GPA, previously called Wegener s granulomatosis, WG [1]), microscopic polyangiitis (MPA) and Churg Strauss syndrome (CSS) are chronic multisystem autoimmune diseases characterized by ANCA C. Dharmapalaiah R. A. Watts (&) Department of Rheumatology, Ipswich Hospital NHS Trust, Heath Road, Ipswich IP4 5PD, UK Richard.watts@ipswichhospital.nhs.uk R. A. Watts Norwich Medical School, University of East Anglia, Norwich, UK production and necrotizing, predominantly medium- and small-vessel vasculitis. They share similar clinical and serologic features and treatment responses. The AAV are rare, with estimated annual incidence of approximately 20/million in Europe, with GPA generally being the most common and CSS the least frequent [2]. In other regions of the world such as Japan, MPA is more common than GPA [3]. The aetiopathogenesis is unknown, but like most autoimmune diseases they are thought to arise from an interaction between an environmental factor and a genetically predisposed host. The prognosis for AAV has improved considerably over the past 30 years. The natural history of untreated GPA and MPA is of a rapidly progressive, usually fatal disease. Walton [4] observed a mean survival in patients with GPA of 5 months, with 82% of patients dying within 1 year and more than 90% dying within 2 years. The introduction of cyclophosphamide (CYC) combined with prednisolone resulted in a significant improvement in mortality of GPA with a 5-year survival rate of 82% [5], although there remains considerable morbidity associated with both disease and treatment. In the European Vasculitis Study Group (EUVAS) s there was 11.1% mortality at 1 year, with 59% of deaths occurring due to adverse effects of therapy compared with 19% of deaths due to active vasculitis and 48% due to infection [6, 7]. The EUVAS cohort has now been followed up for a median of 5.2 years; after the first year the main causes of death are cardiovascular disease (26%), malignancy (22%) and infection (20%) [7]. Multivariate analysis shows that renal function [estimated glomerular filtration rate (GFR) \15 ml/min], increasing age, higher Birmingham Vasculitis Activity Score (BVAS), lower haemoglobin and higher white cell count were significant negative prognostic factors for patient survival [7].

2 320 Mod Rheumatol (2012) 22: The evidence base for management of the AAV is now well established, and the strategy of induction, consolidation and maintenance therapy generally accepted. Patients are staged depending on whether they have limited or early (nonorgan-threatening) disease, generalized disease, or severe disease with imminent threat to life or organ. The British Society for Rheumatology (BSR) [8] and the European League Against Rheumatism (EULAR) have developed guidelines for the management of medium- and small-vessel vasculitis including AAV [9]. These guidelines were for the most part based on the results of a series of randomised controlled s conducted by the EUVAS during the 1990s and 2000s which used this approach to staging treatment [10 13]. The majority of patients with AAV receive glucocorticoids combined with cyclophosphamide for induction followed by azathioprine with a glucocorticoid taper for maintenance. Patients with mild non-organ-threatening disease may receive methotrexate as an alternative to CYC, whilst patients with severe life-threatening disease typically pulmonary haemorrhage or significant renal impairment (serum creatinine [500 lmol/l) receive adjuvant plasma exchange [8, 9]. The significant toxicity, in particular infection, malignancy and haemorrhagic cystitis, associated with currently available cytotoxic immunosuppressants makes therapeutic alternatives highly desirable. Novel therapies are therefore required to reduce toxicity and also to treat patients with relapsing disease refractory to conventional therapies. Advances in the understanding of the pathogenesis of AAV have resulted in s of novel biologic agents. Anti-TNF-a therapy TNF-a plays an important role in the pathogenesis of AAV. It primes neutrophils, resulting in subsequent