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Vasculitis update, 2007.


Vasculitic syndromes are among the most complicated diseases to treat and manage. New medications and new ways of using old medications have provided us with new therapies 1to treat our patients. This review focuses on recent date that may have an impact on the way vasculitis is treated.


Vasculitic syndromes are among the most complicated diseases for primary care physicians and rheumatologists to diagnose and treat, not only because of a myriad of symptoms that can be mimicked by other conditions, but also because of the decision process that needs to take place to determine which medication (sometimes toxic) to use and for how long. Developing new treatments and new ways of using already available therapies, while minimizing potential side effects, is of paramount importance. This review will focus on recently published data that may and, in fact, should have an impact on the way we manage systemic vasculitis patients.

Giant Cell Arteritis

Giant cell arteritis (GCA), a common disease seen in elderly patients, is the most common systemic vasculitis (1) and involves mostly the large to medium blood vessels. The most feared complication is optic nerve ischemia, which develops as anterior ischemic optic neuropathy with central retinal artery occlusion and eventual blindness if not treated promptly and aggressively. Current treatment regimens include high doses of steroids, commonly started with pulse steroids and continued with oral steroids. Treatment over a period of 1 to 2 years is common, and given the long-term adverse events (AE) associated with high-dose steroid use, various steroid-sparing agents have been studied to determine if the duration of steroid treatment could be shortened without leading to flares of disease activity. In some studies, methotrexate (MTX) has emerged as a promising agent. (2)

Nesher and colleagues studied the role of aspirin (acetylsalicylic acid, ASA) for prevention of cranial ischemic complication (CIC) in GCA patients. (3) The well-defined role of ASA in stroke and myocardial infarction (MI) treatment led them to hypothesize its possible use in the treatment of GCA. Concomitantly, they performed a retrospective review of all GCA patients seen between 1980 and 2000 in four hospitals in Jerusalem. A total of 175 patients were included, 166 of whom had follow-up data. One hundred fifty-two subjects had biopsy-proven GCA; the rest fulfilled the 1990 American College of Rheumatology (ACR) criteria for GCA.

At diagnosis, 36 patients were receiving ASA for previous cardiac events, and 139 patients were not taking ASA. Three of 36 (8.3%) ASA-treated and 40/139 (28.8%) untreated patients had CIC, with an odds ratio of developing CIC when already on ASA of 0.22 (0.06-0.8, p = 0.02). After diagnosis, all patients were started on oral steroids. Patients already on ASA maintained their current usage; an additional 41 patients were started on ASA, because their physicians felt it might prove beneficial for them. Over the follow-up period, 2/73 (2.7%) patients on ASA and 12/93 (12.9%) not on ASA developed CIC (p = 0.02), with an odds ratio of 0.18 (0.04-0.84, p = 0.03). There were no differences in AE profiles between the two groups. As also mentioned in an accompanying editorial, (4) the addition of ASA should be considered along with steroids in all GCA patients.

In a retrospective review of 143 patients with GCA, (5) 11/68 (16.2%) patients on anticoagulant/antiplatelet treatment, compared with 36/75 (48.0%) not receiving anticoagulant/ antiplatelet treatment, had an ischemic event (p < 0.0005). This difference is even more significant given that groups on treatment had more risk factors for ischemic events and seems to confirm findings of the study by Nesher and coworkers. (3)

ANCA-Associated Systemic Vasculitis

Wegener's granulomatosis (WG), one of the so-called ANCA-associated vasculitides, has been the most resistant to treatment, with frequent relapses after initial control of disease activity. The disorder is manifested by granulomatous necrotizing inflammatory lesions of the upper or lower respiratory tract, or both simultaneously, and usually accompanied by rapidly progressing glomerulonephritis (RPGN). Two-thirds of patients have pulmonary involvement and one-third have RPGN.

Two forms of WG are recognized: a systemic, generalized severe version seen in two-thirds of patients and a localized, limited version seen in one-third of patients. CANCA (anti-proteinase 3 specific) is positive in over 90% of the systemic form of the disease, whereas it is seen in one-half of the limited version. Up until 20 years ago, WG had a mortality rate of 80% at 1 year; now most patients can achieve remission initially but relapses are common. (6)

Microscopic polyangiitis (MPA) was defined during the early 1990s, following the Chapel Hill consensus statement. (7) MPA is associated with P-ANCA positivity in 75% of cases, with myeloperoxidase specificity. Myalgias and arthralgias are common. Renal involvement is usually seen with necrotizing, crescentic glomerulonephritis and is typically silent, manifesting with silent hematuria. Pulmonary alveolar hemorrhage is associated with worse outcomes. Relapses are common after initial remission; however, they are less frequent than seen in WG.

