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Are There Different Forms of Life in the Antineutrophil Cytoplasmic Antibody Universe?

Gary S. Hoffman, MD, MS; and Carol A. Langford, MD, MHS
[+] Article, Author, and Disclosure Information

From Cleveland Clinic Foundation, Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Gary S. Hoffman, MD, MS, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195.

Current Author Addresses: Drs. Hoffman and Langford: Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195.

Ann Intern Med. 2005;143(9):683-685. doi:10.7326/0003-4819-143-9-200511010-00012
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The causes of most forms of noninfectious vasculitis are unknown, despite being labeled as “autoimmune.” For some autoimmune diseases, autoantibodies and their target antigens provide some information about pathogenesis and disease phenotypes. What do antineutrophil cytoplasmic antibodies (ANCAs) tell us about a patient with vasculitis? Does ANCA or the antigen that it recognizes identify patients whose vasculitis differs in clinical expression and relapse potential? If so, might this information guide treatment? Two articles in this issue (12) address these questions.

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Relapse rates of 2 different European Vasculitis Study Group trials.

Data are from references 9 and 10. In both studies, a 12-month group for cyclophosphamide (CYC) therapy was used, and the response rates seemed to be similar through the first year of follow-up. However, in the study that compared methotrexate (MTX) versus CYC for maintenance of remission (9), relapses progressively increased after immunosuppressive therapies were withdrawn between months 10 and 12. In the study in which maintenance therapy was continued beyond 12 months in both groups, far fewer relapses (about 15%) occurred at 18 months of follow-up (10). AZA = azathioprine.

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Various Foms of Life in ANCA Vasculitis: It's the Genus not the Species
Posted on December 5, 2005
Susan L. Hogan
University of North Carolina at Chapel Hill
Conflict of Interest: None Declared

Dear Editors,

We are intrigued by, yet disagree with, some of the statements made by Hoffman and Langford in their editorial (1) written in response to our evaluation of predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody (ANCA) "“ associated small vessel vasculitis (2). The primary issues addressed in the editorial included: 1) the clinical value of our results given that the cohort included a spectrum of small-vessel vasculitis patients with Wegener granulomatosis, microscopic polyangiitis and renal limited pauci-immune necrotizing glomerulonephritis rather than a more clinically homogeneous cohort; 2) the usefulness of our requirement for ANCA positivity as the primary classification criterion; and 3) disagreement with our suggestion that the risk of prolonged therapy for the prevention of relapse needs to be carefully weighed against the risk of therapeutic complications on therapy and relapse on or off therapy. This final point is one we anticipated may generate controversy because our study challenges the current rote therapeutics used in this disease.

With respect to inclusion of "˜4 diseases as a single disease', we contend that these are phenotypic variants of a single entity, small- vessel vasculitis. There are discrepancies in categorization of these diseases between the definitions most commonly used: the American College of Rheumatology (3) and the Chapel Hill Consensus Conference (4). In fact, any single study that claims inclusion of only Wegener granulomatosis or microscopic polyangiitis by either of these definitions would lead to overlapping categories with use of the other definition (5), making the notion of a "˜pure' sample with either categorization impossible. Most importantly, despite clinical differences at onset, the standard induction therapy across this disease spectrum remains the same, usually cyclophosphamide and corticosteroids, and treatment response has been consistent across many studies. Analysis of our cohort did not suggest differences in predictors of either response to treatment or relapse between Wegener granulomatosis, microscopic polyangiitis or renal limited disease. This suggests that there are more similarities than differences in these phenotypic variants, and challenges the contention by Hoffman and Langford that there are well delineated disease subgroups within the spectrum of ANCA small vessel vasculitis. In fact, rather than confusing the non-expert by academic haggling over criteria for diagnosis, our study proposes a simple, straight forward assessment of risk of relapse based on objective, reproducible and simple criteria: ANCA antigenic specificity and disease involvement of the lungs or upper respiratory tract.

Requiring ANCA positivity for inclusion into our cohort of patients with small vessel vasculitis is based on clinical practice and the emerging and compelling evidence that ANCA are indeed pathogenic (6, 7). The different symptoms and organ involvement by ANCA positivity among patients with Churg-Strauss syndrome as described by Sable-Fourtassou and colleagues (8) suggests that there may indeed be different pathogenesis and disease progression between those with and without ANCA positivity in this sub-set of patients. There is no evidence of such differences in Wegener granulomatosis or microscopic polyangiitis, where ANCA positivity is far more common than in Churg-Strauss syndrome. Only approximately 10% of patients with pauci-immune small vessel vasculitis are ANCA negative (9). A recent study of ANCA-negative pauci-immune vasculitis showed that these patients have clinical features that are quite comparable to patients with ANCA-positive vasculitis (10), thus the inclusion of this uncommon category in our study probably would have had negligible effect on the conclusions.

