Predictors of Relapse and Treatment Resistance in Antineutrophil Cytoplasmic Antibody–Associated Small-Vessel Vasculitis
Publication: Annals of Internal Medicine
Volume 143, Number 9
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Abstract
Background:
Predictors of treatment resistance and relapse have not been well described in antineutrophil cytoplasmic antibody (ANCA)–associated small-vessel vasculitis.
Objective:
To identify clinical, pathologic, and serologic predictors of treatment resistance and relapse in a community-based cohort of patients with ANCA-associated vasculitis.
Design:
Cohort of patients identified at or near the time of biopsy diagnosis and followed as clinically indicated.
Setting:
The Glomerular Disease Collaborative Network.
Patients:
350 patients who received a new diagnosis of ANCA-associated vasculitis between 1985 and 2003 and were followed for a median of 49 months.
Measurements:
Patients were categorized according to whether they had antiproteinase-3 (anti-PR3) antibodies or antimyeloperoxidase (anti-MPO) antibodies. Organ involvement was determined by biopsy or by well-defined clinical criteria. Treatment resistance was defined as progressive decline in kidney function with active urine sediment or the persistence or appearance of extrarenal manifestations. Relapse was defined as the time to the resurgence of vasculitic symptoms.
Results:
Treatment resistance affected 23% of 334 treated patients and was associated with female sex, black ethnicity, and presentation with severe kidney disease (odds ratio per serum creatinine elevation of 100 µmol/L [1.13 mg/dL], 1.28 [95% CI, 1.16 to 1.39]). The following factors were associated with relapse in 258 (77%) patients who attained remission: seropositivity for anti-PR3 antibodies (hazard ratio, 1.87 [CI, 1.11 to 3.14]) and disease of the lung (hazard ratio, 1.71 [CI, 1.04 to 2.81]) or upper respiratory tract (hazard ratio, 1.73 [CI, 1.04 to 2.88]). Relapses occurred in 26% of patients with no risk factors versus 73% of patients with all 3 risk factors (hazard ratio, 3.7 [CI, 1.4 to 9.7]). Among 143 patients attaining remission who subsequently stopped all immunosuppressant therapy, relapse rates were similar for those who had received cyclophosphamide therapy for 6 months or less (34%) compared with those treated for a longer duration (35%), even after adjusting for risk factors for relapse (hazard ratio, 1.41 [CI, 0.80 to 2.50]).
Limitations:
The cohort mostly included patients with biopsy-proven kidney disease. Patients were not followed with uniform treatment protocols, and only limited information about their clinical course before diagnosis was available.
Conclusions:
Female or black patients, or those with severe kidney disease, may be resistant to initial treatment more often than other patients with ANCA-associated small-vessel vasculitis. Increased risk for relapse appears to be related to the presence of lung or upper airway disease and anti-PR3 antibody seropositivity.
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Published In
Annals of Internal Medicine
Volume 143 • Number 9 • 1 November 2005
Pages: 621 - 631
History
Published online: 1 November 2005
Published in issue: 1 November 2005
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© 2005 American College of Physicians.
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Predictors of Relapse and Treatment Resistance in Antineutrophil Cytoplasmic Antibody–Associated Small-Vessel Vasculitis. Ann Intern Med.2005;143:621-631. [Epub 1 November 2005]. doi:10.7326/0003-4819-143-9-200511010-00005
Predictors of Relapse and Treatment Resistance in Antineutrophil Cytoplasmic Antibody–Associated Small-Vessel Vasculitis. Ann Intern Med.2005;143:621-631. [Epub 1 November 2005]. doi:10.7326/0003-4819-143-9-200511010-00005
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TNF-alpha blocking agents in the treatment of ANCA-Associated Small-Vesse Vasculitis
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
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
ANCA-PR3, or ANCA-MPO
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