Necrotizing vasculitis: a 2009 update.
Abstract: Necrotizing vasculitis continues to be a condition where difficult diagnostic and treatment decisions need to be made, with only a few well-done studies as clinical reference and support. New data suggest that both methotrexate and azathioprine may be effective agents for maintaining remission in antineutrophilic cytoplasmic antibody (ANCA)associated vasculitis after remission is achieved with cyclophosphamide-based therapies. In addition, Behcet's syndrome appears to be more common than previously assumed and is likely more common than a combination of ANCA-associated vasculitis (AAV) syndromes.
Article Type: Disease/Disorder overview
Subject: Vasculitis (Care and treatment)
Evidence-based medicine
Authors: Sharaf, Pamela H.
Yazici, Yusuf
Pub Date: 07/01/2009
Publication: Name: Bulletin of the NYU Hospital for Joint Diseases Publisher: J. Michael Ryan Publishing Co. Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 J. Michael Ryan Publishing Co. ISSN: 1936-9719
Issue: Date: July, 2009 Source Volume: 67 Source Issue: 3
Accession Number: 247340119
Full Text: Necrotizing vasculitis persists as an extremely serious condition where complicated diagnostic and treatment decisions may need to be made on an urgent and chronic basis. There have been only several well-designed studies for evidence-based support regarding the diagnosis and treatment of necrotizing vasculitis. Part of the problem is that these are relatively rare diseases; however, another complicating issue is that diagnosing these conditions is not a straightforward process and the diagnosis may even change during the course of disease as new manifestations may become apparent or older ones change in character. This paper reviews some of the more clinically relevant studies published about vasculitic syndromes in 2008.

Pagnoux and colleagues conducted a multicenter trial in France among Wegener's granulomatosis (WG) patients. The study evaluated less toxic immunosuppressants azathioprine (AZA) and methotrexate (MTX) as maintenance treatments for those patients who were in remission after receiving combination corticosteroids and cyclophosphamide (CYC) therapy for WG and microscopic polyangiitis (MPA). (1) The study hypotheses was that MTX would be less toxic than AZA. The primary end point was either an adverse event requiring discontinuation of the study drug or death. The secondary end point consisted of a severe adverse event, relapse, or affected quality of life. The trial was held from 1998 to 2005, and the study drugs were purchased by the patients, who were reimbursed by the French National Health Service. Patients met the Chapel Hill classification criteria for newly diagnosed WG or MPA. WG patients had to have granulomatous inflammation of the respiratory tract and renal disease, and MPA patients had to have histological confirmation for positive ANCA. The treatment protocol for the study consisted of identical induction regimens for all patients with WG and MPA. Combination therapy consisted of a 3-day methylprednisolone pulse, followed by 1 mg/kg oral prednisone for 3 weeks, which was subsequently tapered to an average dose of 12.5 mg/day at 6 months and 5 mg/ day at 18 months, and 3 pulses of CYC every 2 weeks (0.6 g/[m.sup.2]). Treatment continued every 3 weeks until remission was reached, in which three additional consolidation pulses were administered. Seventy-nine percent of the initial set of patients achieved remission (mean time to remission was 6.7 months). Patients in remission, which was determined by the Birmingham Vasculitis Activity Score, were then randomly assigned to either AZA (2 mg/kg/day) or MTX (25 mg/week). Sixty-three MTX patients (76% WG, 24% MPA) and 63 AZA patients (76% WG, 24% MPA) were evaluated every 2 months for the first year, and then every 6 months until they reached an end point. Adverse events that led to discontinuation of the study drug occurred in 11% of AZA patients versus 19% of MTX patients (p = 0.21).

