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

IgG4-related lung disease (IgG4-RLD) is a rare and chronic progressive autoimmune disease. We report a case of IgG4-related inflammatory pseudo-tumor of the lung that was seropositive for proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA). A 61-year-old male had a mass lesion in the right lower lung field in chest X-ray. Transbronchial lung biopsy resulted in a pathological diagnosis of IgG4-RLD. The condition was improved by hormonal therapy.

Introduction

IgG4-related disease (IgG4-RD) has been of interest since 2001, when Hamano reported infiltration of IgG4-positive plasma cells in the pancreas [1]. IgG4-related lung disease (IgG4-RLD) has been described as interstitial pneumonia and inflammatory pseudo-tumor [2], [3], [4], [5], [6], [7]. Proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA) is well known as a disease marker in Wegener's granulomatosis [8]. Here, we report a case of PR3-ANCA-positive IgG4-RLD with a 10-cm tumor lesion.

Case report

A 61-year-old man consulted a local general practitioner in August 2015 with a complaint of cough for a month. He was referred to our hospital because of a 10-cm diameter mass in the right lower lung field in chest X-ray. On admission, a physical examination revealed a temperature of 37.7 °C, and laboratory data showed a white blood cell count of 11,900/μL and serum C-reactive protein (CRP) of 12.3 mg/dL. Chest computed tomography (CT) showed right pleural effusion and a 10-cm diameter mass in the right lower lobe and swelling of mediastinal lymph nodes (Fig. 1A and B).

Fig. 1

(A, B) Plain chest CT on admission showed right pleural effusion and a 10-cm diameter mass in the right lower lobe. (C, D) Plain chest CT after hormonal treatment showed development of pleural effusion and pseudo-tumor.

Flexible bronchial bronchoscopy and transbronchial lung biopsy were performed. The pathological findings from the biopsy showed inflammatory granuloma with infiltration of lymphocytes and plasma cells (Fig. 2A). Immunostaining showed >20 IgG4-positive plasma cells/high-power field (HPF) (Fig. 2B). Serum levels of IgG and IgG4 were elevated to 2,211 and 258 mg/dL, respectively. PR3-ANCA was 246 U/mL (normal range: <3.5 U/mL) with normal range of anti-nuclear antibodies.

Fig. 2

(A) Pathological findings of inflammatory granuloma with infiltration of lymphocytes and plasma cells (red arrow) in trans-bronchial lung biopsy of the pseudo-tumor lesion. (B) Immunohistological images, the deep cells-lgG4-positive plasma cells (>20/HPF) (×400). HPF, high power field.

Diagnosis of IgG4-RLD was made based on the high level of IgG4 and chest CT findings. The patient was started on 30 mg/day of prednisolone for two weeks, and then the dose was tapered to 20 mg/day. Over the following weeks, the patient began to report fewer symptoms. At one month after admission, there was marked reduction of pseudo-tumor and right pleural effusion (Fig. 1C and D) on chest CT, and the patient was discharged. After three months of treatment, IgG4 and PR3-ANCA decreased to 122 mg/dL and 61.6 U/mL, respectively.

Discussion

There are two unique aspects in the present case: infiltrated plasma cells in pseudo-tumor with high serum IgG4; and elevated PR3-ANCA at admission. IgG4-RLD occurs in 12–50% of patients with IgG4-RD [3], [4], [5]. Mediastinal adenopathy is most common and pulmonary involvement takes the form of pulmonary nodules or masses [3], [6], [7], [8]. As shown in Fig. 1A and B, our case presented with mass formation in the right lower lung with mediastinal adenopathy. Pathologically, the lesion consisted of a diffuse lymphoplasmacytic infiltrate with pseudo-tumor (Fig. 2A). In histochemical staining, the case met diagnostic criteria for IgG4-RD published by Umehara et al. [9].

Histologically, granulomatosis with polyangiitis (GPA) can mimic IgG4-RD since the inflammatory background in GPA may be rich in plasma cells and accompanied by fibrosis or obliterated blood vessels, as in IgG4-RD [10]. Della-Torre et al. reported a case of PR3-ANCA-seropositive IgG4-RLD and GPA [11]. However, our case had no findings of GPA. PR3-ANCA is a disease marker autoantibody found in GPA [8] and the clinical manifestations of IgG4-RD and ANCA-associated vasculitis may overlap [12]. Previous case reports have described PR3-ANCA/IgG4-positive fibrotic diseases in the retroperitoneum [13], and cranium [14], without features of GPA. This is the reported case to present with PR3-ANCA/IgG4-positive fibrotic disease in the lung without any manifestation of GPA. Regarding the relationship between IgG4 and PR3-ANCA, several analyses have shown the importance of the IgG4 subclass of PR3-ANCA, which induces inflammation in patients with GPA [8], [15], [16]. IgG4 anti-proteinase 3 antibodies stimulate neutrophils to undergo a pro-inflammatory response and may play a role in the pathogenesis of small vessel vasculitis [8], [17], [18].

The predominance of IgG4 and IgG1 subclasses of ANCA was first reported in patients with GPA and other clinically related disorders by Brouwer et al., in 1991 [17]. Holland et al. later suggested a possible pathogenic role for the IgG4 subclass in GPA [8]. In vitro, ANCA activates neutrophils by co-ligating PR3 and FcγRIIa/IIIb receptors [8]. ANCA are predominantly of the IgG isotype, and the IgG1, IgG3, and IgG4 subclasses are particularly represented. The IgG4 subclass isolated from ANCA-positive sera has varying abilities to stimulate release of superoxide, unrelated to the PR3-ANCA titer, neutrophil donors in vitro, or neutrophil FcγRI expression [8]. Liu et al. suggested that the MPO-ANCA IgG4 subclass might play a role in development of GPA [18], based on titers of the anti-MPO IgG4 subclass in patients with GPA being significantly higher than those with microscopic polyangiitis (MPA). MPO-ANCA in GPA and MPA might recognize overlapping but different epitopes on native MPO molecules. The difference in immunological characteristics of MPO-ANCA might contribute to different disease entities, such as GPA and MPA, and spontaneous regression of both pulmonary and extrapulmonary lesions in IgG4-related lung diseases occurs in GPA, although most patients receive treatment [19], [20], [21].

In our case, the disease condition was improved following hormonal therapy. This is the rare reported case of IgG4-RLD with elevated PR3-ANCA. The mechanism of pseudo-tumor formation in this case may be associated with the IgG4 subclass of PR3-ANCA that induces inflammation in patients with Wegener's granulomatosis. Further accumulation of similar cases is required to understand this mechanism.

Conclusion

This is the rare report of seropositive PR3-ANCA followed with IgG4- RLD. This case indicated that IgG4 subclass of PR3-ANCA might contribute to be different findings of MPA.

Conflict of interest

The authors have no conflict of interest.