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Predictors of Relapse and Treatment Resistance in Antineutrophil Cytoplasmic Antibody–Associated Small-Vessel Vasculitis

Susan L. Hogan, PhD, MPH; Ronald J. Falk, MD; Hyunsook Chin, MPH; Jianwen Cai, PhD; Caroline E. Jennette, MSW; J. Charles Jennette, MD; and Patrick H. Nachman, MD
[+] Article, Author, and Disclosure Information

From the University of North Carolina, Chapel Hill, North Carolina.

Acknowledgments: The authors thank the physicians and medical staff who participate in the Glomerular Disease Collaborative Network and the patients who made this study possible.

Grant Support: In part by a grant from the National Institutes of Health, National Institute of Diabetes & Digestive & Kidney Diseases (program project number P01-DK58335).

Potential Financial Conflicts of Interest: Grants received: S.L. Hogan (National Institutes of Health), R.J. Falk (National Institutes of Health), C.E. Jennette (National Institutes of Health), J.C. Jennette (National Institutes of Health), P.H. Nachman (National Institutes of Health).

Requests for Single Reprints: Susan L. Hogan, PhD, MPH, Division of Nephrology and Hypertension, Department of Medicine, UNC Kidney Center, CB 7156, 7024B Burnett-Womack, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7156; e-mail, slh@med.unc.edu.

Current Author Addresses: Drs. Hogan, Falk, and Nachman, Ms. Chin, and Ms. Jennette: Division of Nephrology and Hypertension, Department of Medicine, UNC Kidney Center, CB 7156, 7024B Burnett-Womack, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7156.

Dr. Cai: School of Public Health, CB 7400, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7400.

Dr. Jennette: Department of Pathology and Laboratory Medicine, CB 7525, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7525.

Author Contributions: Conception and design: S.L. Hogan, R.J. Falk, J.C. Jennette, P.H. Nachman.

Analysis and interpretation of the data: S.L. Hogan, R.J. Falk, H. Chin, J. Cai, J.C. Jennette, P.H. Nachman.

Drafting of the article: S.L. Hogan, R.J. Falk, J.C. Jennette, P.H. Nachman.

Critical revision of the article for important intellectual content: S.L. Hogan, R.J. Falk, H. Chin, J. Cai, C.E. Jennette, J.C. Jennette, P.H. Nachman.

Final approval of the article: S.L. Hogan, R.J. Falk, H. Chin, J. Cai, C.E. Jennette, J.C. Jennette, P.H. Nachman.

Provision of study materials or patients: R.J. Falk, P.H. Nachman.

Statistical expertise: S.L. Hogan, H. Chin, J. Cai.

Obtaining of funding: S.L. Hogan, R.J. Falk.

Administrative, technical, or logistic support: S.L. Hogan, R.J. Falk, J. Cai, C.E. Jennette.

Collection and assembly of data: S.L. Hogan, R.J. Falk, C.E. Jennette, P.H. Nachman.

Ann Intern Med. 2005;143(9):621-631. doi:10.7326/0003-4819-143-9-200511010-00005
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This large observational cohort of patients with ANCA-associated vasculitis suggests many findings and implications. The 77% remission rate was comparable with previously reported rates of 70% to 92% (5, 8, 2123). Treatment resistance was most common among patients presenting with higher serum creatinine levels, greater disease chronicity, and vascular sclerosis on renal biopsy. In previous reports, cumulative organ damage (measured by the Vasculitis Damage Index) (24), glomerular sclerosis, interstitial infiltrates, tubular necrosis, atrophy (25), and other markers of chronic disease were consistently labeled as predictors of treatment resistance, despite differences in statistical models and outcome definitions. These associations were independent of the level of disease activity, disease category, ANCA pattern or specificity, and demographic region. In this cohort, vascular sclerosis on biopsy was also an independent predictor of treatment resistance. We concluded that this association possibly resulted from chronic renal damage secondary to hypertension or other atherosclerotic processes; ANCA-associated nephritis may have also been a contributing factor. The impact of renal damage as a predictor of resistance emphasizes the importance of early diagnosis and prompt institution of therapy.

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Figure 1.
Flow diagram of the study cohort.

ANCA = antineutrophil cytoplasmic antibody.

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Figure 2.
Probabilities of survival without end-stage kidney disease (ESKD) among treatment-resistant and treatment-responsive patients who did and did not relapse (top) and probability of relapse-free survival by risk group (bottom).

The high-risk group included patients with 1 or more of the 3 risk factors for relapse (antiproteinase-3 [anti-PR3] antibodies, lung involvement, upper respiratory disease involvement). The low-risk group included patients with none of these 3 risk factors. The numbers represent the number of patients being followed in each subgroup at the beginning of the study and at 12, 24, 36, and 48 months.

