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Vasculitis nrrheum.2014.67
1.
502 | AUGUST
2014 | VOLUME 10 www.nature.com/nrrheum Introduction Vasculitides encompass large, medium and small-vessel vasculitis, including a number of rare diseases with multisystem presenta- tions.1 Other than those with an infectious aetiology, most vasculitides are thought to be autoimmune in origin and are treated by inducing immunosuppression.2 How ever, immunosuppressant therapies have been associated with infection, leukopenia and certain types of malignancy, whilst corticosteroid use is associated with several complications including infection, weight gain, diabetes mellitus and osteoporosis.3,4 A need exists not only to define effective therapies and evaluate new therapeutics for vasculitis, but also to refine existing treat ments to minimize the exposure of patients to excessive immunosuppression. Several examples are available of successful clini- cal trial execution in vasculitis, especially in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), and these examples have formed the evidence base for our current management protocols. In large-vessel vasculitis (LVV), the clini- cal trial evidence for management is weaker than trial data for AAV; however, the field is moving forward with the establishment of multicentre collaborations, initiatives to standardize diagnostic criteria, and valida- tion of noninvasive imaging modalities and outcome measures. The commencement of a large multicentre randomized controlled trial (RCT) of tocilizumab in giant-cell arteritis (GCA; GiACTA)5,6 will, it is hoped, demonstrate the feasibility of such studies in LVV and facilitate further advances. RCTs performed for AAV and LVV to date, issues in trial design and challenges for the future are discussed in this Opinion article. Prerequisites for trials Box 1 lists the prerequisites for RCTs in vas- culitis. We have chosen to focus on AAV and LVV because these are the most common forms of vasculitis in adults, for which most data are available, but these diseases illus- trate the issues in clinical trial design for all forms of vasculitis. Multicentre collaborations Rare diseases often require multicentre trials to have sufficient statistical power to answer important therapeutic questions; such trials might need organization and collaboration across national borders, and might necessitate longer recruitment periods than trials in more common dis- eases. International conferences, the internet and the drive of medical leaders to spear- head clinical trials have had an important positive effect. Disease registries enabling rapid identification of eligible patients are also beneficial, as are disease interest groups that bring together specialists with a common interest in improving thera- pies. Broad consensus and support for the protocols are required in order for recruit- ment at multiple sites to be successful. This consensus can be difficult to achieve as local variations in management protocols exist, especially when the evidence base is limited. In particular, differences of opinion on the appropriate dosing, rate of tapering or discontinuation of corticosteroids can be an issue in vasculitis trials. Funders and stakeholders (including local investigators) need to have a vested interest in the success of clinical trials because of a genuine inter- est in the results and recognition of their individual input in publication reports. The development of new biologic agents has helped to foster collaborations between the pharmaceutical industry and academia to address unmet needs in rare diseases. How ever, the rapid recruitment targets some- times required by industry have, in our experience, also led to difficulties in some clinical trials in vasculitis because of slow patient recruitment. Efficient trial design Limitations on available patients and resources mean that it is important to define the most pressing questions to address and to predict how relevant the answer will be at the end of the trial, which can be up to 5 years from inception. In some circum- stances, more than one question can be addressed at once. For example, factorial design of the PEXIVAS trial will hopefully answer two questions, namely the roles of plasma exchange and of glucocorticoid dosing in AAV.7,8 Newer methods for clini- cal trial design (including computerized algorithms to avoid bias) are important, and the development of electronic case report forms and adverse-event reporting has streamlined the processes. Traditional trial designs, with fixed protocols in which data are analysed at the termination of the experiment, are mainly required for licensing new medicines. However, there is increasing interest in adaptive trial design in early-phase experimental medicine studies using Bayesian statistics to enable interim OPINION Issues in trial design for ANCA-associated and large-vessel vasculitis Ruth M.Tarzi, Justin C. Mason and Charles D. Pusey Abstract | Randomized clinical trials (RCTs) have informed the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, although challenges still exist. The evidence base for treating large-vessel vasculitis (LVV) is weaker, but initiatives to standardize diagnostic criteria and outcome measures, and to validate biomarkers in LVV, together with newly initiated RCTs should start to address this need. In this Perspectives, we discuss the prerequisites for RCTs in vasculitis, existing trial evidence, continuing unmet needs, potential therapeutic avenues to explore and considerations in the design of future trials. Tarzi, R. M. et al. Nat. Rev. Rheumatol. 10, 502–510 (2014); published online 6 May 2014; doi:10.1038/nrrheum.2014.67 Competing interests C.D.P. has received a research grant from GlaxoSmithKline. R.M.T. and J.C.M. declare no competing interests. PERSPECTIVES © 2014 Macmillan Publishers Limited. All rights reserved
2.