interaction with ANCA and endothelial cells, and also has a role in granuloma formation [14, 15]. On incubation of neutrophils with TNF-a, there is increased expression of myeloperoxidase (MPO) and proteinase 3 (PR3) on the outer membrane of neutrophils, increasing their availability for subsequent binding of ANCA antibodies [16 19]. Based on this, the anti-tnf-a agents infliximab, etanercept and adalimumab have been tried in the treatment of AAV. Infliximab Several case series support induction of remission using infliximab (Table 1) [20 23]. Infliximab, a monoclonal chimeric anti-tnf-a antibody, was used in refractory systemic vasculitis including GPA/MPA at doses of 3 5 mg/kg, mostly given on days 0, 14 and 42, then monthly. Summarizing the evidence from above case series in Table 1, Mukhtyar and Luqmani [24] calculated that remission was achieved in 43/53 (81%) of refractory AAV patients treated with infliximab. Duration of treatment and follow-up were variable, making the numbers difficult to interpret. However, the relapse rate was at least 12% (5 relapses from 43 remissions). In a more recent study by Morgan et al. [25], 33 patients with active AAV participated. They were treated with standard therapy (17 patients) (corticosteroids with CYC with additional plasma exchange in case of life- or organthreatening disease) or standard therapy plus infliximab at weeks 0, 2, 6 and 10 (16 patients). The addition of infliximab to standard therapy did not confer clinical benefit for patients with active AAV. The risk of serious infections, including reactivation of tuberculosis, Haemophilus influenzae pneumonia, Klebsiella urinary tract infection, Staphylococcus aureus skin abscess and Nocardia endophthalmitis requiring evisceration of the eye, have been reported in the studies. The dose of infliximab used in the studies is higher than that used to treat rheumatoid arthritis (RA) (usually 3 mg/kg); the rate of serious infection seen was higher than observed in the RA patients and is probably a consequence of the higher dose used and the more intense immunosuppression used prior to infliximab in AAV patients. Etanercept Etanercept (ETA) is a soluble TNF-a inhibitor consisting of two extracellular p75 TNF-a receptor domains linked to the Fc portion of human IgG1. In a 6-month open-label conducted by Stone et al. [26], etanercept at dose of 25 mg subcutaneously twice weekly was added to standard treatment in 20 patients with persistently active disease or acute flares of GPA. BVAS improved at 6 months, but intermittent flares were common. The Wegener s Granulomatosis Etanercept Trial (WGET) [27] was a multicentre, randomised, placebocontrolled which evaluated ETA for maintenance of remission in 180 patients with GPA (BVAS of at least 3). ETA 25 mg subcutaneously twice weekly or placebo was added to standard therapy after randomisation. In the ETA group 69.7% of patients and 75.3% in the control group attained sustained remission (BVAS = 0) lasting at least 6 months. The rates of disease flares did not differ significantly between the groups. Six solid cancers were identified in the ETA group, with similar rates of infections. The results did not support use of ETA as an adjunct to conventional therapy for maintenance of remission in GPA.

3 Mod Rheumatol (2012) 22: Table 1 Studies using infliximab in treatment of ANCA granulomatosis with polyangiitis and microscopic polyangiitis No. Study type n Diagnosis (n) Intervention Remission (n) Reference 1 Uncontrolled 2 Uncontrolled 3 Uncontrolled 4 Uncontrolled 5 Open-label controlled 6 Refractory GPA (3)/MPA (3) 6 Refractory GPA CS, CYC, IFX (3 5 mg/kg; days 0, 14, 42, then monthly) 32 GPA/MPA (16 first presentation or relapse, 16 persistent disease) 10 Refractory GPA (7)/other (3) 16 IFX arm, 17 control arm (b) GPA/MPA first presentation or relapse CS, IFX (200 mg monthly) 5 (BVAS = 0.8) Booth et al. [20] CS, S/T, CYC, AZA, MTX, MMF, IFX (5 mg/kg; days 0, 14, 42, then monthly) CS, IFX a (5 mg/kg; days 0, 14, 42, then 2 monthly) CS, CYC, IFX (5 mg/kg; days 0, 14, 42 and 70) 5 (BVAS = 