Antiproteinase 3 Antineutrophil Cytoplasmic Antibodies and Disease Activity in Wegener Granulomatosis

  1. Javier D. Finkielman, MD;
  2. Peter A. Merkel, MD, MPH;
  3. Darrell Schroeder, MS;
  4. Gary S. Hoffman, MD;
  5. Robert Spiera, MD;
  6. E. William St. Clair, MD;
  7. John C. Davis, Jr., MD, MPH;
  8. W. Joseph McCune, MD;
  9. Andrea K. Lears, BS;
  10. Steven R. Ytterberg, MD;
  11. Amber M. Hummel;
  12. Margaret A. Viss;
  13. Tobias Peikert, MD;
  14. John H. Stone, MD, MPH;
  15. Ulrich Specks, MD; and
  16. for the WGET Research Group
  1. 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.

    Abstract

    Background: The utility of antineutrophil cytoplasmic antibody (ANCA) levels to guide the management of patients with Wegener granulomatosis remains controversial.

    Objective: To determine whether pro-proteinase 3 (PR3)–ANCA levels are a better measure of disease activity than mature-PR3–ANCA levels, whether decreases in either level are associated with shorter time to remission, and whether increases are followed by relapse.

    Design: Prospective, observational cohort study.

    Setting: 8 United States medical centers that participated in a treatment trial for Wegener granulomatosis.

    Patients: 156 patients with Wegener granulomatosis enrolled during periods of active disease.

    Measurements: PR3-ANCA levels (by capture enzyme-linked immunosorbent assay) and disease activity (by the Birmingham Vasculitis Activity Score for Wegener granulomatosis).

    Results: The ANCA levels were only weakly associated with disease activity across patients. The longitudinal association within patients was stronger, but changes in ANCA levels explained less than 10% of the variation in disease activity. Decreases in mature- and pro-PR3–ANCA levels were not statistically significantly associated with shorter time to remission, and increases in mature-PR3–ANCA levels (adjusted hazard ratio, 0.8 [95% CI, 0.4 to 1.9]; P = 0.67) and pro-PR3–ANCA levels (adjusted hazard ratio, 1.0 [CI, 0.5 to 2.1]; P = 0.99) were not associated with relapse. The proportion of patients who had relapse within 1 year of an increase in PR3-ANCA levels was 40% for mature-PR3 (CI, 18% to 56%) and 43% for pro-PR3 (CI, 22% to 58%).

    Limitations: Samples were collected approximately every 3 months. Sensitivity and specificity of ANCA levels for detecting remission and relapse could not be calculated because each patient had different follow-up times.

    Conclusion: Pro-PR3–ANCA is no better than mature-PR3–ANCA as a measure of Wegener granulomatosis activity. Decreases in PR3-ANCA levels are not associated with shorter time to remission, and increases are not associated with relapse. These findings suggest that ANCA levels cannot be used to guide immunosuppressive therapy.

    Article and Author Information

    • 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{at}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.

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    1. Ann Intern Med November 6, 2007 vol. 147 no. 9 611-619
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