NATURE REVIEWS |
RHEUMATOLOGY VOLUME 10 | AUGUST 2014 | 503 analyses and the use of information gained during the trial to modify the study proto- col.9 In this way, more information can be gained from a smaller pool of patients. This approach has been taken with the CLEAR study, assessing a C5a receptor antagonist in AAV.10 Inclusion criteria Inclusion criteria for any trial need to be well defined. In vasculitis, however, evidence-based diagnostic criteria do not exist. Notably, the ACR classification cri- teria do not include specific criteria for microscopic polyangiitis11 and the Chapel Hill Consensus Conference definitions1 are often used, although they are formed by consensus rather than being evidence- based and do not include classification cri- teria. The DCVAS study (Diagnostic and Classification Criteria in Vasculitis Study) is an observational cohort study with the aim of developing evidence-based diagnos- tic criteria for vasculitic conditions; results are awaited.12 The need for multiple sites in trials means that the inclusion criteria must be well defined, and ideally include ‘hard’ criteria such as laboratory data or histological confirmation. When present, a positive ANCA test is a useful diagnos- tic marker for AAV, but specific serologi- cal biomarkers for LVV are not available.13 Whereas a biopsy is usually performed to confirm diagnosis in suspected AAV, histo- logical confirmation is not always obtained in the setting of characteristic features and a positive ANCA test, particularly in the setting of life-threatening disease. In LVV, arterial specimens are only collected from patients with Takayasu arteritis undergoing surgery; notably, insistence on histological confirmation by temporal artery biopsy in a GCA trial hindered recruitment.14 When biopsy-obtained tissue is available, central review of histological specimens is impor- tant to standardize assessments and confirm the diagnosis, and to stratify responses to therapy on the basis of histological stage. A histological categorization system has been developed that separates patients with glomerulonephritis owing to AAV into crescentic, focal, sclerotic or mixed groups according to analysis of renal biopsy samples.15 This scoring system is being validated to determine whether the histo- logical subgroups correlate with outcome. The ability to stratify disease is important to define more-homogeneous populations who might need to be managed differently. In AAV, the approach taken has been to stratify patients on the basis of the severity of their clinical presentation, and perform separate trials of management of severe, generalized and early systemic AAV. Outcome measures and end points Clinically meaningful outcome measures for vasculitis trials need to be validated, to act as end points that will be recognized by regu latory agencies. The Outcome Measures in Rheumatology group (OMERACT) has developed guidelines for the assessment of potential outcome measures in rheumatic diseases, based on three principles: truth, discrimination and feasibility. In evaluat- ing renal end points, hard composite end points (of death or end-stage renal disease) or doubling of serum creatinine level have been used. However, when multisystem disease manifestations are being studied, these outcomes are not sufficient. For AAV, OMERACT has provided an analysis of the available outcome measures and their valid- ity based on its three principles.16 Poten tial outcome measures for LVV are being evaluated by OMERACT.17 Robust means to monitor disease activ- ity and damage across multiple organ sites and systems are required for vasculitis trials. These tools require standardized definitions of disease activity and damage, and they should be sensitive to change and detect clinically relevant differences that would signal a modification in therapy. The Birmingham Vasculitis Activity Index (BVAS)18 and subsequent iterations (includ- ing the BVAS 3 and BVAS/WG) have been endorsed by OMERACT for AAV. The Dis ease Extent Index19 is another disease activ- ity index that has been used in AAV trials. BVAS was originally designed as a univer- sal vasculitis activity index, but the utility of BVAS for vasculitides other than AAV has not been well established. A Paediatric Vasculitis Activity Index has now been developed,20 and is currently undergoing validation. The Vasculitis Damage Index and the Combined Damage Assessment Index (CDA) are used to assess damage in AAV across multiple organ systems,21,22 although one study found that the Vasculi tis Damage Index was less time-consuming to complete than the CDA and captured similar information.22 For induction trials, remission rates are commonly used as an end point, and in maintenance trials, time to relapse or relapse event rates are often used. However, definitions of remission and relapse vary. For example, in the RAVE trial comparing rituximab to cyclophosphamide for remis- sion induction, remission was based on the absence of clinical features and no gluco corticoid use, whereas in the RITUXVAS trial, examining the same question, treat- ment was not part of the end point.23,24 Vari ations in end points between trials can make comparisons between trials difficult, hence the importance of agreement and standard- ization in analysis and reporting of trials. Surrogate end points using biomarkers, such as C‑reactive protein (CRP) or erythrocyte sedimentation rate (ESR) levels, proteinu- ria and haematuria are sometimes used in proof-of-concept studies. For definitive studies, there is a need to demonstrate that the biomarker in use is predictive of the clinical outcomes of interest. Cost-effectiveness Cost-effectiveness is an important aspect to consider when designing clinical trials, par- ticularly with expensive interventions such as biologic therapies. Cost-effectiveness analysis is based on the cost per quality- adjusted life-year gained by the treatment, compared with conventional therapy. It is therefore mandatory to include assessments of quality of life as one of the outcomes of clinical trials. The patient-reported out- comes form Short-Form 36 is widely used; interestingly, a patient-reported outcome measure that is specific for vasculitis is under development.16 Populations studied In clinical trials, the question always arises of whether the patients recruited truly mirror the population being studied. The AAV and LVV populations include large numbers of elderly patients with comorbidi- ties, who can sometimes be excluded from Box 1 | Vasculitis clinical trial prerequisites ■■ Robust multicentre collaborations ■■ Funding from government, charities or industry ■■ Address clinically important questions ■■ Achievable recruitment targets ■■ Protocols agreed by consensus, comparing to standard best practice ■■ Clear diagnostic criteria ■■ Inclusion criteria clearly defined ■■ Stratification for severity of disease and/or disease manifestations possible ■■ Activity and damage indices and quality of life measures designed and validated ■■ Validated outcome measures and/or end points ■■ Stakeholders, including investigators and funders, motivated and engaged FOCUS ON VASCULITIS © 2014 Macmillan Publishers Limited. All rights reserved
3.
