Vasculitis Highlights

Philip Seo, MD, MHS

Abstract:  550 - Rituximab Versus Cyclophosphamide for Induction of Remission in ANCA-Associated Vasculitis: A Randomized Controlled Trial (RAVE)

Authors: 

J.H. Stone, P.A. Merkel, P. Seo, R. Spiera, C.A. Langford, Gary S. Hoffman, C.G.M. Kallenberg, E. William St. Clair, B.J. Fessler, N. Tchao, L. Ding, L.V. Webber, D. Ikle, D. Weitzenkamp, W. Wu, P. Brunetta, L. Seismundo, F.C. Fervenza, K.A. Keogh, E. Y. Kissin, K.S. Mieras, P.A. Monach, T. Peikert, C. Stegeman, S.R. Ytterberg, U. Specks and The RAVE-ITN Research Group

Background: 

The treatment of systemic vasculitis has not advanced substantially since the introduction of cyclophosphamide for the treatment of severe forms of these diseases.  Although effective, the use of cytotoxic agents is accompanied by substantial morbidity.  The RAVE trial is a multicenter trial that examined the feasibility of using rituximab for the treatment of severe flares of Wegener’s granulomatosis and microscopic polyangiitis.

Methods: 

Mulinational, randomized, double-blind, placebo-controlled trial comparing rituximab (375 mg/m2 IV weekly for 4 weeks) versus cyclophosphamide (2.0 mg/kg/d po) for 3-6 months followed by azathioprine (2 mg/kg/d po) for remission maintenance.  Glucocorticoids were tapered by protocol, and the primary endpoint was defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG) of 0 at 6 months without the use of concurrent glucocorticoids (i.e., low dose prednisone).

Results: 

197 subjects with severe forms of Wegener’s granulomatosis or microscopic polyangiitis were enrolled.  An equal number of subjects in the rituximab and cyclophosphamide arms achieved the primary endpoint (64% versus 55%, P=0.21).  This observation did not change substantially when the analysis was limited to subjects who entered the trial with pulmonary hemorrhage or glomerulonephritis.  When only subjects with relapsing disease were considered, substantially more subjects achieved remission when treated with rituximab (66.7% versus 42.0%, P=0.013). 

Conclusions: 

Rituximab is non-inferior to cyclophosphamide for the treatment of severe flares of Wegener’s granulomatosis and microscopic polyangiitis.

Editorial: 

Advances in the treatment of systemic vasculitis up to this point have been incremental, largely identifying therapeutic strategies that represent small changes over the standard of care.  The RAVE trial for the first time demonstrates that patients with severe forms of Wegener’s granulomatosis and microscopic polyangiitis may be treated successfully without resorting to cytotoxic therapies, a potential boon for younger patients or patients with chronically relapsing disease.  Enthusiasm for rituximab as a vasculitis therapy must be tempered by the relatively short follow-up available at this time.  One must examine the ostensibly low rates of remission in context; the definition of remission used here is considerably more strict than that employed by other studies, which generally have allowed patients in “remission” to have low-level disease activity and/or remain on some low dose of glucocorticoids.  It is worth noting that in post-hoc analysis, allowing subjects to remain on low dose glucocorticoids did not change the overall conclusion.

Abstract:  1975 - Pediatric Takayasu Arteritis: Significance of Central Nervous System Manifestations

Authors: 

Daniela S. Ardelean, Rayfel Schneider, Earl D. Silverman, Ronald M. Laxer, Pascal Tyrell, Michael Seed, Shi-Joon Yoo and Susanne M. Benseler

Background:

Takayasu’s arteritis is one of the rarest forms of systemic vasculitis, affecting approximately 1/million.  Pediatric Takayasu’s arteritis is even more uncommon, making this diagnosis particularly challenging to manage.  This study addresses this important issue by review of a single referral center’s experience with this uncommon diagnosis.

Methods: 

Retrospective cohort of subjects diagnosed with pediatric Takayasu’s arteritis who were evaluated at the University of Toronto between 1986 and 2008, and were followed clinically for at least one year.

