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Antiproteinase 3 Antineutrophil Cytoplasmic Antibodies and Disease Activity in Wegener Granulomatosis

Javier D. Finkielman, MD; Peter A. Merkel, MD, MPH; Darrell Schroeder, MS; Gary S. Hoffman, MD; Robert Spiera, MD; E. William St. Clair, MD; John C. Davis Jr., MD, MPH; W. Joseph McCune, MD; Andrea K. Lears, BS; Steven R. Ytterberg, MD; Amber M. Hummel; Margaret A. Viss; Tobias Peikert, MD; John H. Stone, MD, MPH; Ulrich Specks, MD, WGET Research Group
[+] Article and Author Information

From the Mayo Clinic, Rochester, Minnesota; Boston University, Boston, Massachusetts; The Cleveland Clinic Foundation Center for Vasculitis Research and Care, Cleveland, Ohio; Hospital of Special Surgery, New York, New York; Duke University, Durham, North Carolina; University of California, San Francisco, San Francisco, California; University of Michigan, Ann Arbor, Michigan; and Johns Hopkins University Center for Clinical Trials and Johns Hopkins University, Baltimore, Maryland.


Grant Support: This study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH) grant R01-AR49806 to Dr. Specks and funds from the Mayo Foundation. Dr. Peikert was supported by NIH training grant T32-HL07897. The WGET was supported by the NIAMS, NIH (grant N01-AR92240) and the Office of Orphan Products, U.S. Food and Drug Administration (grant FD-R-001652), General Clinical Research Center Grants M01-RRO-00533 (Boston University), M01-RRO-0042 (The University of Michigan), MO1-RR-30 (Duke University), and M01-RRO-2719 (Johns Hopkins University School of Medicine), from the National Center for Research Resources/NIH. Drs. Stone, Merkel, and St. Clair were supported by NIAMS grants K24 AR049185-01, K24 AR2224-01A1, and K24 AR02126-04. Dr. Stone was a Hugh and Renna Cosner Scholar in the Center for Innovative Medicine at the Johns Hopkins Bayview Medical Center.

Potential Financial Conflicts of Interest: Consultancies: E.W. St. Clair (Genentech, Xoma, Human Genome Sciences, Medimmune, Novartis, Bristol-Myers Squibb). Grants received: E.W. St. Clair (Amgen, Genentech).

Requests for Single Reprints: Ulrich Specks, MD, Thoracic Diseases Research Unit, Stabile Building 8-56, Division of Pulmonary and Critical Care Medicine, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905; e-mail, specks.ulrich@mayo.edu.

Current Author Addresses: Dr. Finkielman: University of North Dakota, Intensive Care Unit, 900 East Broadway Avenue, Bismarck, ND 58501.

Dr. Merkel: Boston University School of Medicine, Vasculitis Center, E-5, 715 Albany Street, Boston, MA 02118.

Mr. Schroeder, Dr. Ytterberg, Ms. Hummel, Ms. Viss, Dr. Peikert, and Dr. Specks: Mayo Clinic, 200 First Street SW, Rochester, MN 55905.

Dr. Hoffman: The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195.

Dr. Spiera: Beth Israel Medical Center, 170 East End Avenue, New York, NY 10128.

Dr. St. Clair: Duke University Medical Center, Box 3874, Durham, NC 27710.

Dr. Davis: University of California, San Francisco, 533 Parnassus Avenue, Box 0633, San Francisco, CA 94143.

Dr. McCune: University of Michigan, Taubman Center, Room 3918-0358, Ann Arbor, MI 48109.

Ms. Lears: Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205.

Dr. Stone: UpToDate, 95 Sawyer Road, Waltham, MA 02453-3471.

Author Contributions: Conception and design: J.D. Finkielman, P.A. Merkel, D. Schroeder, E.W. St. Clair, J.C. Davis, J.H. Stone, U. Specks.

Analysis and interpretation of the data: J.D. Finkielman, P.A. Merkel, D. Schroeder, E.W. St. Clair, A.M. Hummel, M.A. Viss, T. Peikert, J.H. Stone, U. Specks.

Drafting of the article: J.D. Finkielman, D. Schroeder, T. Peikert, U. Specks.

Critical revision of the article for important intellectual content: J.D. Finkielman, P.A. Merkel, D. Schroeder, G.S. Hoffman, E.W. St. Clair, J.C. Davis, S.R. Ytterberg, J.H. Stone, U. Specks.

Final approval of the article: J.D. Finkielman, P.A. Merkel, D. Schroeder, G.S. Hoffman, R. Spiera, E.W. St. Clair, J.C. Davis, W.J. McCune, A.K. Lears, S.R. Ytterberg, U. Specks.

Provision of study materials or patients: P.A. Merkel, G.S. Hoffman, R. Spiera, J.C. Davis, W.J. McCune, S.R. Ytterberg, J.H. Stone, U. Specks.

Statistical expertise: D. Schroeder.

Obtaining of funding: J.H. Stone, U. Specks.

Administrative, technical, or logistic support: J.C. Davis, A.K. Lears, A.M. Hummel, M.A. Viss.