504 | AUGUST
2014 | VOLUME 10 www.nature.com/nrrheum clinical trials for these reasons alone.25 It is therefore important to bear this in mind and for the trials to be as inclusive as pos- sible to enable them to assess the true clini- cal importance of the therapies being tested. A move towards greater transparency in access to patient-level clinical trial data, both in the academic and pharmaceutical sector, is gaining momentum.26,27 When trial results are negative, publication can sometimes be more difficult, but negative results can have important implications in avoiding ineffective therapies. As patients enter clinical trials altruistically, consid- eration of the ethics dictate that the data generated should be fully utilized. Trials of therapy in AAV The introduction of cyclophosphamide in the 1970s changed AAV from a disease with a high mortality to a relapsing–remitting chronic condition.28 However, the high incidence of adverse effects associated with large cumulative doses of cyclophospha- mide provided the impetus for clinical trials to establish less toxic, but nevertheless effec- tive, treatments.29,30 A number of organiza- tions, including national and international vasculitis societies in Europe and the USA have driven a number of successful multi- centre RCTs in AAV over the past 20 years. In particular, several trials have been organ- ized by the European Vasculitis Society, whose premise has been to subgroup vas- culitis according to severity, give high- intensity treatment to induce remission and low-intensity immunosuppression to prevent relapse, to agree a standard regimen by consensus, to test against the best alter- native by RCT and to use standardized scoring systems. Table 1 lists the multicentre RCTs for induction and remission maintenance ther apy that have been completed in AAV and summarizes their outcomes; Supplemen tary Table 1 online lists multicentre RCTs in AAV that are ongoing or just completed and not yet published. Successes RCTs in AAV have been successful in pro- viding an evidence base for the current management protocols, which is a major achievement in these rare diseases. The results of the trials have reduced exposure of patients with AAV to cyclophosphamide, which has helped to improve long-term outcomes, as evidenced by the reduced incidence of late-onset malignancy in current patients with AAV when compared with historical cohorts.4,30 The success of early trials has proven to funders that large multicentre RCTs in rare vasculitic diseases are possible, and facilitated funding of the current generation of clinical trials in vas- culitis. Although the individual trials were not able to capture events such as mortal- ity, long-term malignancy risk and chronic damage, later analysis and pooling of results from a number of trials have enabled these questions to be addressed.3,4,31 The RAVE and RITUXVAS trials have established that rituximab is noninferior to cyclophosphamide for induction of remission in AAV,23,24 adding an alternative option for patients in whom cyclophospha- mide avoidance is desirable. Even larger global collaborations are now occurring, in terms of the number of centres and patients involved in current RCTs; for example, the PEXIVAS trial7,8 and the RITAZAREM trial.32 Academic and industry collabora- tions have also been helpful for funding the use of expensive biologic therapies in RCTs and the vasculitis trials have also enabled the collection of serum, plasma, DNA and cellular samples from well-characterized cohorts of patients, which is an invaluable tool for biomarker research. Issues to consider Owing to the rarity of AAV, most of the trials to date have included patients with both granulomatosis with polyangi itis (GPA) and microscopic polyangiitis (MPA). Although some of the clinical fea- tures overlap, there are notable differences. For example, granulomatous manifesta- tions do not occur in MPA, and the patho genesis of granulomatous disease and time course of response to treatment probably differs from ‘pure’ vasculitis.33 In addition, GPA is substantially more prone to relapse than MPA.34 GPA and MPA have been con- firmed as different diseases with different MHC susceptibilities in a genome-wide association study published in 2012.35 The study also demonstrated that the genetic associations were more robust for the bio markers myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA rather than the clinical phenotypes of MPA and GPA. In view of this finding, and the fact that none of the clinical algorithms currently in use reliably distinguishes MPA from GPA, it has been proposed that ANCA status be used to stratify patients rather than the clinical phenotypes.36 In future trials, it will be important to assess outcomes of MPA and GPA, or MPO-ANCA and PR3-ANCA disease, separately, particularly in trials of remission maintenance; it might also be time to consider whether trials should be designed to address whether GPA and MPA should be treated differently. Because of their short follow-up, results of initial RCTs in AAV have varied to some extent from those of long-term follow-up studies. However, caution should be exer- cised in interpreting the results of long-term follow-up data that have been collected retrospectively after the end of the trials, as these data are weaker and should not be used to contest the primary end point of the properly controlled RCT. In the CYCLOPS study in AAV, no difference was obser ved in the rate of remission between the intravenous and oral cyclophosphamide groups.37 However, the long-term analysis (average follow-up 4.3 years) subsequently demonstrated