Results: 

Six boys and 12 girls who met the inclusion criteria were identified.   Half of these patients presented with CNS manifestations, such as seizure, stroke, or severe headache.  All subjects had evidence of large vessel stenosis; 11% also had evidence of aneurysms.  Two-thirds of patients had both proximal and distal aortic involvement.  Interestingly, 44% of subjects did not have elevation in acute phase reactants at the time of initial evaluation.  Adverse events were not uncommon: in this cohort, there were 2 deaths, 5 subjects had persistent disease, and 4 subjects relapsed while on immunosuppression.

Conclusions: 

CNS events are a common presenting feature of pediatric Takayasu’s arteritis.  Normal acute phase reactants do not rule out this diagnosis.  Even with chronic immunosuppression, flares are not uncommon.

Editorial: 

A former mentor of mine was fond of saying that tests basically show you what you are looking for.  One can imagine that, when faced with a young child following a stroke or seizure, most pediatricians are not looking for evidence of Takayasu’s arteritis.  One wonders if this explains, in part, the poor outcomes experienced by these patients (who were generally diagnosed with advanced disease) and whether more aggressive screening and earlier treatment might have led to better outcomes.  Finally, this study highlights the problems inherent to extrapolating the therapy of children from our experience treating adults, and the importance of multicenter clinical trials to address these fundamental questions regarding natural history and appropriate management.  In particular, TNF blockade has rapidly become part of the standard-of-care for the treatment of adult forms of Takayasu’s arteritis; it is therefore noteworthy that few of the patients in this cohort received anti-TNF therapy, likely reflecting the paucity of data supporting the use of these agents for pediatric Takayasu’s arteritis.

Abstract:  1973 - Long-Term Surgical and Medical Outcome in Takayasu Arteritis: Vascular Procedures Performed in Active Patients Have a Poor Outcome

Authors: 

Muge Bicakcigil, Kenan Aksu, Sevil Kamali, Servet Akar, Omer Karadag, Huseyin T. Ozer, Fatos Onen, Sibel Z. Aydin, Neslihan Yilmaz, Zeynep Ozbalkan, Askin Ates, Ayse Cefle, Veli Cobankara, Mesut A. Onat, Ercan Tunc, Yasar Karaaslan, Nurullah Akkoc, A. Eftal Yucel, Gokhan Keser, Sedat Kiraz, Murat Inanc and Haner Direskeneli, Turkish Takayasu's Arteritis Study Group

Background: 

Large vessel stenosis is a common consequence of Takayasu’s arteritis, potentially leading to claudication and severe ischemic pain. 

Methods:

Prospective cohort of 184 patients recruited from 13 centers in Turkey.

Results: 

Remission was achieved by 89% of subjects after an average of 11.3 months of treatment.  However, only 51% had a sustained remission, and 42% of patients relapsed during follow up, despite the use of chronic immunosuppression.  Of 77 revascularization procedures, restenosis occurred in 35%.  Restenosis was significantly more likely among subjects who were not receiving immunosuppressive therapy at the time of the procedure (23% versus 45%, P=0.04), or who had active disease (80% versus 20%, P=0.02)

Conclusions: 

Glucocorticoids are effective for remission induction of Takayasu’s arteritis, but many subjects will fail to remain in remission despite chronic therapy.  One-third of vascular interventions will fail; failure is more likely among subjects with active disease and/or who are not receiving chronic immunosuppression.

Editorial: 

This abstract, which reflects outcomes of a very large cohort of subjects with this uncommon disease, echoes observations made in other cohorts regarding the long-term efficacy of surgical intervention among subjects with Takayasu’s arteritis.  Ironically, the emergent situations that provide the greatest justification for vascular intervention are also the most likely to fail.  The high failure rate may reflect difficulties achieving sustained remission in this patient population using standard therapies, and emphasizes the need for alternative agents.  A clinical trial of abatacept for the treatment of Takayasu’s arteritis (NCT00556439-44195) is underway in the United States, and may at some point represent a viable therapy for these patients.