0) Lamprecht et al. [21] 28 (BVAS = 0.3) Booth et al. [22] CR 5 (BVAS = 0); PR 5 (BVAS [0 but inferior to the entry score Bartolucci et al. [23] 33 (BVAS \1) Morgan et al. [25] b-ifx arm received standard therapy plus IFX, and control arm received standard therapy alone CS and CYC with additional plasma exchange in case of life- or organ-threatening disease AZA azathioprine, CR complete remission, CS corticosteroids, CYC cyclophosphamide, IFX infliximab, MMF mycophenolate mofetil, MPA microscopic polyangiitis, MTX methotrexate, PR partial remission, S/T sulphamethoxazole/trimethoprim, GPA granulomatosis with polyangiitis a Two patients with severe disease received additional therapy with CYC and with MTX and MMF, respectively Adalimumab Adalimumab (ADA) is a humanised anti-tnf-a monoclonal antibody. It was employed in a phase II, open-label, prospective study that enrolled 14 patients with AAV, either as first manifestation of disease or relapse [28]. ADA was given at dose of 40 mg subcutaneously every 2 weeks for 3 months along with CYC and reducing dose of prednisolone. Remission was achieved in 78.5% within 14 weeks, and BVAS fell from 11.9 to 2. The prednisolone dose reduced from 37.1 to 8.1 mg/day at 14 weeks. In conclusion, the response rates and adverse events were similar to standard therapy alone but with reduced prednisolone exposure. Further randomised controlled s (RCTs) are required to confirm this. In summary, the role of anti-tnf agents in remission induction is uncertain, there are data supporting their use, but only from uncontrolled studies. Randomised controlled s are needed to establish the role of TNF blockers in remission induction. Use of etanercept for remission maintenance is not recommended, as the WGET did not support its use. The incidence of adverse effects such as infections, malignancy, autoimmunity and thromboembolic complications are a concern and need to be evaluated further in this group of patients with significant previous exposure to cytotoxic drugs. Alemtuzumab Auto-reactive T cells are thought to play a major role in the development of AAV [29, 30]. The humanised monoclonal antibody anti-cd52 alemtuzumab (CAMPATH-1H) depletes circulating T lymphocytes, macrophages and monocytes, all of which are important in the pathogenesis of AAV [30, 31]. Walsh et al. employed alemtuzumab for induction of remission in an uncontrolled in 71 patients with refractory or relapsing AAV [32] after stopping other immunosuppressants and tapering prednisolone to 10 mg/day. In a mean follow-up time of 5 years, a total of 60 patients (85%) achieved clinical remission. However, 43/71 relapsed (median 9.2 months), and adverse effects were common, including infections (Staphylococcus species, cytomegalovirus (CMV), Pneumocystis jiroveci, Aspergillus, Pseudomonas, Escherichia, Salmonella, Actinomyces and mixed anaerobes), thyroid disease and malignancy. In conclusion, alemtuzumab appears to be capable of inducing remission of refractory and relapsing AAV. A randomised control testing the efficacy of alemtuzumab is required before recommending alemtuzumab as a standard treatment for refractory AAV. Anti-IL5 antibody Mepolizumab, a humanised anti-interleukin-5 (IL5) monoclonal antibody was used in an open-label pilot study by Kim et al. [33] to treat 7 patients with CSS. The primary objective was to assess whether mepolizumab safely decreased CSS disease activity and permitted steroid tapering. In addition to assessment of treatment-related adverse effects, the primary outcome was the lowest