a higher relapse rate in the intravenous cyclophosphamide group, although there was no notable difference in survival or renal function at long-term follow-up.38 The MEPEX trial was designed to assess dialysis independence at 3 months in patients with AAV and serum creatinine level 500 μmol/l. Although benefit from plasma exchange in terms of this end point was achieved and maintained to 12 months, follow-up for a median of 3.95 years dem- onstrated no difference in mortality.39,40 This uncertainty has led to the design of the PEXIVAS trial, recruiting a larger number of patients (n = 500), and hopefully this study will definitively answer the ques- tion of when plasma exchange is indicated in AAV with glomerulonephritis.7 The REMAIN trial—a remission maintenance trial addressing the length of maintenance therapy in GPA—was instigated in 2003, but the answers have been substantially delayed, as recruitment, follow-up and reporting has taken 10 years.41 This delay challenges the motivation of investigators, and the need to demonstrate outcomes to employers and funders. Future directions Several trials in AAV are ongoing or not yet published (Supplementary Table 1). Priorities that we feel need to be addressed in current and future clinical trials in AAV are listed in Box 2. For example, infections continue to be the most common cause of mortality in patients within the first year after diagnosis of AAV,42 and no reduction in infections was seen in the rituximab- treated groups versus the cyclophosphamide arms in the RAVE or RITUXVAS trials.23,24 PERSPECTIVES © 2014 Macmillan Publishers Limited. All rights reserved
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RHEUMATOLOGY VOLUME 10 | AUGUST 2014 | 505 Table 1 | Published multicentre RCTs in AAV Trials Indication Trial design* Primary end point Brief results Induction trials NORAM64,65 Newly diagnosed GPA or MPA, with early systemic involvement Induction: trial, oral methotrexate 15–25 mg per week + tapering Pred (n =51); control, oral cyclophosphamide 2 mg/kg per day* (tapering to 1.5 mg per day once remission attained) + tapering Pred (n = 49) All treatment discontinued by 12 months Remission at 6 months Methotrexate noninferior to oral cyclophosphamide in inducing remission at 6 months, but relapse rate higher in methotrexate group at 18 months CYCLOPS37,38 GPA or MPA with renal involvement, but serum creatinine 500 μmol/l Induction: trial, IV cyclophosphamide 15 mg/kg for 2–3 weeks + tapering Pred (n = 76); control, oral cyclophosphamide 2 mg/kg per day* + tapering Pred (n = 73) Maintenance: azathioprine 2 mg/kg per day + Pred Time to remission IV cyclophosphamide noninferior to oral cyclophosphamide with lower cumulative dose Less leukopenia in IV group MEPEX39,40 Severe renal GPA or MPA with serum creatinine 500 μmol/l Induction: trial, PLEX + oral cyclophosphamide 2.5 mg/kg per day reducing to 1.5 mg/kg per day at 3 months + Pred (n = 70); control IV methyl Pred 1 g daily for 3 days + oral cyclophosphamide 2.5 mg/kg per day reducing to 1.5 mg/kg per day at 3 months + Pred (n = 67) Maintenance: azathioprine 2 mg/kg + Pred Dialysis independence at 3 months Renal survival better with PLEX than IV methyl Pred No difference in safety or mortality RITUXVAS24 Newly diagnosed GPA or MPA with renal involvement Induction: trial, rituximab 375 mg/m2 per week for 4 weeks + Pred + IV cyclophosphamide 15 mg/kg (weeks 0 and 2) (n = 33); control, IV cyclophosphamide 15 mg/kg + Pred (n = 11) Maintenance: Pred alone (rituximab group) or azathioprine + Pred (cyclophosphamide group) Sustained remission at 12 months and adverse event rates Rituximab noninferior to IV cyclophosphamide; no difference in adverse event rate RAVE23,66 New or relapsing GPA or MPA (excluding serum creatinine 4.0 mg/dl [equivalent to ~354 μmol/l], or pulmonary haemorrhage) Induction: trial, rituximab 375 mg/m2 per week for 4 weeks + Pred (n = 99); control, oral cyclophosphamide 2 mg/kg + Pred (n = 98) Maintenance: Nil (rituximab group) or azathioprine 2 mg/kg (IV cyclophosphamide group) Remission without Pred at 6 months Rituximab noninferior to oral cyclophosphamide Rituximab more effective than cyclophosphamide in relapsing patients Maintenance trials CYCAZAREM67 GPA or MPA, new or relapse with renal or multiorgan involvement Induction: cyclophosphamide 2 mg/kg per day + tapering Pred Maintenance: trial, azathioprine 2 mg/kg per day + 10 mg Pred (n = 71); control, oral cyclophosphamide 1.5 mg/kg once daily + 10 mg Pred (n = 73) Relapse rate No difference in relapse rate IMPROVE68 Newly diagnosed GPA or MPA Induction: oral or IV cyclophosphamide (as per CYCLOPS above) + Pred Maintenance: trial, MMF 2 g per day + tapering Pred (n = 76); control, azathioprine 2 mg/kg per day + tapering pred (n = 80) Relapse-free survival MMF less effective than azathioprine in maintaining remission No difference in adverse events WEGENT69 GPA or MPA with renal or multi-organ involvement Induction: IV cyclophosphamide 15 mg/kg every 2–3 weeks + tapering Pred Maintenance: trial, methotrexate (up to 25 mg per week) + tapering Pred (n = 63); control, azathioprine 2 mg/kg per day + tapering Pred (n = 63) Adverse event causing treatment cessation or death No difference between azathioprine and methrotrexate in adverse events or relapse WGET70 GPA and BVAS 3 Induction: oral cyclophosphamide 2 mg/kg or methotrexate 0.25 mg/kg per week, up to 25 mg per week + Pred Maintenance: trial, methotrexate up to 25 mg per week + etanercept 25 mg subcutaneously twice a week (n = 89); control, methotrexate up to 25 mg per week (n = 92) Remission for 6 months Addition of etanercept failed