Both WG and MPA are treated similarly, both initially with cyclophosphamide (CTX) and steroids for remission induction. After the initial response, relapses are common and seem to depend on various characteristics of the disease. However, which disease features are most relevant is far from clear. More granulomatous inflammation seems to be associated with more relapses, and when initial involvement is mostly limited to glomerulonephritis, patients seem to have more prolonged remissions. (6)

The major problem with current treatment options is that both CTX and steroids are associated with long-term serious side effects. Various immunosuppressants, in particular MTX and azathioprine (AZA), have been studied to observe their role in both remission maintenance and induction of remission in possibly milder cases. However, it is not clear which patient subgroups can benefit to the same degree by starting out with a "milder" immunosuppressant and still achieve similar results.

Recent studies of both patient subgroups have tried to address this issue. Jayne and associates (8) compared AZA and CTX for remission maintenance. Patients with newly diagnosed WG and MPA (N = 155) were treated with CTX to induce remission and 144/155 achieved this status. After remission, 71 patients were randomized to AZA and 73 continued receiving CTX. After 2 years, 11/71 in the AZA group and 10/73 in the CTX group had experienced relapse (p = 0.65). Severe AEs were similar in both groups (AZA = 7, CTZ = 8, 11% versus 10%, p = 0.94). This study provides good evidence that after remission with CTX, AZA can be used with similar success to maintain that remission. However, this was mixed group of patients with WG and MPA. Given that MPA patients tend to relapse less frequently, it is not clear how patients with severe WG would fare with this regimen.

De Groot and colleagues (9) studied MTX as a remission-inducing agent in an unblinded, prospective, randomized controlled trial, in which patients with newly diagnosed ANCA-associated systemic vasculitis (AASV) with no renal disease or critical organ involvement were randomized to CTX (2 mg/kg) or MTX (20 to 25 m/wk). Patients were on similar doses of steroids, which were tapered by 12 months. Fifty-one patients were treated with MTX and 49 were given CTX. At 6 months, 89.9% of patients on MTX and 93.5% of patients on CTX were in remission. By noninferiority testing, MTX was not inferior to CTX in inducing remission (p = 0.04). However, at 18 months, 69.5% of MTX patients and 46.5% of CTX patients had relapsed. Median time from remission to relapse was 13 months with MTX and 15 months with CTX. When patients were studied in subgroup analysis, those with pulmonary involvement and more extensive disease had fared worse on MTX, raising questions about possibly higher dosing of MTX or IV (intravenous) use in this group of patients.

Evidence of effective use of MTX in patients with limited WG also comes from the WGET (Wegener's granulomatosis etanercept trial), (10) which examined whether the addition of etanercept (ETA) would have an effect on maintaining remission in WG patients who were treated with CTX (severe) or MTX (limited) to induce remission. After remission, patients on CTX were switched to MTX. These patients were randomly assigned to ETA or placebo in addition to their current medications. Sustained remission was achieved in 62/89 patients in the ETA group and 64/85 patients in the control group. There were no differences in numbers of flares between the groups.

There were six solid cancers in the ETA arm compared to the control arm (p = 0.01). In a follow-up study of the same cohort, (11) three more cancers were diagnosed in the ETA group. In conclusion, this study seems to suggest that ETA might not have a role in the maintenance of remission in WG patients.

A subgroup analysis of the MTX-treated patients in the WGET provides good information for the possible role of MTX in WG treatment. Fifty-two patients with limited WG were treated with MTX. Of these, 46/52 (88.5%) achieved remission and at 6 months 35/52 (67.3%) were still in remission. These data suggest that for limited WG, MTX may be as good a choice as CTX as remission induction therapy.

Another treatment that has been studied and has shown promising results, albeit in case reports and case series, is rituximab. A chimeric monoclonal IgG1 antibody to CD20, rituximab has been used for the treatment of B-cell lymphomas since the late 1990s. In 2006, rituximab was approved for the treatment of rheumatoid arthritis. Because of a possible role for ANCA in the pathogenesis of AASV, rituximab has been tried in patients who have failed with other treatments. (12) All but one of the studies has shown benefit from use of rituximab. There are no data at this time regarding maintenance of remission. One study that failed to show a benefit was limited to WG patients with granulomatous disease, which was different than the other studies where most of the patients had renal and vasculitic disease. (13) Granulomatous disease is deemed to be more resistant to treatment and may differ in its response to rituximab.