Collection and assembly of data: J.D. Finkielman, P.A. Merkel, G.S. Hoffman, R. Spiera, E.W. St. Clair, J.C. Davis, W.J. McCune, J.H. Stone, U. Specks.


Ann Intern Med. 2007;147(9):611-619. doi:10.7326/0003-4819-147-9-200711060-00005
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This prospective study was done in the context of the WGET (Wegener Granulomatosis Etanercept Trial) (6, 2223), a randomized, placebo-controlled trial that evaluated etanercept for maintenance of remission in 180 patients with Wegener granulomatosis at 8 centers across the United States (Appendix 1). All patients met at least 2 of the 5 modified American College of Rheumatology criteria for classification of Wegener granulomatosis and had active disease within 28 days before enrollment and a Birmingham Vasculitis Activity Score for Wegener granulomatosis (BVAS/WG) of at least 3 (22, 24). Follow-up evaluations were done at baseline, after 6 and 12 weeks, and then every 3 months until the end of the trial. Two additional evaluations took place at 3 and 6 months after the end of the trial. During each visit, disease activity was measured by using the BVAS/WG, and serum samples were obtained, frozen, and stored at −80 °C.

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Appendix Figure 1.
Diagram of the initial 4 clinical visits.

The fourth clinical visit was the first point at which a patient could meet the study definition of sustained remission (SR) (a Birmingham Vasculitis Activity Score for Wegener granulomatosis [BVAS/WG] of 0 for 6 months) and was the first time we looked for an increase in proteinase 3 (PR3) antineutrophil cytoplasmic antibody (ANCA) levels. We compared the net absorbance of PR3-ANCA at this visit with that of the previous 2 visits or the previous 6 months (curved lines). The same comparison was done at every subsequent visit.

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Appendix Figure 2.
Patterns of disease activity and antineutrophil cytoplasmic antibody (ANCA) levels in individual patients.

Arrowheads indicate a decrease in proteinase 3 (PR3)–ANCA levels during the initial 6 months of follow-up, and circles indicate an increase in PR3-ANCA level. The horizontal line at 0.1 represents the cutoff value of the tests; results above or equal to this value are considered positive. A. Increase in PR3-ANCA levels followed by relapse (R). The increase in PR3-ANCA levels began before the patient met the definition for sustained remission (SR). B. Increase in PR3-ANCA levels with no subsequent relapse in the following 2 years. C. Relapse without a preceding increase in mature- or pro-PR3–ANCA levels. D. Unchanging PR3-ANCA levels during follow-up after sustained remission. This patient achieved and remained in sustained remission. E. Continued disease activity with a decrease in PR3-ANCA levels, although with improvement as PR3-ANCA levels decreased. F. Continuously negative PR3-ANCA levels without achieving sustained remission. BVAS/WG = Birmingham Vasculitis Activity Score for Wegener granulomatosis.

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Appendix Figure 3.
Proteinase 3 (PR3) antineutrophil cytoplasmic antibody (ANCA) levels at baseline and at sustained remission.

Mature- and pro-PR3–ANCA levels were statistically significantly higher at baseline (median Birmingham Vasculitis Activity Score for Wegener granulomatosis [BVAS/WG], 6.5) than at sustained remission (BVAS/WG, 0). The median level decreased from 1.46 to 0.92 for mature-PR3 ANCA and from 0.88 to 0.40 for pro-PR3–ANCA. In this analysis, only the 101 patients who were positive for mature-PR3–ANCA at baseline and had sustained remission were included. The middle horizontal lines represent the median, and the bars represent the interquartile range.

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Figure 1.
Time to sustained remission after induction therapy.

Top. Mature proteinase 3 (PR3) antineutrophil cytoplasmic antibody (ANCA) levels and remission. Bottom. Pro-PR3–ANCA levels and remission. Data are Kaplan–Meier estimates of time to sustained remission in the 134 patients who were positive for mature-PR3–ANCA at baseline. Time 0 corresponds to the date of enrollment in the study. Sustained remission was defined as a Birmingham Vasculitis Activity Score (BVAS/WG) of 0 for a minimum of 6 months. Adjusting variables were age, sex, disease severity (severe vs. limited), treatment group (etanercept vs. placebo), disease duration, baseline BVAS/WG, and clinical center.

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Figure 2.
Proteinase 3 (PR3) antineutrophil cytoplasmic antibody (ANCA) levels and relapse.

*The increase in PR3-ANCA levels took place at or after the patient achieved sustained remission. †Fourteen of these patients had gaps in PR3-ANCA measurements longer than 6 months; of those, 4 had relapse. ‡Seventeen of these patients had gaps in PR3-ANCA measurements longer than 6 months; of those, 4 had relapse. §Seven of these patients had gaps in PR3-ANCA measurements longer than 6 months; of those, 1 had relapse.

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Figure 3.
Changes in mature proteinase 3 (PR3) antineutrophil cytoplasmic antibody (ANCA) levels at the time of remission.

The vertical dotted line marks the time of sustained remission. The x-axis corresponds to the 6 months preceding and the time following sustained remission. In patients with relapse (top), the mature-PR3–ANCA levels for each patient were plotted to the time of relapse. In patients without relapse (bottom), the mature-PR3–ANCA levels for each patient were plotted to the end of the trial.

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