to improve remission rates German Network of Rheumatic Diseases study71 GPA and serum creatinine level 1.3 mg/dl (equivalent to ~115 μmol/l) Induction: oral cyclophosphamide 2 mg/kg per day + Pred Maintenance: trial, leflunomide 30 mg per day + Pred (n = 26); control, methotrexate 7.5–20 mg per week + Pred (n = 28) Relapse Leflunomide more effective than methotrexate in maintaining remission, but with more adverse events *Cyclophosphamide doses adjusted for age and renal function in all of the trials. Abbreviations: AAV, antineutrophil cytoplasmic antibody-associated vasculitis; BVAS, Birmingham Vasculitis Activity Score; GPA, granulomatosis with polyangiitis; IV, intravenous; MMF, mycophenolate mofetil; MPA, microscopic polyangiitis; Pred, prednisolone or prednisone; PLEX, plasma exchange; RCT, randomized controlled trial. FOCUS ON VASCULITIS © 2014 Macmillan Publishers Limited. All rights reserved
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2014 | VOLUME 10 www.nature.com/nrrheum A reduction in corticosteroid exposure might be an avenue to explore in this regard. The PEXIVAS and CLEAR studies are both investigating whether reductions in steroid exposure are possible in AAV induction therapy. Another issue to address is the man- agement of frequent relapse, which is espe- cially common in those with granulomatous upper airway disease, who can often be exposed to several courses of induction treatment during their lifetime, with atten- dant treatment-related comorbidity and the potential for cumulative disease-induced damage. The RITAZAREM trial is examin- ing whether repeated dosing of rituximab will have an effect on relapse rates in AAV compared with azathioprine.32 A number of other biologic agents targeting pathways of importance in the pathogenesis of AAV are available, some of which are currently under evaluation (Figure 1). Ultimately, a means to restore immunological tolerance in AAV is required. Trials in eosinophilic granulomatosis with polyangiitis (EGPA) are scarce, owing to its rarity when compared with GPA and MPA.43 Glucocorticoids are effective for nonsevere presentations, but patients with cardiac, neurological or renal involvement with a five-factor score of ≥1 have been shown to benefit from the addition of cyclophospha- mide to the steroid-containing regimen.44 Reports of successful treatment of EGPA with rituximab are available, but no RCT at present.45,46 A trial of the anti-IL‑5 mono clonal antibody mepolizumab in EGPA is now recruiting.47 Clinical trials in LVV LVV is characterized by granulomatous inflammation in the aorta and its major branches.48 The two main forms of LVV are GCA, which is reasonably common, with an incidence of 7–29 per 100,000 in white Europeans 50 years old, and Takayasu arteritis, which is rare, with an incidence of 3 per 1 million population, and presents predominantly in women 40 years of age.48,49 Clinical trials including therapies other than corticosteroids in LVV com- pleted to date and their major findings are listed in Table 2; trials in progress are listed in Supplementary Table 2. Issues to consider Imaging The gold standard for diagnosis of GCA is evidence of arteritis in a temporal artery biopsy sample. The TABUL trial is cur- rently evaluating whether colour Doppler ultrasonography is sensitive and specific for this condition, and whether it might, in due course, represent a less-invasive diagnostic technique.50 A study suggests that this benefit might indeed be the case, which will help standardize clinical trial recruitment.51 Moreover, advances, avail- ability and understanding of the role of other noninvasive imaging modalities, including contrast-enhanced MRI, CT Box 2 | Priorities for future clinical trials in vasculitis AAV ■■ Development of biomarkers for the identification of patients with AAV at risk of relapse ■■ Corticosteroid minimization protocols to reduce steroid-induced adverse-effect burden ■■ Refinements to reduce the toxicity of induction therapy for elderly patients ■■ Therapeutics with faster speed of onset of action for induction therapy ■■ Therapies with faster speed of onset in granulomatous disease ■■ Trials addressing the management of the maintenance phase of PR3-ANCA and MPO-ANCA disease as separate entities ■■ More-effective maintenance strategies for relapsing patients ■■ Therapies to re-establish immunological tolerance LVV ■■ Clear definition of outcome measures and the role of imaging in clinical trials ■■ Development of biomarkers to enable patient stratification in GCA at diagnosis ■■ Development of biomarkers for the identification of patients with LVV at risk of relapse ■■ Corticosteroid minimization protocols to reduce steroid adverse-effect burden ■■ Trials to address the role of adjunctive immunosuppressive therapy in GCA and Takayasu arteritis (e.g. methotrexate as a steroid-sparing drug) ■■ Development of international clinical trial networks for LVV including patients from Asia, Europe and the Americas Abbreviations: AAV, ANCA-associated vasculitis; ANCA, antineutrophil cytoplasmic antibody; GCA, giant-cell arteritis; LVV, large-vessel vasculitis; MPO, myeloperoxidase; PR3, proteinase 3. C5a Myofibroblast Vascular DC C5a–C5aR Eculizumab CCX168 BAFF–APRIL Belimumab Atacicept Veltuzumab Ocrelizumab Ofatumumab Rituximab* CD20 Epratuzumab CD22 Everolimus Sirolimus mTOR Belatacept Abatacept CTLA-4 TH 17 cell TH 1 cell IL-6–IL-6R Tocilizumab IL-1–IL-1R Anakinra Canakinumab Macrophage ANCA Neutrophil SYK Fostamatinib Ustekinumab Briakinumab IL-12/IL-23 Belatacept Abatacept CTLA-4 Brodalumab Ixekizumab Secukinumab IL-17 AAV targets TH 17 response B cells