Antineutrophil cytoplasmic antibody positivity in IgG4-related disease

Abstract

Background:IgG4-related disease (IgG4-RD) is a fibroinflammatory condition characterized by serum IgG4 elevation and tissue infiltration of IgG4-positive plasma cells. Substantial overlap between IgG4-RD and antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) exists in terms of organ involvement and histopathological features. A positive ANCA assay is regarded as a highly specific finding in favor of an AAV, and generally influences away from a diagnosis of IgG4-RD. Recent reports, however, have raised the possibility that some patients with IgG4-RD are ANCA positive, thus suggesting reconsideration of the role of ANCA in the diagnostic workup. In the present work, we describe the first case of concomitant biopsy-proven IgG4-RD and granulomatosis with polyangiitis (GPA), demonstrating antiproteinase 3 (PR3) ANCA of the IgG4 subclass in the patient's serum. We also review the literature in order to provide clinicians with tools for interpreting ANCA positivity in IgG4-RD patients.Case summary:A 51-year-old woman was referred for left exopthalmos due to lacrimal gland enlargement and increased serum IgG4 concentration. IgG4-RD was suspected and further imaging studies disclosed multiple pulmonary masses in the right lung. Histological analysis of the left lacrimal gland was diagnostic for IgG4-RD, but lung biopsy showed typical features of GPA. ANCA assay was positive for anti-PR3 antibodies. Further immunofluorescence studies demonstrated anti-PR3 antibodies of IgG1 and IgG4 subclass. Treatment with rituximab induced swift remission of both IgG4-RD and GPA manifestations. We identified 9 other reports of patients with IgG4-RD and positive ANCA in the English literature, 5 cases with biopsy-proven IgG4-RD and 4 cases in whom IgG4-RD was diagnosed presumptively. Four patients had also histological evidence of concomitant AAV.Conclusion:The present work demonstrates that ANCA positivity in patients with biopsy-proven IgG4-RD should prompt the exclusion of a concomitant vasculitic process; a positive ANCA does not exclude the diagnosis of IgG4-RD; confirmation through immunoenzymatic assays of the ANCA specificity, clinical-pathological correlation, and histopathological evaluation remain crucial steps for the differential diagnosis between AAV and IgG4-RD.

A case of proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA) positive/IgG4-related lung disease

“…Della-Torre et al. reported a case of PR3-ANCA-seropositive IgG4-RLD and GPA [11]. However, our case had no findings of GPA.…”

Neurological Manifestations of IgG4-Related Disease

“…Of these, it is worth considering ANCA-associated vasculitis (particularly GPA) as it shares many of the multisystem features of IgG4-RD, including pachymeningitis and hypophysitis [49, 105, 106]. Furthermore, increased serum levels of IgG4 and infiltrating IgG4 + plasma have also been described in GPA [15, 107–109].…”

“…Serologically, both may be associated with high serum levels of IgG4, but GPA is usually ANCA-positive with antigen specificity for proteinase 3 (less often for myeloperoxidase), and ANCA is typically negative in IgG4-RD. Indeed, although ANCA positivity does not exclude the diagnosis of IgG4-RD, it should prompt the exclusion of a concomitant vasculitic process [105]. Histologically, GPA is usually associated with foci of necrosis, granulomatous inflammation and giant cells, and neutrophils invariably constitute a prominent part of the infiltrate, features not seen in IgG4-RD [110].…”

Update on systemic vasculitides

“…Serum IgG4 levels and immunostaining of biopsies for IgG4-positive plasma cells are important if IgG4-RD is considered a possible differential diagnosis. However, increased IgG4-plasma cells can be seen in GPA, and reports of ANCA positivity exist in IgG4-RD 27 28. IgG4 levels are not a useful test for monitoring in AAV, although are used in follow-up of IgG4-RD.…”