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Prevalence of Antineutrophil Cytoplasmic Antibodies in a Large Inception Cohort of Patients with Connective Tissue Disease

Peter A. Merkel, MD, MPH; Richard P. Polisson, MD, MHS; YuChiao Chang, PhD; Steven J. Skates, PhD; and John L. Niles, MD
[+] Article and Author Information

From Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Acknowledgments: The authors thank Ms. Beatrice Mendez, Ms. Charyl Urbano, Dr. GouLi Pan, Dr. Guillermo Saurina, and Ms. Karen Convery for their technical efforts and Dr. John Mills for his thoughtful review of an earlier version of this manuscript. Requests for Reprints: Peter A. Merkel, MD, MPH, Arthritis Unit, Bulfinch 165, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. Current Author Addresses: Drs. Merkel and Polisson: Arthritis Unit, Bulfinch 165, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1997;126(11):866-873. doi:10.7326/0003-4819-126-11-199706010-00003
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Background: Two types of antineutrophil cytoplasmic antibodies (ANCA), antiproteinase 3 antibodies (anti-PR3) and antimyeloperoxidase antibodies (anti-MPO), are useful in the diagnosis of such types of vasculitis as Wegener granulomatosis and microscopic polyangiitis. Connective tissue diseases frequently appear in the differential diagnosis of this spectrum of vasculitis.

Objective: To determine the prevalence of ANCA in patients with connective tissue disease.

Design: Blinded, controlled study of a 5-year inception cohort.

Setting: Tertiary-care university teaching hospitals.

Patients: 70 patients with rheumatoid arthritis, 70 patients with systemic lupus erythematosus, 45 patients with scleroderma, 36 patients with inflammatory myositis, 44 patients with the Sjogren syndrome, 33 patients with the antiphospholipid syndrome, and 165 patients with early undifferentiated connective tissue disease (EUCTD). Serum was taken from 200 blood donors and 52 patients who had known vasculitis and positive results on tests for anti-PR3 or anti-MPO; these patients served as controls.

Measurements: The presence of anti-PR3 and anti-MPO was determined by combining the results of indirect immunofluorescence tests for cytoplasmic (C-ANCA) and perinuclear (P-ANCA) patterns with the results of enzyme-linked immunosorbent assays (ELISAs) directed to measure antigen.

Results: Cytoplasmic ANCA was not detected in any study or control patient. Perinuclear ANCA was commonly detected among patients with lupus (31%) but was uncommon among patients in other groups (0% to 5%). In all cases, P-ANCA was associated with the presence of antinuclear antibodies. Atypical ANCA immunofluorescence patterns were fairly common in all groups (11% to 39%).

Antiproteinase 3 was detected by ELISA in 9 study patients (1 patient with rheumatoid arthritis, 1 with lupus, 1 with polymyositis, and 6 with EUCTD).Antimyeloperoxidase was detected by ELISA in 2 study patients (1 with rheumatoid arthritis and 1 with lupus). None of the patients with positive ELISA results had evidence of renal vasculitis during follow-up. When an ANCA scoring system that combines immunofluorescence and ELISA was used, the test specificity for vasculitis was 99.5% among patients with connective tissue disease.

Conclusions: Patients with connective tissue disease are known to develop multiple autoantibodies; positivity for anti-PR3 and anti-MPO ANCA in such patients is rare. Cytoplasmic ANCA immunofluorescence is highly specific for anti-PR3. However, P-ANCA immunofluorescence, which may have positive results because of the presence of antinuclear antibodies, is not a specific marker of anti-MPO. A rigorous ANCA testing system that combines the results of immunofluorescence with those of ELISA is highly specific for Wegener granulomatosis and related vasculitides even in patients with connective tissue disease.

Figures

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Figure 1.
Testing algorithm used for the final determination of the presence of antiproteinase 3 antibodies (anti-PR3).

⊕ = positive final interpretation; ⊖ = negative final interpretation; ELISA = enzymelinked immunosorbent assay; P-ANCA = perinuclear pattern of staining for antineutrophil cytoplasmic antibodies.

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Figure 2.
Results of direct enzyme-linked immunosorbent assay (ELISA) for antiproteinase 3 antibodies (anti-PR3) in the serum of patients with connective tissue disease.

The sample size (n) for each study group is given. A logarithmic scale is used for the ELISA results; the dotted line represents the positivity cutoff for the direct anti-PR3 ELISA (5.0 U). All measurements on or above the dotted line are considered to indicate positivity for anti-PR3. APS = the antiphospholipid syndrome; BD = blood-donor controls; EUCTD = early undifferentiated connective tissue disease; MPO+ = controls with vasculitis positive for antimyeloperoxidase antibodies; PM/DM = inflammatory myositis; PR3+ = controls with vasculitis positive for anti-PR3; PS = scleroderma; RA = rheumatoid arthritis; SJ = the Sjogren syndrome; SLE = systemic lupus erythematosus.

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Figure 3.
Results of sandwich enzyme-linked immunosorbent assay (ELISA) for antiproteinase 3 antibodies (anti-PR3) in the serum of patients with connective tissue disease.

The sample size (n) for each study group is given. A logarithmic scale is used for the ELISA results; the dotted line represents the positivity cutoff for the sandwich anti-PR3 ELISA (20.0 U). All measurements on or above the dotted line are considered to indicate positivity for anti-PR3. APS = the antiphospholipid syndrome; BD = blood-donor controls; EUCTD = early undifferentiated connective tissue disease; MPO+ = controls with vasculitis positive for antimyeloperoxidase antibodies; PM/DM = inflammatory myositis; PR3+ = controls with vasculitis positive for anti-PR3; PS = scleroderma; RA = rheumatoid arthritis; SJ = the Sjogren syndrome; SLE = systemic lupus erythematosus.

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Figure 4.
Results of direct enzyme-linked immunosorbent assay (ELISA) for antimyeloperoxidase antibodies (anti-MPO) in the serum of patients with connective tissue disease.

The sample size (n) for each study group is given. A logarithmic scale is used for the ELISA results; the dotted line represents the positivity cutoff for the direct anti-MPO ELISA (2.8 U). All measurements on or above the dotted line are considered to indicate positivity for anti-MPO. APS = the antiphospholipid syndrome; BD = blood-donor controls; EUCTD = early undifferentiated connective tissue disease; MPO+ = controls with vasculitis positive for anti-MPO; PM/DM = inflammatory myositis; PR3+ = controls with vasculitis positive for antiproteinase 3 antibodies; PS = scleroderma; RA = rheumatoid arthritis; SJ = the Sjogren syndrome; SLE = systemic lupus erythematosus.

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