Journal
CLINICAL AND EXPERIMENTAL IMMUNOLOGY
Volume 188, Issue 1, Pages 174-181Publisher
WILEY
DOI: 10.1111/cei.12925
Keywords
alveolar haemorrhage; ANCA-associated vasculitis; anti-neutrophil cytoplasmic antibodies; granulomatosis with polyangiitis; immunoglobulin M; microscopic polyangiitis
Categories
Funding
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIH N01-AR92240]
- Office of Orphan Products, Food and drug Administration (FDA) [FD-R-001652]
- National Institute of Allergy and Infectious Diseases [N01-AI-15416, ITN021AI]
- Genentech, Inc.
- Biogen IDEC, Inc.
- National Center for Research Resources (NCRR) at Johns Hopkins University [RR024150]
- NCRR [RR025005]
- Boston University [RR 025771]
- National Institutes of Health [M01 RR00533, K24 AR02224]
- Arthritis Foundation Investigator Award
- Mayo Foundation
- [K24 AR049185]
- [K23 AR052820]
- [261382]
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Anti-neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme-linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)-ANCA], which we applied to two large, clinically well-characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3-ANCA occurred with a frequency of 150%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (296 versus 157%, P=010). Analysis of follow-up samples in this cohort showed that the presence of IgM PR3-ANCA was transient, but could recur. In the second cohort, IgM PR3-ANCA occurred with a frequency of 411%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3-ANCA (453 versus 158%; P<0001). The association of transient IgM PR3-ANCA with an acute respiratory manifestation of AAV suggests a possible link between an infectious trigger and AAV disease activity.
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