4 322 Mod Rheumatol (2012) 22: prednisone dose achieved at the end of the treatment phase. It was safe and well tolerated, offering clinical benefit by enabling steroid tapering from a baseline of mg/day at the end of 12 weeks of therapy. However, on cessation of mepolizumab, CSS manifestations recurred, necessitating further courses of glucocorticoids. Rituximab Granulomatosis with polyangiitis and MPA are systemic vasculitides associated with production of ANCA by plasma cells. Activated B cells correlate with disease activity, and auto-antigen-specific B cells are present at sites of inflammation. The regulation of T lymphocytes is dependent on B cell function. B cell depletion using rituximab (RTX) has therefore been proposed as a therapeutic strategy for AAV. Rituximab is an anti-cd20 chimeric monoclonal antibody that depletes B cells and plasma cells; it has been licensed for treatment of non-hodgkin s lymphoma and RA. Several small studies with RTX for treating refractory GPA and MPA have demonstrated promising evidence with remission induction rates often [80% [34 42]. Rituximab has been used successfully with induction of remission in three patients with CSS and renal involvement [43]. RAVE and RITUXVAS are two randomised controlled s that have evaluated the efficacy of B cell depletion in remission induction of AAV (Table 2). The RAVE [44, 45] compared RTX (375 mg/m 2 iv weekly 9 4) with oral CYC (2 mg/kg/day) in patients with new or relapsing AAV, excluding those with serum creatinine [4 mg/dl or severe alveolar haemorrhage. Patients were followed for a minimum of 18 months. CYC was replaced by AZA between 3 and 6 months if remission was achieved, and AZA continued for remainder of 18 months, whereas RTX group received placebo. All patients received 1 3 g iv methylprednisolone followed by 1 mg/kg/day prednisolone tapered over 5.5 months. The primary end-point was remission defined as BVAS for GPA (BVAS/GPA) of 0 in the absence of prednisolone at month 6. One hundred ninety-seven patients with severe active (mean BVAS/GPA 8.4) GPA or MPA were enrolled (3:1). All patients were ANCA positive. The groups were matched for disease severity, subtype, organ involvement and ANCA type. Patients with a new diagnosis of AAV accounted for 49% of patients in each arm. Sixty-four per cent of the RTX group and 53% of the CYC group achieved primary end-point at 6 months. At 12 and 18 months, 42% and 36% in the RTX arm compared with 38% and 31% in the CYC arm remained in remission off glucocorticoids. Relapse rates were not different, but relapse was more common in PR3-positive patients. The average cumulative glucocorticoid dose was significantly lower in the RTX arm (3270 versus 3678 mg, p = 0.031) by 12 months but not at 18 months. There was no difference in the adverse events rate between the 2 arms at 18 months. A planned subgroup analysis of those entering with relapsing disease demonstrated the superiority of RTX over CYC for this group of patients. RAVE demonstrated that a single course of RTX was as effective for remission induction and maintenance as 18 months of conventional therapy. The RITUXVAS [46, 47] compared a RTX regimen (375 mg/m 2 iv weekly 9 4 along with mg/kg iv CYC) with a standard iv CYC regimen ( mg/kg), both with the same iv and oral glucocorticoid regimen, in 44 (33 RTX arm, 11 CYC arm) newly diagnosed patients with AAV with renal vasculitis and mean egfr at entry of 21 ml/min. The primary end-point at 12 months was BVAS = 0 for at least 6 months. Initial follow-up at 1 year showed a 76% remission rate in the RTX arm and 82% in the CYC arm. At 2 years, the primary composite outcome of relapse, death or end-stage renal failure occurred in 42% in the RTX group compared with 36% in the CYC group. There was no difference in safety. RAVE and RITUXVAS did not demonstrate the expected benefit of RTX with respect to safety. RAVE showed equivalent side-effect rates between RTX and oral CYC. This is perhaps surprising since oral CYC has been previously shown to be inferior to iv CYC pulses regarding cumulative toxicity (CYCLOPS ) [12]. Infection rates were similar in both arms in RITUXVAS, and mild to moderate infusion reactions were not uncommon. This would suggest that infections are more due to glucocorticoids than to CYC. The rate of malignancy shown in RAVE was concerning (5% of the RTX group compared with 1% in the control arm). It is worth noting that, in the RITUXVAS study, the patients enrolled had more severe disease, as demonstrated by higher BVAS scores on enrollment, which might account for the higher death rates. Nevertheless, the deaths occurring early in the course of treatment were indeed a point of concern. There are many unanswered questions regarding optimum use of RTX, because of which recommendations have recently been developed for its use in AAV [48]. The optimum dose regimen for RTX in induction in AAV has not been determined. The lymphoma regime uses a dose of 375 mg/m 2 /week for 4 consecutive weeks with a cumulative dose of g. The RA regime administers two infusions of 1 g RTX given