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TNF-alpha blocking agents in the treatment of ANCA-Associated Small-Vesse Vasculitis
Posted on November 7, 2005
Francisco R. Lafita
Gabinet Mèdic. 43850 Cambrils.Baix Camp. Spain
Conflict of Interest: None Declared

Hogan and coworkers thoughtful cohort study (1) points out some interesting conclusions on prediction of relapse and treatment resistance in Antineutrophil Cytoplasmic Antibody-Associated Small-Vessel Vasculitis. In addition, as we observe these results it seems interesting to underlie that 23% of patients who underwent to therapy with corticosteroids and cyclophosphamide showed resistance to the treatment and those who were initially responders to the treatment, 42% presented a relapse. That means that 55% of patients treated with conventional therapy showed treatment resistance or presented disease relapse. Moreover and according the authors, relapses were not related to the therapy length. In the last years there have appeared many publications on the usefulness of TNF-alpha blocking agents in Systemic Vasculitis (2) and specifically in refractory Wegener Granulomatosis (3). Beside the results found in some studies where Etanercept failed to maintain remissions in patients with Wegnener granulomatosis (4), there are many others (3, 5) suggesting that TNF-alpha inhibition constitutes a promising treatment in refractory Wegener granulomatosis. Indeed, studies have shown expansion of circulating TNF-alpha producing cells (Th1-type CD4(+)CD28(-) T-cell effector memory T-cells ) and their presence in granulomatous lesions (5). This fact would provide a rationale for treating patients with Wegener granulomatosis with TNF-alpha blocking agents. This is especially important in patients who undergoing conventional therapy, were found to show treatment resistance, or to be at risk of resistance, given the scarce probability to survive without end-stage kidney disease and its early presentation as authors describe in their results and in figure 2 in the paper. This thrilling paper should be continued on introducing therapies with TNF -alpha blocking agents mainly in patients found to be resistant to conventional therapies and in those who presented risk of resistances.

1. Hogan SL, Falk RJ, Chin H, Cai J, Jennette CE, Jennette JC, Nachman PH. Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Ann Intern Med. 2005 ;143:621-31. 2. Booth AD, Jayne DR, Kharbanda RK, McEniery CM, Mackenzie IS, Brown J, Wilkinson IB. Infliximab improves endothelial dysfunction in systemic vasculitis: a model of vascular inflammation. Circulation. 2004;109):1718- 23. 3. Kleinert J, Lorenz M, Kostler W, Horl W, Sunder-Plassmann G, Soleiman A. . Refractory Wegener's granulomatosis responds to tumor necrosis factor blockade. Wien Klin Wochenschr. 2004;116:334-8. 4. Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med. 2005;352:351-61 5. Lamprecht P, Gross WL. Wegener's granulomatosis. Herz. 2004;29:47-56.

Conflict of Interest:

None declared

Treatment Resistance in Antineutrophil Cytoplasmic Antibody"“Associated Small-Vessel Vasculitis
Posted on November 10, 2005
Dr Shamsul A Bhuiyan
No Affiliation
Conflict of Interest: None Declared

Dear editor,

I am writing this letter regarding the article by Susan L. Hogan et al published in your journal "Predictors of Relapse and Treatment Resistance in Antineutrophil Cytoplasmic Antibody"“Associated Small-Vessel Vasculitis "(November 1, 2005). I would like to add some more information to this article. Specific enzyme immunoassays for antibodies to proteinase-3 or myeloperoxidase (the 2 antigens known to be associated with systemic vasculitis) are negative in classic PAN (where no lungs involvement seen). Positive enzyme immunoassays for antibodies to these specific antigens are much more consistent with Wegener granulomatosis, microscopic polyangiitis, or the Churg-Strauss syndrome. Classic PAN is p- ANCA positive, on the other hand others are c-ANCA positive. Systemic vasculitidies is seen (1) mainly now a days. Classic form of PAN (polyarteritis nodosa) is rarely seen. PAN appears to affect men and women with approximately equal frequencies and to occur in all ethnic groups. This study would be more valuable if they could include all ethnic groups, both male and female. The weak area of this study is that they did not subdivide the people among male/female, absence of different ethnicity people, age determination. If they could mentioned how many patients were classic polyarteritis Nodosa patients and how many of them had systemic vasculitis, would be more useful. This article showed only the kidney and lungs involvement. Intraparenchymal renal inflammation is a major feature of PAN, found in 40% of patients (2) The gastrointestinal manifestations of PAN occur in approximately half of all patients (2). There was no information regarding this major disease affect and treatment follow-up. The new findings of "Increased risk for relapse appears to be related to the presence of lung or upper airway disease and anti-PR3 antibody seropositivity" is really encouraging and needs more research.

Reference: 1. John H. Stone, Polyarteritis Nodosa JAMA, Oct 2002; 288: 1632 - 1639. 2. Guillevin L. Polyarteritis nodosa and microscopic polyangiitis. In: Ball GV, Bridges SL Jr, eds. Vasculitis. Oxford, England: Oxford University Press; 2002:300-320.

Conflict of Interest:

None declared

Posted on December 4, 2005
seongjae choi
Korea University guro hospital
Conflict of Interest: None Declared

all the way, the ANCA-PR3 is important for the relapse (RR=1.87). But in the end of the left paragraph on page 628, the MPO-seropositivity was associated with treatment resistance. which one is right? is this just a typing error?

Conflict of Interest:

None declared

Submit a Comment/Letter

Summary for Patients

Relapse and Treatment Resistance in Patients with Small-Vessel Vasculitis

The summary below is from the full report titled “Predictors of Relapse and Treatment Resistance in Antineutrophil Cytoplasmic Antibody–Associated Small-Vessel Vasculitis.” It is in the 1 November 2005 issue of Annals of Internal Medicine (volume 143, pages 621-631). The authors are S.L. Hogan, R.J. Falk, H. Chin, J. Cai, C.E. Jennette, J.C. Jennette, and P.H. Nachman.


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