Auto-antibody production Co-stimulation Inflammatory cells Complement Fcγ receptors Cytokines LVV targets TH 1 response Vascular DC activation Cytokines Inflammatory cells Myofibroblast proliferation Reactive oxygen species Neovascularization B cell IFN-γ Fontolizumab Figure 1 | Potential therapeutic targets in AAV and LVV. Schematic diagram showing potential therapeutic targets in AAV and LVV, including examples of biologic therapies and small-molecule inhibitors targeting these pathways. *Of these agents, only rituximab is licensed for the treatment of AAV, whereas several of the other agents are under evaluation. Abbreviations: AAV, ANCA-associated vasculitis; ANCA, antineutrophil cytoplasmic antibody; APRIL, a proliferation- inducing ligand (also known as TNF ligand superfamily member 13); BAFF, B-cell activating factor of the TNF family (also known as TNF ligand superfamily member 13B); CTLA-4, cytotoxic T-lymphocyte protein 4; DC, dendritic cell; LVV, large-vessel vasculitis; mTOR, mammalian target of rapamycin; SYK, spleen tyrosine kinase; TH (cell), helper T (cell). PERSPECTIVES © 2014 Macmillan Publishers Limited. All rights reserved
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RHEUMATOLOGY VOLUME 10 | AUGUST 2014 | 507 angiography and 18 FDG-CT-PET might also facilitate trials in LVV, particularly if they can be shown to correlate with disease activity or damage and be incorporated into appropriate disease-scoring systems.49 Outcome measures Disease activity indices for LVV are less developed than for AAV, which has made clinical trial implementation difficult. A particular problem has been the identi- fication of valid biomarkers to distinguish active disease from damage. An initiative to develop a core set of outcome measures for use in clinical trials of LVV was launched by the international OMERACT Vasculitis Working Group in 2009.17 In addition, The Indian Takayasu Clinical Activity Score (ITAS2010) was published in 2013 and validated in 300 patients with Takayasu arteritis.52 Multiple different end points have been used in clinical studies of LVV; the main categories used in clinical trials for GCA relate to clinical outcomes (time to remission, time to relapse, relapse rates), laboratory measures and glucocorticoid- sparing effects. However, some of the clini cal outcomes are rather vague and subjective (fatigue, headache, arthralgia), whereas other manifestations can be asymptomatic until later stages when they are irreversible (for example, sudden-onset visual loss). Steroid tapering Standard treatment of GCA with cortico steroids is highly effective in inducing remission,48 but relapses on steroid taper- ing are common, and the need to avoid the adverse effects of prolonged steroid courses in elderly patients has provided an impetus to develop steroid-sparing regimens. Trials of adalimumab and etanercept in GCA have proven negative.14,53,54 Trials using metho- trexate as a steroid-sparing agent in GCA have given conflicting results. Mahr et al.55 performed a meta-analysis of three placebo- controlled trials (comprising a total of 161 patients across the three trials) of patients with new-onset GCA who were randomly assigned to either corticosteroids alone or with the addition of methotrexate or placebo. Despite the mean dose of methotrexate over the total period of intake being lower than the recommended dose at only 11.1 mg per week, a steroid-sparing effect in GCA was found.55 However, further analysis of these trials, and indeed many vasculitis studies, raises the important and unresolved issue of optimal corticosteroid-tapering schemes. In all vasculitis trials, decisions regard- ing steroid-tapering protocols are challeng- ing. A balance needs to be drawn between the desire to optimise the chance of dem onstrating a beneficial effect of adjunctive therapy, and too rapid a reduction in the corticosteroid dose with the associated risk of disease flare and complications. Likewise, too cautious tapering might mask the bene ficial effect of a new therapeutic approach. The three trials designed to assess the role of methotrexate in the treatment of GCA illustrate this problem.56–58 These trials used different steroid-reduction regimens, all of which were more rapid than many practitioners would use in clinical practice. Relapse rates were fairly high, with 61% and 29% of patients experiencing a first and second relapse, respectively.55 In particular, a switch to alternate-day prednisone dosing seemed to lead to a high incidence of vision loss.56 Ideally, steroid-tapering regimens for future studies should be consistent. Two possible approaches might be consid- ered. The first would be to adopt a standard Table 2 | Published RCTs of therapeutics in LVV, excluding trials of steroid dosing alone Trials Indication Trial design Primary end point Brief results Induction trials Jover et al. (2001)57 Biopsy-proven new-onset GCA Induction: trial, 10 mg methotrexate weekly plus Pred (tapering) (n = 21); control, placebo plus Pred (tapering) (n = 21) Number of disease relapses and cumulative corticosteroid dose Substantial reduction in relapses and reduced corticosteroid dose in methotrexate group at 24 months Speira et al. (2001)58 Biopsy-proven new-onset GCA or ESR 50 mm/h and clinical features Induction: trial, methotrexate 7.5–20 mg per week plus Pred (n = 12); control, placebo plus Pred (n = 9) Cumulative corticosteroid dose No statistically significant difference in corticosteroid dosage between the groups at 12 months Only one major relapse occurred Hoffman et al. (2002)56 Patients 50 years old with diagnosis of GPA within 6 months of entry by