The hazard ratio for MTX was 1.65 (CI = 0.65 to 4.18, p = 0.29). Forty-six percent of AZA patients versus 56% of MTX patients (p = 0.29) experienced at least one adverse event. Mean follow-up time was 29 months, in which 36% of AZA patients and 33% of MTX patients relapsed (p = 0.71). Seventy-three percent of these relapses occurred after the medication was discontinued. Relapse-free survival after 24 months occurred in 71.8% of AZA patients and 74.5% of MTX patients. Event-free survival after 24 months occurred in 69.9% of AZA patients and 60.8% of MTX patients. Of the total number of patients, two died and three developed cancer during follow-up. In conclusion, MTX seemed to be associated with a slight increase in adverse events. There was no difference between AZA and MTX in maintaining remission, and they can both be considered for use after achieving remission in WG and MPA. Treatment decision, as always, is based on the individual patient's preexisting condition and concurrent prioritization of safety issues. In another analysis, Pagnoux and coworkers, this time, evaluated the consistency of identified predictors of treatment resistance and relapse by two independent ANCA vasculitis cohorts, the Glomerular Disease Collaborative Network (GDCN) in the southeastern U.S. and the French Vasculitis Study Group (FVSG). The GDCN consisted of mostly renal patients referred by nephrologists. As published by the GDCN, (3) therapy resistance (29%) in this cohort was found to be associated with female gender, African-American race, older age, and severity of renal disease at diagnosis. When the French cohort was analyzed to investigate these risk factors, female gender and African-American race were not identified as risk factors. By the GDCN, relapse (42%) was associated with factors such as proteinase 3 ANCA, disease involvement of lungs, and upper respiratory system involvement. Of patients with no risk factors, 26% relapsed; whereas, among patients who presented one or more risk factors, 47% relapsed (median time was 39 months). These risk factors were compared to those of the French cohort to assess their applicability to ANCA-associated vasculitis (AAV) patients of a different geographical location. Of 434 AAV patients studied by the FVSG, all were diagnosed in France, were positive for ANCA, and had MPA, WG, ChurgStrauss syndrome (CSS), or renal-limited disease. Remission occurred in 86% of patients, continued remission in 46%, relapse in 54% (median time to relapse was 44 months), and resistance in 14%. Factors such as socioeconomic status and access to care were not identified by either cohort. Both cohorts identified prime factors for predicting relapse to be lung involvement and ANCA presence.

In another study, Mukhtyar and associates performed a systematic literature review to analyze outcomes and quality of evidence of outcomes of clinical trials in AAV. (4) Factors affecting remission, relapse, renal function, and overall survival were compared, in which immunosuppressive therapy, the type of organ involvement, the presence of ANCA, older age, and male gender were risk factors of AAV. Among the studies analyzed for WG, there was a substantial amount of inconsistency, as the definitions of remission and relapse varied, which made the data difficult to interpret. Methodological differences among cohorts also led to inconsistencies. Likelihood of remission was independent of treatment intensity, and patients with higher disease activity had lower rates of survival. Renal damage rendered the disease less responsive to therapy. Treatment, ANCA positivity, and target organ involvement were all associated with relapse, which was common for WG. Insufficient amounts and excessively high amounts of medication led to an increased risk of relapse. Unnecessarily high amounts of medication were also detrimental to low-risk patients, because the immunosuppressive treatment inadvertently worsened their condition. Those patients who tested positive for ANCA at diagnosis were four-times as likely to relapse. Cardiac involvement, increased creatinine clearance, and inflammatory response from chronic nasal carriage were associated with higher target organ involvement, in which the relapse risk was subsequently increased. Dialysis dependence, increased serum creatinine, increased urinary protein, and decreased hemoglobin were factors that potentially led to end stage renal disease.

Factors affecting survival of WG include age, target organ damage, and vasculitic damage. Higher age is correlated with lower chance of survival. Vasculitic manifestations, such as renal involvement, and granulomatous manifestations, such as upper respiratory tract involvement, are components of target organ damage, in which the former is associated with poorer survival and the latter with better survival. Lung involvement may also be a risk factor. Increased vasculitic damage as presented from venous duplex imaging is associated with a higher risk of mortality. Fewer studies were available for MPA and CSS. MPA and CSS have lower relapse rates than does WG. MPA has a lower survival rate than does WG, nevertheless. Relapse rates in CSS increase with years of the disease, and gastrointestinal involvement is a risk factor for relapse.