Abstract:  1972 - Adding Hydroxychloroquine to Prednisone Does Not Improve the Outcome in Giant Cell Arteritis. A Double Blind Randomized Controlled Trial

Authors: 

Laurent Sailler, Maryse Lapeyre-Mestre, Loïck Geffray, Philippe Letellier, Eric Liozon, Philippe Montané de La Roque, Mohamed Hamidou, Eric Oziol, Nadine Magy, Philippe Arlet,, Jean-Louis Montastruc and the investigators of the Horton-hydroxychloroquine trial

Background: 

Glucocorticoids are the cornerstone of therapy for giant cell arteritis.  The impact of adjunctive therapies to date has been disappointing.  Hydroxychloroquine is an immunomodulatory drug that has been effective for the treatment of systemic lupus erythematosus and rheumatoid arthritis; this French trial explored the possibility that hydroxychloroquine might benefit patients with giant cell arteritis as well.

Methods: 

Multicenter, double-blind, placebo-controlled trial of 74 patients randomized to receive treatment with hydroxychloroquine 400 mg po daily or placebo for up to 96 weeks.

Results: 

Ten subjects were randomized, but did not receive study drug.  The remaining 64 subjects were evenly divided between hydroxychloroquine and placebo.  There was no difference in cumulative corticosteroid exposure in the two groups.  Use of hydroxychloroquine did not impact on the percentage of subjects who achieved the primary endpoint, which was defined as clinical remission for ≥ 3 months while taking ≤ 5 mg/day of prednisone.  Post-hoc analysis indicated that subjects who were randomized to receive treatment with hydroxychloroquine were actually act greater risk of disease flare (hazard ratio 2.52, 95% confidence interval 1.1-5.6).

Conclusions: 

Hydroxychloroquine is not effective for the treatment of giant cell arteritis.

Editorial: 

Finding a steroid-sparing agent that is effective for the treatment of giant cell arteritis has been an elusive goal.  Epidemiologic research indicates that patients who take low-dose aspirin may be at lower risk of cranial ischemic events such as blindness, but this does not eliminate the need for glucocorticoids.  Infliximab failed to demonstrate a significant benefit in a multinational randomized trial.  A much smaller series similarly failed to demonstrate benefit to cyclosporine.  Methotrexate likely has some impact on disease outcomes, but the impact is small, and the drug seems to be more effective in theory than in practice for the treatment of this disease.  Hydroxychloroquine is now added to the long list of drugs that provide no benefit to patients with giant cell arteritis.  The post-hoc analysis indicating that it may actually place giant cell arteritis patients at greater risk of disease flare is intriguing, and this observation may overlie an important insight regarding the pathogenesis of this disease.

Abstract:  1971 - Aortic Involvement in Patients with Newly Diagnosed Giant Cell Arteritis (GCA). A Prospective Study Using Computed Tomography (CT) Angiography

Authors: 

Sergio Prieto-González, Pedro Arguis, Ana García-Martínez, Georgina Espígol-Frigolé, Montserrat Butjosa, Itziar Tavera, Josep M. Grau, José Hernández-Rodríguez and Maria C. Cid

Background: 

A small number of patients with giant cell arteritis will present with symptoms mimicking Takayasu’s arteritis, such as arm claudication.  A larger number of patients will present with the canonical headache syndrome.  Recently, it has become clear that even these patients often have significant aortic involvement, and are at substantial risk of developing complications involving the aorta.  This study attempts to define this risk among subjects newly diagnosed with giant cell arteritis.

Methods: 

Subjects who presented to the University of Barcelona with new diagnoses of giant cell arteritis were eligible for this trial.  CT angiography was used to identify evidence of aortitis, aneurysmal dilatation, or stenosis.

Results: 

13 women and 11 men underwent CT angiography, 12.5% of whom were found to have previously-unsuspected aortic aneurysms.  The majority of subjects (70%) were found to have aortic wall enhancement consistent with aortitis.  Almost all subjects (94%) had involvement of the descending aorta.  No abnormalities were detected in CT angiograms of control subjects who were matched for age, sex, and cardiovascular risk factors.

Conclusions: 

Aortitis and aortic dilatation are frequently found among patients with giant cell arteritis.