biopsy or clinical features and raised ESR level Induction: trial, methotrexate median dose 15 mg per week plus Pred (tapered off by 6 months) (n = 51); control, placebo plus Pred (tapered off by 6 months) (n = 47) First relapse and treatment failure rates No notable difference in treatment failures between the groups Seror et al. (2013)14 Patients 50 years old with new-onset GCA Induction: trial, adalimumab (40 mg every 2 weeks) for 10 weeks + tapering Pred (n = 34); control, placebo plus tapering Pred (n = 36) Remission on 0.1 mg/ kg Pred at week 26 Adjunctive adalimumab did not increase the proportion of patients achieving the end point Maintenance trials Infliximab-GCA study group (2007)53 Newly diagnosed GCA with ESR 40 mm/h and clinical criteria for GCA in corticosteroid- induced remission Induction: Pred Maintenance: trial, infliximab 5 mg/kg IV (week 0, 2, 6 then every 8 weeks) + Pred tapering over 24 weeks (n = 28); control, placebo + Pred tapering over 24 weeks (n = 16) Number of patients relapse free at week 22 and adverse events No benefit of infliximab in reducing relapse rates Etanercept trial in GCA (2008)54 Biopsy-proven GCA in remission with corticosteroid-induced adverse effects Induction: Pred Maintenance: trial, etanercept 25 mg subcutaneous twice a week plus Pred (tapering; n = 9); control, placebo plus Pred (tapering; n = 8) Rates of steroid discontinuation with controlled disease at 12 months No statistically significant difference in percentage of patients steroid-free at 12 months (50% vs 22%), but small patient numbers Abbreviations: ESR, erythrocyte sedimentation rate; GCA, giant cell arteritis; IV, intravenous; LLV, large-vessel vasculitis; Pred, prednisone or prednisolone; RCT, randomized controlled trial. 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2014 | VOLUME 10 www.nature.com/nrrheum protocol described in guidelines such as those proposed by the British Society for Rheumatology.59 Second, the GiACTA trial will compare two clearly defined prednisone tapering regimens, the first a rapid reduction from 60 mg to withdrawal over 26 weeks, and the second, which is more representa- tive of clinical practice, with tapering from 60 mg to 1 mg over 52 weeks.5 Recruitment A trial of adjunctive adalimumab in GCA published in 201314 illustrates some of the problems in recruiting to clinical trials. Initi ally, the trial required histological confirma- tion of GCA with temporal artery biopsy, but this criterion was dropped during the trial because of slow recruitment of participants. Statistical power calculations suggested that 100 patients were required, but due to slow recruitment the trial was terminated after recruiting 70, 10 of whom had not received their allocated therapy. This difficulty in recruitment reduced the power of the study to 72%, although it is questionable whether it affected the outcome.14 Trials in progress The GiACTA trial, an RCT of the anti-IL‑6 receptor antibody tocilizumab in GCA, has started recruiting; it is the largest RCT in GCA to date, aiming to recruit 250 patients over 100 centres worldwide (Supplemen tary Table 2).5,6 In this trial, the entry cri teria include either positive temporal artery biopsy, or evidence of LVV by noninvasive imaging with magnetic resonance angio graphy, CT angiography or CT‑PET. These criteria represent an important change for GCA trials and should improve the homo- geneity of the study population, compared with reliance on clinical criteria, as positive biopsies are often not obtained. The trial will use the absence of GCA symptoms, together with normal levels of ESR and CRP, as the primary efficacy end point at 52 weeks; how ever, it is important to note that the effect of IL‑6 inhibition on the synthesis of acute- phase reactants, including potent suppres- sion of CRP, might not necessarily reflect control of inflammation in the arterial wall. A second trial currently recruiting is the ABVAS trial, evaluating the efficacy of abatacept in treating GCA and preventing disease relapse (Supplementary Table 2).60 In Takayasu arteritis, no RCTs have been completed to date, which reflects the rarity of the disease, the lack of suitable activity and damage indices, and difficulty sur rounding selection of suitable end points. The ABVAS trial is underway and aims to evaluate abatacept in treating both GCA and Takayasu arteritis.60 Hopefully, if this trial is successful, it will enable trials of other potential therapies, such as TNF inhibitors and tocilizumab to be formally evaluated in Takayasu arteritis. Evidence from small open-label studies of the latter biologic agents in patients with refractory Takayasu arteritis are encouraging and reveal pro- longed efficacy.61–63 However, important caveats remain surrounding biologic thera- pies in Takayasu arteritis, including whether tocilizumab attenuates arterial wall inflam- mation, in addition to suppressing the acute- phase response. Multinational RCTs are now required to generate convincing evidence of efficacy for both anti-TNF and anti-IL-6 receptor therapies. Future directions The paucity of clinical trials in LVV and the lack of progress when compared with AAV, although in urgent need of redress, empha- sises the considerable challenge in planning effective trials in LVV. A key factor is the use of high-dose corticosteroids as the main stay of treatment in LVV, and the tendency in GCA for overtreatment with steroids owing to concern regarding the risk of blindness. A second critical factor is the need to define, agree and validate outcome measures for LVV trials. Many queries remain and these include whether end points can be agreed