5 Mod Rheumatol (2012) 22: Table 2 Comparison of the main features of the RAVE and RITUXVAS studies RAVE RITUXVAS Study design Double-blind double-dummy Open-label randomised Randomised Two-group parallel design Non-inferiority Non-superiority Multicentre (9 centres) Multicentre (8 centres) (USA based) (Europe/Australia) Number of patients 197 (all included in analysis) 44 (all included in analysis) Randomisation 99 RTX? PLC versus 98 CYC? PLC 33 RTX versus 11 CYC RTX versus control 1:1 3:1 Inclusion criteria (i) ANCA? (i) ANCA? (ii) Severe disease (ii) Renal involvement (iii) BVAS/GPA [3 (iii) New Dx (iv) New or old Dx Diagnosis breakdown GPA:MPA 3:1 GPA:MPA 1:1 Median age (years) 54 (at onset of symptoms) 68 Newly diagnosed at enrolment 49% 100% BVAS at entry (median) RTX group Control group Remission induction RTX group GC? RTX GC? RTX? CYC (29 pulses) Control group GC? CYC GC? CYC Dosing Rituximab 375 mg/m weeks 375 mg/m weeks Cyclophosphamide RTX group Placebo 15 mg/kg iv (29 pulses, 1st and 3rd) Control group 2 mg/kg/day po 15 mg/kg iv (6 10 cycles) Glucocorticoids iv 1 g methylpred (1 3 pulses), po prednisolone 1 mg/kg iv 1 g methylpred, po prednisolone 1 mg/kg Taper to 0 by 5 months Taper to 5 mg by 6 months Maintenance therapy RTX group RTX? none (tapering GC) RTX? none (tapering GC) Control group CYC? AZA at 3 6 months CYC? AZA at 3 6 months End-points Primary end-point 6/12 12/12 BVAS/WG = 0 BVAS = 0 for at least 6/12 Completion of GC taper in 6/12 SAE rates Outcome RTX versus control All patients at 6 months 64% versus 53% (p value 0.13) 76% versus 82% (p value 0.68) New diagnosis versus relapsing disease at 67% versus 42% (p value 0.01) n/a 6 months Follow-up RAVE 18 months 36% versus 31% in remission of glucocorticoids 21% versus 18% relapse 18% versus 27% death RITUXVAS 24 months ESRD 6% versus 0% Refs. [44 47] RTX rituximab, PLC placebo, CYC cyclophosphamide, GC glucocorticoids, BVAS Birmingham Vasculitis Score, AZA azathioprine, SAE severe adverse event, GPA granulomatosis with polyangiitis, MPA microscopic polyangiitis, methylpred methylprednisolone, ESRD end-stage renal disease

6 324 Mod Rheumatol (2012) 22: with a 2-week interval. Both RAVE and RITUXVAS used the lymphoma regime. In a retrospective review of 65 patients, Jones et al. [49] compared the two regimes for AAV and found them of equal efficacy. There was no difference in duration of B cell depletion or therapeutic effect, despite the fact that the mean serum concentration after using the lymphoma regime is higher than that achieved with the RA regime. The latter results in a lower total dose of RTX over a shorter period of time, but is more convenient for patients and also for cost and administration purposes. For remission maintenance there is no clear evidence as to the best strategy. There are several possible approaches: (1) treat only on relapse, (2) treat prophylactically on rising ANCA level and (3) treat routinely every 6 months irrespective of clinical status or ANCA level for 2 years. Rituximab is, however, effective at relapse. Jones and colleagues in a single-centre open study compared protocolised retreatment with RTX using 1 g 9 2 followed by 1 g every 6 months for 2 years (total 5 g) with early immunosuppression and glucocorticoid withdrawal versus non-protocolised treatment (either 1 g 9 2, 375 mg/m 2 9 4) only repeated at relapse [47]. At 2 years, relapse had occurred in 11/49 (22%) patients in the protocol group versus 26/34 (76%) in the non-protocol group. Infection rates were similar (14% versus 18%). There remain concerns about long-term toxicity, especially