Mahr and colleagues studied the prevalence of Behcet's syndrome in France and have reported some interesting findings. (5) The purpose of the study was to estimate the prevalence of Behcet's syndrome in and around Paris, France. Those patients were identified by community physicians and hospital staff, as well as through searches of the National Health Insurance database. Of the Parisian and surrounding area residents who were diagnosed with Behcet's syndrome, 26% were of non-European descent. The prevalence rate of Behcet's syndrome was 7.1 persons per 100,000. Of this prevalence, 2.4 were of European origin, 17.5 of North African, and 34.6 of Asian. Other reported prevalence rates for European subpopulations living in France were consistent with the pattern of a decrease in the frequency of Behcet's syndrome with increasing latitude within Europe. Age at immigration was found to be non-influential to prevalence or risk. Thus, the prevalence rates were similar to those rates in the countries of origin. Prevalence rates by ethnicity were similar in both the country of origin and a different country of current residence, which may point to a primarily hereditary basis, although acquirement of Behcet's syndrome is likely associated with both environmental (geographic location) and hereditary factors (genetic predisposition). Interestingly, prevalence rates of Behcet's syndrome were similar to combined rates of other primary small vessel vasculitides, such as WG, CSS, and MAP, suggesting that Behcet's syndrome may be more prevalent than previously assumed. In an accompanying editorial, Yazici and coworkers also suggest that the prevalence of Behcet's syndrome is underestimated and point out the importance of knowing the true prevalence of any disease in making a diagnosis of that condition in any given geography, as the pretest odds of any diagnosis play heavily into diagnostic considerations. (6)


Necrotizing vasculitis continues to be difficult to diagnose and treat. The increasing number of well-done randomized clinical trials will certainly help physicians better treat their patients. Considerations into the process and methods of diagnosis, especially in the use of classification and diagnostic criteria without data on the true prevalence of these rare diseases are problematic areas in which more studies are needed, along with more and improved efforts to better define prognostic factors for treatment response and relapse.

Disclosure Statement

Yusuf Yazici, M.D., participates in the speaker bureau for BMS and is a consultant to BMS, Celgene, Centocor, Genentech, Roche, and UCB.


(1.) Pagnoux C, Mahr A, Hamidou MA, et al. French Vasculitis Study Group. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med. 2008 Dec 25;359(26):2790-803.

(2.) Pagnoux C, Hogan SL, Chin H, et al. Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis: comparison of two independent cohorts. Arthritis Rheum. 2008 Sep;58(9):290818.

(3.) Hogan SL, Falk RJ, Chin H, et al. Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibodyassociated small-vessel vasculitis. Ann Intern Med. 2005 Nov 1;143(9):621-31.

(4.) Mukhtyar C, Flossmann O, Hellmich B, et al. European Vasculitis Study Group (EUVAS). Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism systemic vasculitis task force. Ann Rheum Dis. 2008 Jul;67(7):1004-10; Epub 2007 Oct 2.

(5.) Mahr A, Belarbi L, Wechsler B, et al. Population-based prevalence study of Behcet's disease: differences by ethnic origin and low variation by age at immigration. Arthritis Rheum. 2008 Dec;58(12):3951-9.

(6.) Yazici H, Seyahi E, Yurdakul S. Behcet's syndrome is not so rare: why do we need to know? Arthritis Rheum. 2008 Dec;58(12):3640-3.

Correspondence: Yusuf Yazici, M.D., 246 East 20th Street, New York, New York 10003;

Pamela H. Sharaf, B.S., is a Research Assistant in the Division of Rheumatology, Department of Medicine, NYU Hospital for Joint Diseases, New York, New York. Yusuf Yazici, M.D., is an Assistant Professor of Medicine, New York University School of Medicine, and is from the Division of Rheumatology, Department of Medicine, NYU Hospital for Joint Diseases, NYU Langone Medical Center, New York, New York.
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