Editorial: 

It has recently become clear that all patients with giant cell arteritis are at substantial risk of future complications involving the aorta, whether or not such symptoms were part of their initial presentation.  This risk seems to exist despite the use of adequate immunosuppression.  This study demonstrates that many patients who develop aortic aneurysms years after diagnosis likely had some involvement of the aorta at the time of disease inception that was both undetected and unsought.  Screening MRI or CT scan may be an important method of identifying subjects at the highest long-term risk of developing an aortic aneurysm, although data to support this strategy are currently lacking.  Also, it would be premature to make too many decisions based on the presence of aortitis (here defined by aortic enhancement), since analogous studies using MRI have demonstrated that enhancement does not always indicate the presence of active disease. 

Abstract:  1970 - Hidden Diagnoses in Temporal Artery Biopsy Paraffin Blocks : The GRACG Study

Authors: 

Pierre Duhaut, Jean Schmidt, Denis Chatelain, Fabienne Bellarbre, Amar Smail, Valery Salle, Sylvie Bosshard, Jean -Charles Piette, Hélène Pellet, Henri Sevestre, Jean-Pierre Ducroix and GRACG study members

Background: 

Not all patients with giant cell arteritis will have a temporal artery biopsy that confirms the diagnosis.  From previous studies, we know that giant cell arteritis is characterized by skip lesions that may make the diagnosis difficult to establish pathologically, especially if a sufficiently large segment of artery is not taken.  This interesting study asks whether more diagnoses could be established if we simply looked more carefully.

Methods: 

Bilateral temporal artery biopsies from 145 patients previously evaluated for giant cell arteritis were re-processed with 50-100 micrometer sections throughout the block.  All biopsies were previously felt to have no evidence of vasculitis.  Each slide was reviewed by a pathologist blinded to the clinical history and diagnosis.

Results: 

Reprocessing of these temporal artery biopsy specimens yielded a new diagnosis of vasculitis in 12% of cases.  Three cases demonstrated arteritis with giant cells, 2 cases demonstrated arteritis alone, 3 cases demonstrated healed arteritis, and 9 demonstrated evidence of small vessel vasculitis in the area surrounding the temporal artery.  In almost all cases (88%), these new findings were present unilaterally.  These data changed the clinical diagnosis for 10 subjects, who were previously diagnosed with headache syndrome, fever of unknown origin, and other diagnoses.

Conclusions: 

Biopsy-negative giant cell arteritis may, in some cases, reflect the way in which temporal artery biopsies are obtained and processed.  Unilateral biopsies are not adequate to detect evidence of vasculitis in all cases.

Editorial: 

Approximately 10% of patients with giant cell arteritis are said to be “biopsy-negative”.   This study implies that at least some of these patients may actually be biopsy-positive, and might benefit from a closer look.  In absolute terms, this observation would likely affect only a small number of patients, but it may be worthwhile to examine temporal artery biopsies in cases in which there is insufficient clinical evidence to justify empiric treatment for giant cell arteritis.  This study also highlights the importance of bilateral temporal artery biopsies, given that evidence of vasculitis was present unilaterally in the majority of specimens reviewed.  Finally, this study reminds us that giant cell arteritis is not the only form of vasculitis that can be diagnosed by temporal artery biopsy; ANCA-associated vasculitis and cryoglobulinemic vasculitis in particular can affect the temporal arteries and surrounding small vessels.

Abstract:  647 - Comparison of Disease Manifestations of ANCA-Associated Vasculitis Based On ANCA Type Among Participants in a Multicenter Clinical Trial

Authors: 

U. Specks, P.A. Merkel, P. Seo, R. Spiera, C. A. Langford, C.G.M. Kallenberg, E. William St. Clair, B.J. Fessler, N. Tchao, L.V. Webber, L. Ding, W. Wu, D. Ikle, D. Weitzenkamp, F.C. Fervenza, K.A. Keogh, P. Brunetta, E. Y. Kissin, K.S. Mieras, P.A. Monach, T. Peikert, L. Seismundo, C. Stegeman, S.R. Ytterberg, J. H. Stone and The RAVE-ITN Research Group

Background: 

Most patients with Wegener’s granulomatosis are PR3-ANCA positive, while the majority of patients with microscopic polyangiitis are MPO-ANCA positive.  This raises the question of whether ANCA-status is more important than clinical diagnosis when it comes to patient classification.  This study examined subjects in the Rituximab for ANCA-associated Vasculitis (RAVE) trial to address this question.