development of multifocal leucoencephalopathy [50] in patients with autoimmune disease. Hypogammaglobulinaemia occurs with repeat dosing, with up to 47% developing IgG \7.0 g/l and 4% IgG \3.0 g/l, and is associated with severe infection [51]. Previous immunosuppression is a probable contributor to development of hypogammaglobulinaemia. Late-onset neutropaenia following RTX is well recognised in lymphoma patients and has been reported occurring in 23% of patients receiving RTX for GPA [52]. Median time to onset of neutropaenia was 102 days, and occurrence was associated with B cell depletion and a significant risk of infection. Treatment with granulocyte colony-stimulating factor may be required. There are, however, several groups in which use of RTX is justified now. Patients with relapsing disease who have been treated with CYC respond to RTX and therefore should receive RTX in place of second or more courses of CYC, because CYC toxicity (infection and bladder cancer) is closely related to cumulative CYC dose. Pre-menopausal women in whom the risk of permanent infertility is high should be considered for RTX, as RTX is not known to be associated with infertility. The rates of infection are generally low in RTX-treated patients [53], and therefore RTX is justified in patients at high risk of infection. Discussion The AAV used to be fatal diseases with very high mortality, which has been transformed in recent years by the introduction of aggressive immunosuppressive therapies. However, these therapies are associated with significant toxicity, co-morbidity (e.g. infection, malignancy, infertility) and often do not have the desired efficacy due to recurrent relapses. Modern treatment protocols are still associated with significant mortality, which early in the disease is due to active uncontrolled vasculitis or infection and late in the disease due to cardiovascular disease. Relapse is still a problem, especially in the PR3-positive patient, and recent data suggest that these patients are at much greater risk of relapse than MPO-positive patients. There is therefore an urgent need to develop new, less toxic but more effective treatments for both induction and remission maintenance. Targeted therapies against the B cell are currently the great hope. Understanding the implications of B cell activity in the pathophysiology of AAV has created a clinical need for more targeted treatment, which should aim to minimise toxicity. Currently, RTX is the best studied B cell-depleting agent. RAVE and RITUXVAS, whilst providing evidence that RTX is at least as effective as CYC for induction, have not so far shown significantly superior relapse rates or toxicity profiles. However, in refractory and relapsing patients, RTX was found to be superior to standard treatment. However, it is this group of patients where the cumulative exposure to immunosuppressive agents is highest that the implementation of a safer and less toxic treatment is more compelling, making the need for further data on the long-term safety profile of RTX even more relevant. In these straitened financial times, cost is an issue and so far no costeffectiveness data have been published for use of RTX in place of CYC. However, RTX should be considered in the younger female patient at risk of infertility and also in those at high risk of infection. Further studies are urgently required to answer some of the many questions posed above, in particular the most appropriate regimen, frequency of readministration and long-term outcome in terms of clinical effectiveness and safety. The next generation of s will need to be stratified and powered adequately for ANCA type. Conflict of interest R.A.W. has been a consultant to Euro Nippon Kayaku GmbH, Frankfurt/M, Germany, and to Roche Pharmaceuticals. All other authors have declared no conflicts of interest. References 1. Falk RJ, Gross WL, Guillevin L, Hoffman GS, Jayne DRW, Jennette JC, Kallenberg CGM, Luqmani R, Mahr AD, Matteson EL, Merkel PA, Specks U, Watts RA, for the American College

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