These data indicate that there might be options other than CTX for possible induction of remission, at least in patients with a limited version of WG, and also several agents that can be used to maintain remission, after remission is initially achieved with CTX. This would help to limit the time a patient is exposed to CTX and decrease the associated side effects. However, relapse remains common and head-to-head studies are probably required to better define the role of treatment regimens other than CTX.

Current accepted treatment algorithms for AASV include CTX with corticosteroids and, once remission is achieved, maintenance therapy with AZA or MTX. A good proportion of patients relapse and may need to be maintained on CTX for a longer time period. An additional controversy between European and U.S. groups interested in vasculitis is related to IV or oral CTX use for remission induction. EULAR (European League Against Rheumatism) recommendations state that IV bolus therapy should be preferred to oral CTX, with infusions every 3 to 4 weeks until remission is achieved and then infusions every 3 months for maintenance therapy. U.S. guidelines prefer oral treatment for remission and maintenance but also leave room for IV bolus therapy.

Systemic vasculitis remains a difficult disease to treat. However, new medications and new ways of using older medications are providing us with new treatment algorithms and helping us treat our patients more successfully. Future studies comparing treatment plans and possibly different combinations may provide more answers.

Disclosure Statement

Yusuf Yazici, M.D., participates in the speaker bureau for the companies of Pfizer, Amgen, Boehringer Ingelheim, Genentech, and BMS; consults for Roche, Celgene, Schering Plough, and BMS; is an advisory board member to Centocor, BMS, and Genentech; and has received educational grants from Abbott, Centocor, and Genentech.


(1.) Gonzalez-Gay MA, Garcia-Porrua C, Miranda-Filloy JA. Giant cell arteritis: Diagnosis and therapeutic management. Curr Rheumatol Rep. 2006 Aug;8(4):299-302.

(2.) Nuenninghoff DM, Matteson EL.The role of disease-modifying antirheumatic drugs in the treatment of giant cell arteritis. Clin Exp Rheumatol. 2003 Nov-Dec;21(6 Suppl 32):S29-34.

(3.) Nesher G, Berkun Y, Mates M, et al. Low-dose aspirin and prevention of cranial ischemic complications in giant cell arteritis. Arthritis Rheum. 2004;50:1332-7.

(4.) Hellmann DB. Low-dose aspirin in the treatment of giant cell arteritis. 2004;50:1026-7.

(5.) Lee MS, Smith SD, Galor A, Hoffman GS. Antiplatelet and anticoagulant therapy in patients with giant cell arteritis. Arthritis Rheum. 2006 Oct;54(10):3306-9.

(6.) Bacon PA. The spectrum of Wegener's granulomatosis and disease relapse. N Engl J Med. 2005 Jan 27;352(4):330-2.

(7.) Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 1994 Feb;37(2):187-92.

(8.) Jayne D, Rasmussen N, Andrassy K, et al; European Vasculitis Study Group. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003 Jul 3;349(1):36-44.

(9.) De Groot K, Rasmussen N, Bacon PA, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005 Aug;52(8):2461-9.

(10.) Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med. 2005 Jan 27;352(4):351-61.

(11.) Stone JH, Holbrook JT, Marriott MA, et al. Solid malignancies among patients in the Wegener's Granulomatosis Etanercept Trial. Arthritis Rheum. 2006 May;54(5):1608-18.

(12.) Flossmann O, Jones RB, Jayne DR, Luqmani RA. Should rituximab be used to treat antineutrophil cytoplasmic antibody associated vasculitis? Ann Rheum Dis. 2006 Jul;65(7):841-4.

(13.) Aries PM, Hellmich B, Voswinkel J, et al. Lack of efficacy of rituximab in Wegener's granulomatosis with refractory granulomatous manifestations. Ann Rheum Dis. 2006 Jul;65(7):853-8.

Yusuf Yazici, M.D., is Assistant Professor of Medicine, New York University School of Medicine and from the Division of Rheumatology, NYU Hospital for Joint Diseases, New York University Medical Center, New York, New York.

Correspondence: Yusuf Yazici, M.D., 246 East 20th Street, New York, New York 10003;
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Article Details
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Author:Yazici, Yusuf
Publication:Bulletin of the NYU Hospital for Joint Diseases
Article Type:Clinical report
Geographic Code:1USA
Date:Sep 1, 2007
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