Methods: 

Subjects in the RAVE trial were stratified by ANCA status and baseline characteristics were examined.

Results: 

All of the 197 subjects enrolled in the RAVE trial were ANCA-positive; two-thirds were PR3-ANCA positive, and one-third were MPO-ANCA positive. Half of the patients in the RAVE trial were newly diagnosed with vasculitis at the time of enrollment.  When only these newly-diagnosed patients were examined, it was found that PR3-ANCA positive patients were younger (49 versus 61, P<0.05), more likely to be male (64% versus 39%, P<0.05), and had higher activity scores (BVAS/WG 9.8 versus 8.3,P<0.05).    PR3-ANCA positive patients were also more likely to have joint, mucous membrane, ENT, and granulomatous lung involvement than patients who were MPO-ANCA positive.  MPO-ANCA positive patients, on the other hand, were more likely to present with glomerulonephritis.

Conclusions: 

Clinical phenotypes correlate with ANCA status.  It is reasonable to stratify patients enrolled in a clinical trial based on ANCA status.

Editorial: 

Clinical trials depend on clinical phenotyping to ensure a homogeneous population, a process that is especially fraught in multinational trials.  Stratification by ANCA type may be an easy way to obviate this problem, by replacing clinical assessment with an objective test.  It is important to remember, however, that this trial only examined subjects with the most severe forms of vasculitis; it therefore remains to be seen whether these observations apply to the entire spectrum of patients with Wegener’s granulomatosis and microscopic polyangiitis.  It is also interesting to note that another poster presented at this meeting (1833) concludes that mortality and relapse rates among subjects with Wegener’s granulomatosis are not influenced by ANCA subtype, indicating that this question is not as straightforward as it may appear at first blush.

Abstract:  646 - Proteinase 3 Transcription in Peripheral Blood Mononuclear Cells Predicts Disease Activity in Wegener's Granulomatosis

Authors: 

Chris Cheadle, Alan E. Berger, Felipe Andrade, Regina James, Kristen Johnson, Tonya Watkins, Yu-Chi Chen, Eva Ehrlich, Marissa Mullins, Kathleen C. Barnes and Stuart M. Levine,

Background: 

Intuitively, one would expect ANCA titers to correlate with disease activity in Wegener’s granulomatosis.  Unfortunately, this has not been a useful strategy in practice, and several studies have previously demonstrated that ANCA titers do not reliably predict disease flares.  This study attempts to address this question by examining PR3-transcription as it relates to vasculitis activity among subjects with Wegener’s granulomatosis. 

Methods: 

Total RNA was isolated from peripheral blood mononuclear cells and neutrophils collected form 43 subjects with Wegener’s granulomatosis and 23 controls.  Differentially upregulated genes were identified using parametric and non-parametric approaches to gene set analysis.

Results: 

Most of the upregulated genes identified (86 from mononuclear cells and 40 from neutrophils) are relevant to myeloid differentiation.  PR3 transcription was significantly upregulated in mononuclear cells from patients with active Wegener’s granulomatosis, and correlated with disease activity better than ANCA titers.

Conclusions: 

These data suggest that PR3 transcription in the peripheral blood mononuclear cells of WG patients may represent a novel marker for assessing disease activity in WG.

Editorial: 

Anyone who has seen patients with vasculitis quickly realizes that there are limits to clinical assessment.  Often it is not clear if a patient’s complaints are due to disease activity, previously incurred damage, infection, or some combination of these factors.  In the past, we have tried to use ANCA titers to assist in the assessment of disease activity, but experience has been mixed, and seems to differ among centers.   This work proposes a novel approach that is particularly intriguing because it demonstrates a potential role for proteinase 3.  How this observation might fit into models of the etiopathogenesis of MPO-ANCA positive Wegener’s granulomatosis and other forms of ANCA-associated vasculitis merits further consideration.

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