that are the same for GCA and Takayasu arteritis, so that patients with either condi- tion can be included in a single trial. The role of imaging must also be determined. Although noninvasive imaging can detect arterial damage, its role in assessing disease activity in the arterial wall as increased wall thickness, oedema or wall enhancement has yet to be established. These questions are being addressed by OMERACT, and OMERACT 10 has initiated an international expert Delphi exercise, the results of which are awaited.17 Results of trials of methotrexate therapy in LVV have produced conflicting results.55 However, we would argue that this conflict could reflect underpowered clinical trials, inadequate doses of the immunosuppressive drug and the lack of reliable outcome meas- ures. When considering future clinical trials, there is a strong case for a large, adequately powered placebo-controlled trial of metho- trexate as an adjunct to corticosteroids. This trial should be of sufficient duration (ideally 2-year follow-up) and investigate a steroid- sparing effect and improved maintenance of remission in GCA and Takayasu arteritis. In a reasonably common disease such as GCA, and a rare disease such as Takayasu arteri- tis that affects patients in countries where access to biologic agents is limited, there is a strong case for studying a fairly cheap and widely used drug such as methotrexate. The well-designed, large and comprehensive GiACTA trial will hopefully set a benchmark for the study of biologic therapies and a suc- cessful outcome would be a huge stimulus to this field and lead to further pharmaceutical company interest. Improved understanding of the patho- genesis of GCA and the identification of a persistent relatively corticosteroid-resistant type 1 helper T‑cell response in the arterial wall has helped identify novel therapeutic targets (Figure 1).48 Consideration must also be given to combination therapy that is not restricted to control of inflammation; thus, vascular dendritic cell activation, myo fibroblast proliferation, generation of reac- tive oxygen species and neovascularisation of the arterial wall all contribute to patho- genesis in LVV and should be considered in future trials. The antiproliferative actions of the mammalian target of rapamycin (mTOR) antagonists sirolimus and everolimus, which can suppress myofibroblast proliferation, might well have a part to play, particularly in patients developing arterial stenoses.48,49 Conclusions In conclusion, the future of clinical trials in vasculitis is looking brighter, due to the for- mation of networks of individuals with the motivation to improve the evidence base for the management of vasculitis. A number of new potential therapies are on the horizon. In AAV, more evidence is required for indi- vidualizing therapy for PR3-ANCA and MPO-ANCA disease (or GPA and MPA), and for therapy for EGPA, and steroid- sparing protocols are required. Biomarkers to identify those patients most likely to relapse and more effective means to maintain remission in relapsing patients are required. In LVV, not enough data is available yet to validate the end points and outcome meas- ures that are in use, but that situation should change after the current generation of RCTs in LVV are completed. Studies of new imaging modalities in LVV are also under- way and these might well provide important biomarkers for future clinical trials if they can be validated. Large studies will always require consortia with established leaders, and large-scale governmental, charitable or industry funding. However, there is still PERSPECTIVES © 2014 Macmillan Publishers Limited. All rights reserved
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RHEUMATOLOGY VOLUME 10 | AUGUST 2014 | 509 a place for experimental medicine studies that can be performed with smaller groups of intensively studied patients. These studies can be followed up by larger trials in which the protocol in use shows promise. Although there is no doubt that biologic therapies will have an important effect on the manage- ment of vasculitis in the coming years, one should bear in mind that many advances have been achieved by simple refinements to existing therapies, such as a reduction in cyclophosphamide exposure in AAV. Renal and Vascular Inflammation Section, Department of Medicine (R.M.T., C.D.P.), Vascular Sciences Unit, National Heart and Lung Institute (J.C.M.), Hammersmith Hospital Campus, Imperial College London, Du Cane Road, London W12 0NN, UK. Correspondence to: R.M.T. r.tarzi@imperial.ac.uk 1. Jennette, J. C. et al. 2012 revised international Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum. 65, 1–11 (2013). 2. Hamour, S., Salama, A. D. Pusey, C. D. Management of ANCA-associated vasculitis: current trends and future prospects. Ther. Clin. Risk Manag. 6, 253–264 (2010). 3. Robson, J. et al. Damage in the ANCA- associated vasculitides: long-term data from the European Vasculitis Study group (EUVAS) therapeutic trials. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis- 2013-203927. 4. Heijl, C. et al. Incidence of malignancy in patients treated for antineutrophil cytoplasm antibody-associated vasculitis: follow-up data from European Vasculitis Study Group clinical trials. Ann. Rheum. Dis. 70, 1415–1421 (2011). 5. Unizony, S. H. et al. Design of the tocilizumab in giant cell arteritis trial. Int. J. Rheumatol. 2013, 912562 (2013). 6. US National Library of Medicine. Clinical trials.gov [online], http://www.clinicaltrials.gov/ct2/show/ NCT01791153?term=NCT01791153rank=1 (2013). 7. Walsh, M. et al. 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