Most concerning to us is the suggestion that even without a single clinical trial specifically designed to address the duration of maintenance therapy against a control group, the editorial suggests use of maintenance therapy over the course of at least 1 year beyond unequivocal remission (1). Our cohort evaluation includes the necessary caveats to prevent over-interpretation of our results regarding treatment duration. The editorial compares the treatment results of our studies to two different treatment trials (11,12), but as the authors point out, comparing the results of different trials is "˜risky"¦and may introduce bias.' Therefore, both our study and the authors of the editorial highlight the fact that clinicians have no evidence-based guidance for how long to treat these patients to prevent disease relapse. Even among the various trials by the European Vasculitis Study Group (EUVAS) (11-13), the relapse rates have been vastly different with various treatment approaches and regimens, demonstrating that we do not know which drug is effective and that subtle differences in patient populations may have a great impact on relapse. The stakes for disease relapse as well as for adverse events from treatment are too high to leave these decisions to unsubstantiated notions. Large, collaborative clinical trials designed specifically to address these questions with limited biases must be conducted.

Ironically, the two trials cited in the editorial (11,12) included patients with both Wegener granulomatosis and microscopic polyangiitis, and required patients to be ANCA positive, the very characteristics criticized with regard to our study. Similar sustained remission rates were specifically reported in patients with Wegener granulomatosis compared to those with microscopic polyangiitis (11), further supporting similar treatment responses across the disease spectrum of ANCA small vessel vasculitis. Although the comparison of results between trials is ill advised, the similarity of the disease definition and ANCA positive inclusion criteria suggest a precedent for studying this spectrum of disease.

In summary, ANCA small vessel vasculitis represents a spectrum of disease that is diagnosed, treated and managed similarly and may have a related pathogenesis. Induction therapy is reasonably well understood. The critical question is who needs long term immunomodulating therapy to maintain remission and who can be spared long-term treatment. Decisions by patients and physicians to stop or continue maintenance therapy must be lead by evidence and not by the ominous unknown. Although our cohort study does not answer all of the unknowns, it challenges the concept that long- term maintenance therapy should be considered the standard of care, especially among patients at low risk for relapse.

Susan L. Hogan, PhD, MPH

Ronald J. Falk, MD

Patrick H. Nachman, MD

Division of Nephrology and Hypertension, UNC Kidney Center, University of North Carolina at Chapel Hill, 7024 Burnett-Womack, Campus Box #7155, Chapel Hill, NC 27599-7155

J. Charles Jennette, MD

Department of Pathology, University of North Carolina at Chapel Hill, 303 Brinkhous-Bullitt, Campus Box #7525, Chapel Hill, NC 27599-7525


1. Hoffman GS, Langford CA. Are There Different Forms of Life in the Antineutrophil Cytoplasmic Antibody Universe? Ann Int Med. 2005; 143:683- 85.

2. 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; 145:621-31.

3. Hunder GG, Arend WP, Bloch DA, et al. The American College of Rheumatology 1990 Criteria for the classification of vasculitis. Arthritis Rheum 1990; 33:1065-7.

4. Jennette JC, Falk RJ, Andrassy K, et al. Arthritis Rheum. 1994; 37:187-92.

5. Bruce IN, Bell AL. A comparison of two nomenclature systems for primary systemic vasculitis. Br J Rheumatol. 1997; 36:453-8.

6. Falk RJ, Jennette JC. ANCA are Pathogenic "“ Oh Yes They Are! J Am Soc Nephrol. 2002, 13:1977-79.

7. Heeringa P, Huugen D, Cohen Tervaert JW. Anti-neutrophil cytoplasmic autoantibodies and leukocyte-endothelial interactions: a sticky connection? TRENDS in Immunol. 2005; 26:561-64.

8. Sable-Fourtassou R, Cohen P, Mahr A, Pagnoux C, Mouthon L, Jayne D et al. Antineutrophil cytoplasm antibodies and the Churg-Strauss syndrome. Ann Int Med. 2005; 43:632-8.

9. Savige J, Pollock W, Trevisin M. What do antineutrophil cytoplasmic antibodies (ANCA) tell us? Best Pract Res Clin Rheum. 2005; 19:263-76.

10. Eisenberger U, Fakhouri F, Vanhille P, Beaufils H, Mahr A, Guillevin L, Lesavre P, Noel LH. ANCA-negative pauci-immune renal vasculitis: histology and outcome. Nephrol Dial Transplant 2005;20:1392-9.

11. De Groot K, Rasmussen N, Bacon PA, Tervaert JW, Feighery C, Gregorini G, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005; 52:2461 -9.

12. Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniene J, et al. A raomdomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003; 349:36-44.

13. Tesař V, Řihová Z, Jančová E, Ryšavá R, Merta M; Current treatment strategies in ANCA-positive renal vasculitis-lessons from European randomized trials. European randomized trials.Nephrol Dial Transplant. 2003;18 Suppl 5:v2-4.

Conflict of Interest:

None declared

response to letter by Hogan and colleagues
Posted on January 11, 2006
Gary S. Hoffman
Cleveland Clinic Foundation
Conflict of Interest: None Declared

Hogan and colleagues have restated their belief that the four diseases included in their study under the rubric of "ANCA vasculitis" are "phenotypic variants of a single entity, small vessel vasculitis." This assertion ignores abundant evidence of important differences between these diseases that influence presentation, complications, selection of treatment strategies, and outcomes.

These disease entities have unique clinical differences. Consider, for example, the patient with Wegener's granulomatosis (WG) who presents with chronic ear, nose, throat or tracheal damage, none of which are components of microscopic polyangiitis (MPA) or renal-limited pauci-immune glomerulonephritis and rarely emerge in the context of Churg-Strauss syndrome (CSS). The strategies to treat such complications extend beyond what cytotoxic agent to add to corticosteroid therapy. In WG, one must consider whether chronic otitis media and conductive hearing loss may require placement of tympanotomy tubes, if nasal complications require debridement of crusts or measures to improve moisturization, and whether subglottic or large bronchus stenosis requires surgical interventions. Unlike MPA or renal limited disease, active WG can also present with inflammatory mass lesions, which can appear in any organ and which must be differentiated from a co-morbid malignancy, or an abscess. Asthma and peripheral eosinophilia are infrequently found in WG, MPA, and renal- limited disease but are characteristic manifestations of CSS that can influence clinical decision-making.

Microscopic characteristics of lesions also demonstrate striking histopathologic differences that provide further testimony to the distinct nature of these diseases. While the renal histopathology of WG, MPA, CSS and "renal-limited ANCA disease" are similar, lesions in other organs are quite distinct. Non-specific inflammation and granulomatous lesions are common in WG, and are often present in the absence of vasculitis. However, granulomatous changes are not part of disease pathology in MPA or renal- limited disease. Biopsies in CSS usually show an abundance of eosinophils, which is not characteristic for the other disease entities.

Hogan and colleagues argue that these diseases are also similar and within a common spectrum based on their responses to broad-based immunosuppressive therapy. We find this analytical approach to be no more sound than to argue that rheumatoid arthritis and inflammatory bowel diseases are more similar than different because of improvement when treated in a similar manner.

Hogan and associates also note that the issue of how long to treat patients with WG, MPA or CSS is unsettled. We agree that large clinical trials will be required to best determine duration of treatment following induction of remission for each disease and perhaps even for subsets within each disease. However, until such studies have been performed, the data that we had cited by DeGroot (1) and Jayne (2) and the European Vasculitis Study Group that were the result of trials conducted in a prospective standardized manner, support the notion that relapses can be diminished with more prolonged therapy and that such therapy need not include cyclophosphamide. In addition, increased rates of relapse have been noted by others concordant with withdrawal of maintenance therapies (3-4).

We believe it is not wise to assume that these diseases are phenotypic variants of ANCA- associated small vessel vasculitis. Despite important and insightful investigations of these antibodies that have come from in vitro studies and murine models, we lack definitive evidence to prove that ANCA is crucial to disease pathogenesis in humans. The absence of ANCA in a significant number of patients with WG and CSS supports the notion of a non-essential role. However, it does not rule out the possibility that ANCA, when present, may influence disease expression in certain organs. Vasculitis is not a constant feature of lesions in WG or CSS. To think of these disease entities as merely expressions of small vessel vasculitis is an over-simplification that does not serve to inform discussions of pathogenesis. We conclude that differences in disease presentation, organ involvement and complications that require unique treatment strategies make this debate clinically relevant and not one that should be dismissed as being merely a matter of "academic haggling".

1. De Groot K, Rasmussen N, Bacon PA, Tervaert JW, Feighery C, Gregorini G, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005;52:2461- 9. [PMID: 16052573]

2. Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniené J, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003;349:36-44. [PMID: 12840090]

3. Sanders J-S F, Slot MC, Stegeman CA. Maintenance therapy for vasculitis associated with antineutrophil cytoplasmic antibodies. N Engl J Med. 2003; 349: 2072-3.

4. Hoffman GS, Kerr GS, Leavitt RY et al. Wegener's granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992; 116: 488-98.

Gary S. Hoffman MD, MS Carol A. Langford MD, MHS Center for Vasculitis Care and Research Cleveland Clinic Foundation

Conflict of Interest:

None declared

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